Peptide KED: Molecular-Genetic Aspects of Neurogenesis Regulation in Alzheimer's Disease.

Neuroprotective peptides are promising candidate molecules for the treatment of Alzheimer's disease (AD). Oral application of KED (Lys-Glu-Asp) improved memory and attention in elderly individuals with functional CNS disorders. Peptide KED also restores synaptic plasticity in in vitro model of AD. This review is focused on the analysis of the influence of KED peptide on the expression of genes and synthesis of proteins regulating apoptosis, aging, neurogenesis, and involved in AD pathogenesis. Analysis of published reports and our experimental findings suggests that KED regulates the expression of genes of cell aging and apoptosis (р16, р21), genes (NES, GAP43) and proteins (nestin, GAP43) of the neuronal differentiation, and genes involved in AD pathogenesis (SUMO, APOE, and IGF1). The study the effectiveness of neuroprotective peptide KED in animal models of AD seems to be very important.

Results and Prospects of Using Activator of Hematopoietic Stem Cell Differentiation in Complex Therapy for Patients with COVID-19.

The paper presents the results of a standard and complex treatment method using the peptide drug thymus thymalin in patients with COVID-19. One of the mechanisms of the immunomodulatory effect of thymalin is considered to be the ability of this peptide drug to influence the differentiation of human hematopoietic stem cells (HSCs). It was found that, as a result of standard treatment, patients in the control group showed a decrease in the concentration of the pro-inflammatory cytokine IL-6, C-reactive protein, D-dimer. The addition of thymalin to standard therapy accelerated the decline in both these indicators and the indicators of the T cell system. This has helped reduce the risk of blood clots in COVID-19 patients. The revealed properties of the thymus peptide preparation are the rationale for its inclusion in the complex treatment of coronavirus infection. Peptideswith potential biological activity against SARS-CoV-2 virus [29]. Note: Nitrogen atoms are shown in blue, oxygen atoms - in red, carbon atoms - in gray, hydrogen atoms - in white, and phosphorus atoms - in yellow.

Thymalin: Activation of Differentiation of Human Hematopoietic Stem Cells.

Thymalin is a polypeptide complex isolated from the thymus and regulating the functions of the immune system. Thymalin is effective in therapy of acute respiratory syndrome, chronic obstructive bronchitis, and other immunopathology. Thymalin increases functional activity of T lymphocytes, but the targeted molecular mechanism of its biological activity requires further study. We studied the influence of thymalin on differentiation of human hematopoietic stem cells (HSC) and expression of CD28 molecule involved in the implementation of antiviral immunity in COVID-19 infection. It was found that thymalin reduced the expression of CD44 (stem cell marker) and CD117 (molecule of the intermediate stage of HSC differentiation) by 2-3 times and increased the expression of CD28 (marker of mature T lymphocytes) by 6.8 times. This indirectly indicates that thymalin stimulated differentiation of CD117+ cells into mature CD28+T lymphocytes. It is known that in patients with severe COVID-19, the number of CD28+, CD4+, CD8+T lymphocytes in the blood decreased, which attested to a pronounced suppression of immunity. It is possible that the antiviral effect of thymalin consists in compensatory stimulation of HSC differentiation into CD28+T lymphocytes at the stage of immunity suppression in unfavorable course of viral infection. Thymalin can be considered as an immunoprotective peptide drug for the prevention of COVID-19.

Comparison of the Effects of KE and AED Peptides on Functional Activity of Human Skin Fibroblasts during Their Replicative Aging.

We studied the effect of KE and AED peptides on the expression of sirtuin-1, sirtuin-6, collagen I, cytokines (IL-1, TGF-ß), and transcription factor NF-κB in human skin fibroblasts during their replicative aging. Immunocytochemical analysis and confocal microscopy showed that KE peptide reduces the synthesis of factors of the inflammatory response IL-1, NF-κB, and TGF-ß and stimulates the synthesis of sirtuin-6. KE peptide normalizes the immunological function of human skin fibroblasts during their aging. AED peptide activates the synthesis of sirtuin-1, sirtuin-6, and collagen I in human skin fibroblasts during their replicative aging, which attests to its geroprotective effect.

Peptide KE in Human Proteome.

