[Chondrocytes secretory phenotype associated with aging: role in the pathogenesis of osteoarthritis and prospects for peptide bioregulation.]

Osteoarthritis (OA) is a socially significant age-associated disease, for the treatment of which a search for new effective drugs is underway. The development of OA correlates with the development of the aging-associated secretory chondrocyte phenotype (SASP). The purpose of the review is to analyze the pool of signaling molecules that form SASP of chondrocytes in OA and substantiate the possibility of peptide chondroprotection. It has been established that SASP of chondrocytes is characterized by a decrease in the synthesis of sirtuins, impaired remodeling of the extracellular matrix, and activation of cytokine production. Sigumir, a polypeptide complex of cartilage and bone tissues of young animals, and the AED tripeptide (Kartalax) have shown high efficacy in animal models of OA and oral administration in patients with OA of older age groups. These peptide substances regulate the synthesis of proapoptotic and proliferotropic molecules that form the SASP of chondrocytes.

[The influence of peptides on the chondrogenic differentiation of human mesenchymal stem cells during replicative aging.]

Osteoarthritis is a widespread age-related disease, that has no effective targeted therapy. In this regard, bioengineering methods are being actively developed that can stimulate the restoration of cartilage tissue. These methods include chondrogenic differentiation of stem cells, which is stimulated by various biomolecules, including short peptides and polypeptide complexes. It was studied the effect of the cartilage polypeptide complex (CPC) and AED peptide on gene expression and protein synthesis of chondrogenic differentiation - SOX9, aggrecan, type II collagen and COMP - in human mesenchymal stem cell (MSC) during replicative aging. AED peptide at the concentration of 200 ng/ml activates gene expression and protein synthesis during aging of MSCs. CPC has the same effect in the concentration 2000 ng/ml. These data indicate the stimulating effect of studied peptides on regulation of chondrogenesis and open up prospects for further investigation of their effectiveness in osteoarthritis models.

[Peptides prevent the forming of secretory phenotype of chondrocytes associated with the aging.]

Secretory phenotype associated with the aging (SASP) of chondrocytes forms the conditions for the musculoskeletal system diseases development, in particular, osteoarthritis (OA). The search for effective methods for OA treating is an urgent task of molecular gerontology. The purpose of this work is to characterize the SASP of chondrocytes and to conduct a comparative assessment of the effect of AED peptide and the cartilage polypeptide complex (CPC). It was found that chondrocyte's SASP is characterized by an increase of the synthesis of p16, p21, p53 pro-apoptotic proteins, TNF-α, IL-1α pro-inflammatory cytokines and a decrease of Sirt1synthesis. Peptides AED and CPC normalize the synthesis of molecules that form SASP of chondrocytes. This effect may explain their geroprotective effect and effectiveness in studies of various pathologies of the musculoskeletal system, including OA.

[AEDG peptide regulates human circadian rhythms genes expression during pineal gland accelerated aging.]

Night work provides biorhythms desynchronization, disorder of melatonin-producing function and accelerated pineal gland aging. One of the promising geroprotectors restoring the pineal melatonin synthesis is the AEDG (Ala-Glu-Asp-Gly) peptide. AEDG peptide increases in 1,7 times the 6-sulfatoxymelatonin (6-SOMT) excretion in the urine of middle-aged people. Moreover, AEDG peptide normalized circadian Clock and Csnk1e genes hyper expression in leukocytes in 1,9-2,1 times and increases the Cry2 gene hypo expression in peripheral blood lymphocytes in 2 times in people with reduced melatonin-producing epiphysis function. The geroprotective effect of the AEDG peptide is based on its ability to restore the epiphysis melatonin-producing function by means regulation of human circadian genes expression.

[The influence of polypeptide liver complex and tetrapeptide KEDA on organism physiological function in norm and age-related pathology.]

The applying of many drugs in elderly and old people often is the reason of liver dysfunction. Thereat, the risk of liver fibroid induration, acute and chronic hepatitis increases during aging. It is the reason to find new, effective and harmless hepatoprotectors. In the review is shown the data of hepatoprotective, immunoprotective and antiageing properties of liver polypeptide complex (Ventvil) and KEDA tetrapeptide (Lys-Glu-Asp-Ala, Livagen). In liver pathology experimental models (liver fibroid induration, acute and chronic hepatitis) in amimals and in vitro was shown high efficiency of Ventvil and KEDA peptide. Ventvil and KEDA peptide had concordant effects - normalized immune and antioxidant status, restored liver function during hepatitis. It was demonstrated, that maximal hepato- and immunoprotective effect of peptides verified in aging.

