Dipeptides Increase Functional Activity of Human Skin Fibroblasts.

We analyzed the effect of dipeptide Glu-Trp and isovaleroyl-Glu-Trp in concentrations of 0.2, 2 and 20 µg/ml and Actovegin preparation on functional activity of human skin fibroblasts. Dipeptides, especially Glu-Trp, produce a stimulating effect on human skin fibroblasts and their effect is equivalent to that of Actovegin. Dipeptides stimulate cell renewal processes by activating synthesis of Ki-67 and reducing expression of caspase-9 and enhance antioxidant function of the cells by stimulating the expression of Hsp-90 and inducible NO-synthase. These findings suggest that dipeptides are promising candidates for preparations stimulating reparative processes.

Effects of Lys-Glu-Trp peptide on cell-cell interactions and vascular endothelium proliferation under normal conditions and during atherosclerosis.

The molecular mechanism of atherosclerosis is based on decreased expression of signal molecules connexin (Cx37 and Cx40), vascular endothelial growth factor (VEGF), and proliferative protein Ki-67, which characterize the processes of cell-cell interactions and proliferation of vascular endotheliocytes. Lys-Glu-Trp peptide in doses of 4 and 40 µg/ml promoted recovery of Cx37, Cx40, and VEGF expression in cultured endotheliocytes from the aorta of patients with atherosclerosis, which attests to vasoprotective effects of this agent.

Hypolipidemic and hypoglycemic effect of peptide Lys-Glu-Trp-NH(2) in rats with associated metabolic disorders.

The effect of peptide Lys-Glu-Trp-NH2 in doses of 0.2, 20, and 2000 µg/kg on lipid and carbohydrate metabolism was studied in Wistar rats with experimental hyperlipidemia and diabetes mellitus. This tripeptide in a dose of 2000 µg/kg produced a hypolipidemic effect on atherogenic lipoproteins, decreased the intensity of LPO, improved the state of the antioxidant system, and normalized the content of HDL. Treatment with this tripeptide had a hypolipidemic effect and reduced the severity of specifi c morphofunctional changes in the pancreatic and hepatic tissue.

[Effect of prostatilen AC suppositories on course of experimental prostatitis].

The article presents the results of evaluation of efficacy of new drug prostatilen AC (rectal suppositories), containing regulatory peptides of the bovine prostate and zinc arginate-glycinate complex, in the treatment of prostatitis. The experiment was conducted on 40 Sprague-Dawley rats weighing 180-200 g. Chronic prostatitis was modeled by injection of 10% Dimexidum in combination with water, mixed with turpentine, a volumetric ratio of 4:1. It is shown that prostatilen AC has pronounced organotropic antiinflammatory effect, which manifests in reducing the weight of the prostate, reducing the protein level in the urine, activity of acid phosphatase, and levels of ceruloplasmin and C-reactive protein. In addition, this drug normalizes the act of urination and increases the diurnal diuresis, has antioxidant properties and increases the blood level of the male sex hormone testosterone.

Role of peptides in epigenetic regulation of gene activities in ontogeny.

The authors develop a new concept most fully reflecting the evolutional and biological role of peptides in the organism. Wide spectrum of peptide effects realized through regulation of the expression of certain genes is aimed at the maintenance of homeostasis, inhibition of the genetic aging program realization, and lifespan prolongation.

[Peculiarities of treatment of elderly and old patients with femoral neck fractures].

The article presents a review of recent issues of diagnostics and general and surgical treatment of the aged patients with cervical hip fractures. The authors describe an approach of surgical treatment of these fractures requiring enhanced "vital" indications for operation in case of the aged patients due to their desperate state. In compliance with a patient's general state, level of physical activity, bone tissue state the authors formulate indications for inner osteosynthesis, unipolar, bipolar or total endoprosthesis replacement.

[Gastroprotective activity of modified glutamyl-tryptophan dipeptide analogs and melatonin].

The gastroprotective action of synthetic dipeptides glutamyl-tryptophane (EW), iso-valeroyl-glutamyl-tryptophane (ivEW) and nicotinoyl-glutamyl-tryptophane (nEW) in comparison to melatonin was studied in experiments on male with the model indometacine and starvation stress-induced stomach ulcers. It was shown, that EW and melatonin exhibit antiulcer activity upon preventive intragastric administration on the model of starvation stress stomach ulcers. At the same time, ivEW, nEW, EW and melatonin exhibit antiulcer activity during the treatment of model indometacine-induced stomach ulcers. The maximum gastroprotective action was observed for ivEW on the model of indomethacin-induced stomach ulcer. The therapeutic efficiency of substances studied is based on their cytoprotective, antioxidant and immunomodulating action.

Comparative analysis of the expression of c-Fos and interleukin-2 proteins in hypothalamus cells during various treatments.