Peptide KE exhibits immunoprotective, geroprotective, and oncostatic activities and stimulates functional activity of fibroblasts. The KE motif is present in amino acid sequences of some cytokines and peptide hormones functionally similar to KE peptide. However, the relationship between the presence of KE motif and protein functions on the scale of known human proteome has not yet received sufficient attention. The incidence of bioregulatory peptide KE in proteins of various functional groups constituting human proteome is studied. The study is carried out with the use of the available data on the human proteome (UniProt portal) comprising 20,417 proteins. The levels of KE motifs were maximum in cytoplasmic and nuclear proteins, while the presence of KE in the membrane and all other proteins was the minimum. KE peptide molecules released from nuclear proteins during limited proteolysis can bind to DNA and regulate gene expression.

Effect of Peptide AEDG on Telomere Length and Mitotic Index of PHA-Stimulated Human Blood Lymphocytes.

We studied the effect of peptide AEDG on telomere length and mitotic index of PHA-stimulated blood lymphocytes from young (18-22 years, N=5) and middle-aged (49-54 years, N=6) men. In the younger age group, no significant changes in the mitotic index were detected, while in the middle-aged group, a decrease in this parameter was found in one case. The relative length of telomeric regions of metaphase chromosomes was evaluated by in situ fluorescence hybridization with DNA probes specific to telomeres. After incubation with peptide AEDG, significant changes in the relative telomere length were found in 7 of 11 individuals (3 cases in the younger age group and 4 cases in the middle age group). Significant increase in telomere length after exposure to peptide AEDG was revealed in 5 cases, including two individuals of the younger age group (by 41 and 55%) and three individuals of the middle age group (by 156, 18, and 76%). In one individual of the younger age group and in one of the middle-age group, a significant decrease in telomere length (by 37 and 15%, respectively) was found. A tendency to normalization of telomere lengths was noted: this parameter increased in individuals with initially lower telomere length relative to the group mean value and decreased in individuals with initially longer telomeres compared to the mean length in the group.

[Epigenetic Mechanisms of Peptide-Driven Regulation and Neuroprotective Protein FKBP1b].

Cortexin is a clinically approved cerebral cortex polypeptide complex in calves. The mechanism of cortexin action is not understood well. Two cortexin derivatives, short peptides EDR and DS with neuroprotective activity, were synthesized. According to the data of molecular modeling, these peptides are able to bind to the histone H1.3 protein. This can affect the conformation of histone H1.3, which leads to a change in the chromatin structure in the loci of some genes, in particular Fkbp1b encoding the FK506-binding protein. Electrophysiological processes associated with the Ca^(2+) exchange are disturbed in the pyramidal neurons of the hippocampus during aging of the brain. The Fkbp1b gene encodes peptidyl-prolyl cis-trans isomerase, regulating the release of calcium ions from the sarcoplasmic and endoplasmic reticulum of neurons. The activation of the Fkbp1b gene transcription under treatment with short peptides can promote the synthesis of its protein product and the activation of the Ca^(2+) release from organelles of the sarcoplasmic and endoplasmic reticulum of neurons, which, in turn, can lead to an increase in the functional activity of neurons.

Identification of Peptide AEDG in the Polypeptide Complex of the Pineal Gland.

The polypeptide complex of the epiphysis and the peptide AEDG, constructed on the basis of its amino acid analysis, exert similar biological effects. Both bioregulators normalize melatonin synthesis in the pineal gland, functioning of the brain, eye retina, cardiovascular, endocrine, and immune systems; they also act as antioxidants, stress-protectors, and geroprotectors. Within the epiphysis polypeptide complex, free amino acids (3.26%), dipeptides (23.19%), tripeptides (50.72%), tetrapeptides (22.10%), and pentapeptides (0.72%) were revealed by mass spectrometry and HPLC. Peptide AEDG was detected among the tetrapeptides of the epiphysis polypeptide complex by selective reaction monitoring method. The biological effects of the epiphysis polypeptide complex are determined by the effect of its component AEDG.

[A new stage of development of gerontology and geriatrics in Russia: Problems o creation of a geriatric care system. Part 2. The structure of the system, scientific approach].

The publication is the second part of the analytical review on the new stage of development of gerontology and geriatrics in Russia. Components of social support system for senior citizens and the structure of social-medical care as its crucial components are presented. The problem of positioning of geriatric care within the system of social support for senior citizens, as well as its peculiarities and the algorithm providing geriatric care are discussed. The analysis of this algorithm allowed us to justify the indissoluble link and continuity of individual components of geriatric care and its cost-effectiveness. The position of the Russian Federation Ministry of Health concerning of introduction of geriatric care as an element in the system of medical care for older citizens was looking through. The pilot project «Territory of Care¼ proposed by the Russian Federation Ministry of Labor and Ministry of Health for establishment of long-term system of medical and social care to citizens of the older generation on the principles of multidisciplinary and interdepartmental interaction was elucidated as well. Some failures of the project have been highlighted and recommendations for its development were stressed. The role of gerontology as a systemic basis for creation of geriatric service in Russia and for the development of an integrated social and medical care to citizens of the older generation was underlined. The main priorities in the field of aging in the forthcoming decade are formulated. The most promising areas of research in the field of gerontology were discussed, the implementation of which will allow to realize the State social policy goals focused on the quality of life of senior citizens. Finally, the position of Gerontological Society of the Russian Academy of Sciences on the creation of mechanisms of scientific support for the renovation of geriatric services, including collaboration with experts in the field of practical medicine, social workers, and organization of scientific coordination of all efforts for the development of geriatric care to citizens of the older generation are presented.