[Polypeptide vessel complex and its role in physiology function regulation in aging pathology.]

In review it is shown data about polypeptide vessel complex, extracted from calf vessel and named Slavinorm® (Vasolin). Slavinorm® had therapeutic effects in cardio-vascular age related pathology in animal models. Slavinorm® prevents atherosclerosis, normalizes lipid metabolism, lipid peroxidation parameters, station of congenital and adaptive immunity, callicrein-kinins system, vessel and trombocitary hemostasis, blood coagulability, fibrinolysis, activates vessel wall reparation. Slavinorm® has positive effects in other age-related diseases (arthritis, pancreatitis, respiratory distress).

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.

[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.

Effect of Polypeptides on Cell Proliferation and Apoptosis during Aging.

Polypeptide complexes derived from the bronchi, blood vessels, muscles, kidneys, ovaries, testes, and retina stimulated the processes of cell renewal in organotypic cultures of the corresponding organs of young and old animals. A correlation between the intensity of regeneration and animal' age was revealed. The polypeptide complexes reduced the expression of apoptotic factors p53 and caspase 3 and increased the expression of proliferation protein Ki-67. These results provide the basis for further study of the polypeptide complexes as stimulators of regenerative processes in different tissues during ageing.

Effects of Vascular Peptide Bioregulator on the Density of Microvascular Network in the Brain Cortex of Aged Rats.

Using a TV unit for microcirculation studies, we studied the density of the entire microvascular network and its arterial compartment in the pia mater of the sensorimotor cortex in intact young and aged rats (2-3 and 22-24 months) and aged rats after a course of vascular peptide bioregulator Slavinorm. The experiments showed that the density of microvascular network in intact animals decreased by 1.6 times with aging. Treatment with the peptide bioregulator 2.5-fold increased the density of the microvascular network in aged rats in comparison with intact animals of the same age, the density of the arterial compartment of the microvascular network in the pia mater increased by 2.8 times.

[OPTIMIZATION OF REPARATIVE OSTEOGENESIS JAWS ON AGING (PRECLINICAL STUDIES)].

The article presents the results of pre-clinical studies of the possibility of optimization of reparative osteogenesis in postoperative bone cavities of the jaws in old rats with a peptide bioregulator of Kartalaks. Using histological and morphometric methods in the experimental study, it is shown that the use of Kartalaks positive effect on the course of the process of reparative osteogenesis of the mandible in old rats. The features of the Kartalaks drug investigated for optimization of reparative osteogenesis jaw during aging. It is found that by using Kartalaks in old animals to 30 days before the surgical intervention, the process of reparative osteogenesis standard defect of mandible occurs at early stages (before 30 days), similar to the control. The deadlines for 60-120 days from the beginning of the experiment using the peptide bioregulator Kartalaks, noted the formation of a complex regenerate tissue containing a smaller proportion of connective tissue and cartilage, as well as more advanced remodeling of newly formed bone tissue compared with the control group, and older animals who received the drug after performing surgery.

[Diagnostics of the changes arising in an oral cavity at oncological sick senior age groups (review)].

Article is devoted to the changes happening in an oral cavity and in oral liquid under the influence of preparations of the oncological diseases used for treatment. Considering that research of oral liquid belongs to one of noninvasive methods of diagnostics and can be used with success for definition and correction of conditions of the mucous membrane of an oral cavity at the patients of advanced and senile age passing polychemotherapeutic treatment, this type of research is the extremely perspective for a gerontostomatology.

["Protein of senility" CCL11, "protein of juvenility" GDF11 and their role in age-related pathology].

The paper presents the latest literature data on the structure and functions of «protein of juvenility¼ - CCL11 and «protein of senility¼ - GDF11. Chemokine CCL11 injected to young animals has been shown to lead to degenerative changes in the central nervous system (CNS), disturb cognitive functions and impede tissue regeneration. CCL11 concentration increases dramatically in schizophrenia, Alzheimer's disease, neuro-inflammatory disorders, cerebral malaria, drug addiction, as well as in atherosclerosis, periodontal disease, macular degeneration, cancer and other pathologies. In contrast to CCL11, differentiation growth factor 11 (GDF11), being administered to old mice, eliminates age-associated hypertrophy of the heart, improves muscle tone and prevents degenerative changes in the CNS, improves cognitive functions and enhances tissue regeneration. Its concentration decreases in cardiovascular disease, osteoporosis, and other «diseases of old age¼. At the same time, the higher the GDF11 level in the blood, the milder myocardial infarction, stroke and other age-related diseases of the cardiovascular system.