The aim of the present work was to perform a combined analysis of the degree of activation of the anterior hypothalamus of the rat and expression of the interleukin-2 gene during treatments of different types: mild stress ("handling") and adaption to it, as well as intranasal administration of physiological saline and the peptides Vilon (Lys-Glu) and Epitalon (Ala-Glu-Asp-Gly). Changes in the numbers of c-Fos-and IL-2-positive cells in structures of the lateral area (LHA) and anterior (AHN), supraoptic (SON), and paraventricular (PVN) nuclei of the hypothalamus in Wistar rats. Ratios of the quantities of c-Fos-and IL-2-positive cells were determined in intact animals and after activation of brain cells initiated by different treatments; the influences of adaptation to handling on the nature of changes in the expression of these proteins was also studied. Combined analysis of the intensity of expression of these two proteins - c-Fos, a marker of neuron activation and a trans-factor for the IL-2 cytokine gene and other inducible genes, and IL-2 - in intact animals and after various treatments showed that the process of cell activation in most of the hypothalamic structures studied correlated with decreases in the quantity of IL-2-positive cells in these structures; different patterns of changes in the numbers of c-Fos-and IL-2-positive cells were seen in response to different treatments in conditions of stress and adaptation to it.

Biofilm penetration, triggered release and in vivo activity of inhaled liposomal amikacin in chronic Pseudomonas aeruginosa lung infections.

OBJECTIVES: Chronic infections of Pseudomonas aeruginosa in the lungs of cystic fibrosis patients are intractable antibiotic targets because of their biofilm mode of growth. We have investigated the biofilm penetration, mechanism of drug release and in vivo antimicrobial activity of a unique nanoscale liposomal formulation of amikacin designed specifically for nebulization and inhaled delivery. METHODS: Penetration of fluorescently labelled liposomes into sputum or P. aeruginosa (PA3064) biofilms was monitored by a filter assay and by epifluorescence or confocal scanning laser microscopy. Amikacin release in vitro and rat lung levels after inhalation of nebulized material were measured by fluorescence polarization immunoassay. A 14 day agar bead model of chronic Pseudomonas lung infection in rats was used to assess the efficacy of liposomal amikacin versus free aminoglycosides in the reduction of bacterial count. RESULTS: Fluorescent liposomes penetrated readily into biofilms and infected mucus, whereas larger (1 microm) fluorescent beads did not. Amikacin release from liposomes was mediated by sputum or Pseudomonas biofilm supernatants. Rhamnolipids were implicated as the major releasing factors in these supernatants, active at one rhamnolipid per several hundred lipids within the liposomes. Inhaled liposomal amikacin was released in a slow, sustained manner in normal rat lungs and was orders of magnitude more efficacious than inhaled free amikacin in infected lungs. CONCLUSIONS: Penetration of biofilm and targeted, sustained release from liposomes can explain the superior in vivo efficacy of inhaled liposomal amikacin versus free drug observed in a 14 day infection model. Inhaled liposomal amikacin may represent an important therapy for chronic lung infections.

[Parallel analysis of c-Fos protein and interleukin-2 expression in hypothalamic cells under different influence].

The objective of this work was to perform a parallel analysis of activation of the rat anterior hypothalamus cells as judged by c-Fos protein expression, and of the expression of interleukin-2 (IL-2) under different influences, i. e., mild stress (handling) and adaptation to it, and intranasal administration of saline and the peptides Vilon (Lys-Glu) and Epithalon (Ala-Glu-Asp-Gly). Changes in the counts of cells positive for c-Fos- and IL-2 proteins were studied in structures of the lateral (LHA) area, anterior (AHN), supraoptic (SO) and paraventricular (PVH) nuclei of Wistar rat hypothalamus. Quantity of the interleukin-2-positive and c-Fos-positive cells was calculated. The findings were: a negative correlation between the activation of cells and the amount of IL-2 in the cells in the hypothalamic structures under study, and the specific patterns of changes in the counts of cells positive for c-Fos and IL-2 under stress and adaptation to stress.

Effect of pancragen on blood glucose level, capillary permeability and adhesion in rats with experimental diabetes mellitus.

The effects of tetrapeptide pancragen (Lys-Glu-Asp-Trp-NH2) on blood glucose level and permeability and adhesion of mesenteric capillaries were studied in Wistar rats with experimental streptozotocin-induced diabetes mellitus. Oral pancragen produced a pronounced hypoglycemic effect during treatment. Intramuscular pancragen normalized the adhesion of mesenteric capillary endothelium, but did not modify capillary permeability. The results indicate homeostatic and endothelioprotective effects of pancragen during the early period of diabetes mellitus.

Interleukin-2 concentration in hypothalamic structures of rats receiving peptides during mild stress.

The number of hypothalamic IL-2-containing cells changed in rats receiving Vilon and Epithalon during mild stress (handling). The number of IL-2-positive cells in hypothalamic structures decreased 24 h after intramuscular injection of Epithalon and 2 h after intranasal administration of the test peptides. Adaptation of animals to experimental conditions prevented the decrease in the number of IL-2-positive cells in the supraoptic nucleus after intranasal administration of Epithalon.