[Effects of vascular peptide bioregulator on cerebral microcirculation of old hypertensive rats].

Using a TV device to study brain microcirculation, we found that after a course of vascular peptide bioregulator the density of microvascular network of pia matter of old hypertensive rats (12 months) sensomotor cortex increased about 1,7 times compared to intact old rates SHR. This perfusion in the tissue of the cerebral cortex and the degree of blood oxygen saturation in the microvasculature of this tissue region raised.

Correction to: Tripeptides Restore the Number of Neuronal Spines under Conditions of In Vitro Modeled Alzheimer's Disease.

On the page 553 Acknowledgements should be as follows: The study was supported by the Russian Science Foundation (grant 14-25-00024-P).

Peptides (Epigenetic Regulators) in the Structure of Rodents with a Long and Short Lifespan.

We have discovered motives of short-chain epigenetically active peptides in some proteins of long-lived African mole rat Heterocephalus glaber. These epigenetic regulators are located in the protein structure between lysine and arginine residues, thus facilitating their release in limited proteolysis. Some of these epigenetic regulators are not found in the proteins of short-lived species - Norway rat Rattus norvegicus and house mouse Mus musculus.

Tripeptides Restore the Number of Neuronal Spines under Conditions of In Vitro Modeled Alzheimer's Disease.

In primary culture of mouse hippocampal neurons, peptide EDR (200 ng/ml) under conditions of amyloid synaptotoxicity (a model of Alzheimer's disease) increased the number of mushroom spines by 71% and returned this parameter to the normal level. Under the same conditions, tripeptide KED (200 ng/ml) increased the number of mushroom spines in hippocampal neurons by 20%. Tripeptide EDR can be recommended for further experimental study as a candidate neuroprotective agent for prevention and treatment of Alzheimer's disease.

[Pineamin increased pineal melatonin synthesis in elderly people].

It was investigated the influence of polypeptide complex Pineamin on the 6-sulfatoxymelatonin (aMT6S) excretion in urine by ELISA test of 55 elderly patients with diminished melatoninsynthesis pineal gland function. Pineamin in course dose 100 mg has increased night level of aMT6S urine excretion in 1,9 times in comparison with relevant value untreated. Similar effect was obtained early for medical drug Epithalamin. Epithalamin also restored melatonin level in human and animals during aging. Thus, Pineamin and Epithalamin have similar stimulate effect on melatonin synthesis in elderly people pineal gland.

Nephroprotective Effect of EDL Peptide at Acute Injury of Kidneys of Different Genesis.

EDL peptide produced a nephroprotective effect on experimental models gentamycin-induced nephropathy and ischemia/reperfusion kidney injury in rats. The nephroprotective effect of EDL peptide manifested in prevention of oliguria and retention azotemia, a decrease in proteinuria and sodium excretion, prevention of critical decrease in activities of antioxidant enzymes, suppression of LPO, and normalization of energy supply to kidneys cells. Our findings confirm the prospects of further studies of the nephroprotective properties of peptide EDL in various pathologies of the kidneys.

[A new stage of development of gerontology and geriatrics in Russia: problems of creation of a geriatric care system. Part 1. Relevance, regulatory infrastructure].

This article is a 1st part of the analytical review, focused on a new step in development of geriatrics in Russia. Creation of state system geriatric care as important part of state politics in the area of enhancement of quality of life was proved. General aspects of improvement of social support of disable elderly persons in condition of restricted budget and interagency separation was presented. Establishment of unified system of medical social support and gerotechnologies for the elderly was substantiated, as a mechanism facilitated life activity and decreasing of demographic loading on economic status of regions of Russian Federation. Legislative and normative regulations of gerontology and geriatric development were observed as well. Accepted legislative and normative acts were analyzed for period since 1977 to 2014. The necessity of approaches to regulation modernization for elderly was demonstrated. Analytical review on number of legislative state documents issued after meeting of Presidium of State Council of the Russian Federation being in August 2014 was also presented. Applicability of these documents for realization new strategy of gerontology and geriatrics development in Russia was proved.