[POLYPEPTIDES INFLUENCE ON TISSUE CELL CULTURES REGENERATION OF VARIOUS AGE RATS].

A comparative study of polypeptides extracted from the tissues of calves: Cortexin (from brain cortex), Epinorm (from pineal gland), Ventvil (from liver), Prostatilen (from prostate), Thymalin (from thymus), Chelohart (from heart), Chondrolux (from cartilage) on the relevant organotypic tissue cultures of young and old rats, in concentration 0,01-100 ng/ml was performed. Polypeptides specifically stimulated "young" and "old" cell cultures growth in concentration 20-50 ng/ml. This effect correlates with increasing of PCNA and decreasing of p53 expression in brain cortex, pineal gland, liver, prostate, heart, cartilage. Moreover, Thymalin activated CD5, CD20 expression--markers of B-cells differentiation. These data show that polypeptides isolated from different tissues have selective molecular activity on the regeneration of suitable tissues in aging.

Peptide Regulation of Cells Renewal Processes in Kidney Tissue Cultures from Young and Old Animals.

Polypeptide complex isolated from calf kidneys stimulates the processes of cell renewal in organotypic kidney tissue cultures from young and old rats. The polypeptide complex enhances expression of proliferation marker Ki-67 and reduces expression of proapoptotic peptide p53 in kidney explants obtained from young and old animals. Short peptides T-31 (AED) and T-35 (EDL) also stimulate proliferation and reduce apoptosis of the kidney cells, but to a lesser degree than the polypeptide complex. The results provide the basis for further investigation of the polypeptide complex as a preparation for the therapy of kidney diseases, including age-related pathologies.

[Pinealon and Cortexin influence on behavior and neurochemical processes in 18-month aged rats within hypoxia and hypothermia].

The research of Cortexin and Pinealon within two models of stress, acute hypobaric hypoxia and mild hypothermia, within 18-month aged rats has been held. The peculiarities of peptide preparations' influence on behavior and neurochemical indeces have been identified. Cortexin shows a more pronounced effect on free radical processes and caspase 3 activity in brain than Pinealon. Both preparations forward an accumulation of adrenergic mediator within rats' brains in the model of acute hypobaric hypoxia, as well as serotonin within cerebrum cortex in the model of mild hypothermia, which may underlie their geroprotective effects.

[Regulation of content of cytokines in blood serum and of caspase-3 activity in brains of old rats in model of sharp hypoxic hypoxia with Cortexin and Pinealon].

While studying the effects of Cortexin and Pinealon (Glu-Asp-Arg) on the caspase-3 activity in the brain, an interleykin-6 and a factor of tumor necrosis in blood serum of old rats under the sharp hypoxic hypoxia it was suggested that in hypoxia of brain conditions Pinealon forwards the increase of the neurogenesis and the decrease neuroinflammatory reactions to a reference level. With the sharp hypoxic hypoxia Cortexin reduces an ability of brain tissue of programmed cells death, but saves the content of interleykin-6 at high level.

[Peptide bioregulators: the new class of geroprotectors. Message 2. Clinical studies results].

The review summarizes the results of long-term studies of the authors on the clinical efficacy of peptide bioregulators (Timalin, Thymogen, Vilon, Epithalamin, Prostatilen, Cortexin, Retinalamin) for the prevention of diseases and treatment of people of different age. Special attention is given to the analysis of the use of peptide bioregulators as geroprotectors.

[The influence of age of donors on the ability of cells to homologous recombination DNA repair].

Old and young donors cells show different ability to homologous recombination (shown on the first stage--the chromosome transference) in vitro, that we suppose could be the reasons of the genome instability in aging. Homologous recombination, induced by X-radiation, is limited in cells taken from donors older than 70 years. Alpha-amanitin, the RNA-polymerize II repressor, in toxic doze, could induce the chromosome transference in the cells from all studied groups: from old and young donors and donors with repair process defect (with BRCA 1, 2 mutations). Summarized effect of X-radiation and alpha-amanitin does not increase the induction of the chromosome transference.

[The role of oxidative stress in skin aging].

The review covers the literature proving that ROS formation in aging overbalances the antioxidant defense system potential of the skin structure (horny layer, epidermis and dermis). It has been shown that ROS are involved in the pathogenesis of inflammatory processes and allergic responses in the skin. The role of ROS and antioxidant systems in the cell-mediated responses associated with the MAP kinase activity in the skin is discussed. Special attention is paid to the ultraviolet irradiation exposure, which accounts for its genotoxic, immunosuppressive and carcinogenic effects on the skin.