Production of lymphocyte-activating factors by mouse macrophages during aging and under the effect of short peptides.

Age-specific characteristics of production of lymphocyte-activating factor by mouse peritoneal macrophages and modulation of this production by short synthetic peptides (Vilon, Epithalon, and Cortagen) were studied. The production of lymphocyte-activating factors by macrophages stimulated with lipopolysaccharides in vitro was lower in old animals. The opposite modulating effects of short peptides on the production of lymphocyte-activating factors by resident and lipopolysaccharide-stimulated macrophages in young and old mice were demonstrated for the first time. This is a possible mechanism of immune system dysfunction during aging, which opens new vistas for its correction with short synthetic peptides.

[The effect of vilon (Lys-Glu) on 1.2-dimethylhydrazine-induced neoplasia].

The influence of vilon (Lys-Glu) on 1.2-dimethylhydrazine-induced neoplasia in mice has been studied. After treatment with 10 microg/kg, tumors developed in 14.3% which survived until first tumor detection (46 weeks) while, in control group, tumors occurred in 60%. Vilon-related inhibition of preneoplastic alterations in the kidneys was reported.

Synthesis of IL-2 mRNA in cells of rat hypothalamic structures after injection of short peptides.

In situ hybridization on paraffin sections of the rat brain showed that synthetic peptides Vilon, Epithalon, and Cortagen modulated the expression of IL-2 gene in vivo in cells of some hypothalamic structures depending on the terms and routes of administration.

Effect of peptide Vilon on the content of transforming growth factor-beta and permeability of microvessels during experimental chronic renal failure.

We studied the effect of Vilon in rats 2, 4, and 6 months after the onset of chronic renal failure. Subcutaneous injection of Vilon significantly decreased serum concentration of transforming growth factor-beta(1) and permeability of mesenteric microvessels in rats 2 months after the onset of chronic renal failure. Our results indicate that the preparation produces a potent homeostatic effect in the early period of chronic renal failure.

[Vilon effect on consequences of repeated radioactive and mercuric impact in small doses].

The purpose of the study was to determine the efficacy of vilon administration in rats after reiterated exposure to ecotoxicants (mercury in concentration near to maximum allowable one and gamma-radiation in small dose). In 24 hours after repeated radioactive and mercuric impact (RMI) and for 30 consecutive days the animals reported lymphopenia. At the same time the indices of DNA leucocytes content and structure did not differ from the parameters of intact animals, this could evidence the development of adaptation reactions. Vilon administration led to the normalization of the lymphocytes number by the 30th day after repeated irradiation (contrary to the radioactive- chemical control), while the number of granulocytes in the test group was higher than that in the intact control group. Study of the survival rate in rats revealed that Vilon reduced morbidity of rats in the course of 15 months after RMI.

[Effect of peptide Livagen on activity of digestive enzymes in gastrointestinal tract and non-digestive organs in rats of different ages].

It is stated that Livagen (Lys-Glu-Asp-Ala) is a weakly hydrolyzed peptide. Peptide hydrolases of small intestine do not hydrolyze Livagen even to a small extent. Under in vitro conditions Livagen reduces glycil-L-leucinedipeptidase activity in small intestine by 50%. After two weeks of Livagen administration per os in rats the digestive enzymes activity in young animals reduces, while in old animals it increases. It should be mentioned that the activity of enzymes in old rats after Livagen administration in the majority of cases approaches to the level of the activity in young animals of control group.

[Effect of epitalon on the immunity and hemostasis in hypophysectomized chicken and old hens]. / Vliianie épitalona na immunitet i gemostaz u gipofizéktomocheskikh tsypliat i starykh kur.

Neonatal hypophysectomy in chicken, as well as that in old hen has been established to entail in 1,5 months after surgery cellular and humoral immunity disturbances, pronounced hypercoagulation and fibrinolysis depression. Administration of Epitalon (Ala-Glu-Asp-Gly) to a large extent eliminates revealed shifts. This effect appeared to be stronger in neonatally hypophysectomized chicken than in old hens.

Effects of short peptides on lymphocyte chromatin in senile subjects.

Effects of synthetic short peptides (Vilon, Epithalon, Livagen, Prostamax, and Cortagen) on activity of ribosome genes, parameters of common heterochromatin melting, polymorphism of structural heterochromatin (C segments) of chromosomes 1, 9, and 16, and variability of facultative heterochromatin were studied in leukocytes of subjects aged 75-88 years. All the studied peptides induced activation of ribosome genes, decondensation of densely packed chromatin fibrils, and release of genes repressed as a result of age-specific condensation of the cellular euchromatin regions (deheterochromatinization of facultative chromatin). Treatment with Epithalon, Livagen, and Prostamax led to decondensation of chromosome 1 pericentromeric structural chromatin, while Epithalon and Livagen treatment led to changes in chromosome 9 as well. Hence, short peptides activate heterochromatin and heterochromatinized regions of cell chromosomes in senile subjects.