[Transcription factor p53 and skin aging].

The review is devoted to an actual problem of cosmetics in gerontology, one of molecular aspects of skin aging. Cell renewal processes slow down with aging, and the proliferation apoptosis ratio shifts towards cell death. One of the most pivotal apoptotic markers is the transcription factor p53. p53 protein expression in the skin keratinocytes increases under the influence of ultraviolet radiation. Wherein when exposed to ultraviolet radiation mutant forms of p53 have been revealed in 70 % of keratinocytes. On the one hand, suppression of p53 expression decreases apoptosis in skin cells that slows down the process of aging. On the other hand, it promotes the development of tumors in the skin. Thus, maintaining the physiological balance of p53 expression in skin cells is important for the basic and practical cosmetic medicine in gerontology. In addition, p53 protein may be used as a functionality marker of skin cells when administered with geroprotective cosmetic means and instrumental cosmetology methods.

Short Exogenous Peptides Regulate Expression of CLE, KNOX1, and GRF Family Genes in Nicotiana tabacum.

Exogenous short biologically active peptides epitalon (Ala-Glu-Asp-Gly), bronchogen (Ala-Glu-Asp-Leu), and vilon (Lys-Glu) at concentrations 10-7-10-9 M significantly influence growth, development, and differentiation of tobacco (Nicotiana tabacum) callus cultures. Epitalon and bronchogen, in particular, both increase growth of calluses and stimulate formation and growth of leaves in plant regenerants. Because the regulatory activity of the short peptides appears at low peptide concentrations, their action to some extent is like that of the activity of phytohormones, and it seems to have signaling character and epigenetic nature. The investigated peptides modulate in tobacco cells the expression of genes including genes responsible for tissue formation and cell differentiation. These peptides differently modulate expression of CLE family genes coding for known endogenous regulatory peptides, the KNOX1 genes (transcription factor genes) and GRF (growth regulatory factor) genes coding for respective DNA-binding proteins such as topoisomerases, nucleases, and others. Thus, at the level of transcription, plants have a system of short peptide regulation of formation of long-known peptide regulators of growth and development. The peptides studied here may be related to a new generation of plant growth regulators. They can be used in the experimental botany, plant molecular biology, biotechnology, and practical agronomy.

[Functional cumulation of influence of vascular peptide bioregulator on microcirculation in the brain cortex of spontaneously hypertensive rats.]

We investigated the influence of vascular peptide bioregulator on microcirculation in the brain cortex of spontaneously hypertensive rats of different ages and figured out whether there is functional cumulation during two-time application of the drug «Slavinorm¼ by above-mentioned animals. It was shown that a single course treatment with vascular peptide bioregulator had increased the density of microvascular network of the pia mater in young animals ca. 1,2-fold and had not affected the perfusion and oxygen saturation of sensorimotor cortex. The second course treatment with «Slavinorm¼ was provided in a 6 months. Functional cumulation was revealed in 12 month-aged rats which had 2 course treatments with vascular peptide bioregulation: the density of microvascular network of the pia mater was increased ca. 1,6-fold; level of perfusion was increased ca. 15% in comparison with intact animals of the same age. These animals were more tolerant to cerebral vasospasm (the application of vasoconstrictor on the surface of the brain): the highest level of tissue oxygen saturation was remained at fairly constant perfusion in comparison with other animals.

[Effect of combined application of ozone therapy and gravitational therapy on the remote results of complex treatment of geriatric patients].

Skin aging is one of the topical issues in modern gerontocosmetology. Application of cosmetic products with short peptides is a promising measure for retardation of skin aging. This research is aimed at investigation of KE (Lys-Glu, Vilon) dipeptide influence on the expression of markers of aging in human skin fibroblasts in vitro. Collagen type I and sirtuin-6 expression in «young¼ and «old¼ skin cell fibroblasts cultures was studied using immunofluorescence confocal microscopy method. The areas of expression of collagen type I and sirtuin-6 are known to decrease in skin fibroblasts with aging by 3,5 and 3,6 times accordingly. KE dipeptide increases collagen type I expression area in «old¼ skin fibroblasts cultures by 83%. KE dipeptide increases expression area of sirtuin-6 in «young¼ and «old¼ skin fibroblasts cultures by 1,6 and 2,6 times correspondingly. Thus, KE dipeptide promotes functional activity of skin fibroblasts and inhibits their aging.