[In vitro lipid-lowering and fibrinolytic effects of regulatory leucine-containing glyprolines in human blood].

The lipid-lowering, fibrinolytic, and anticoagulant effects of leucine-containing glyprolines, Pro-Gly-Pro-Leu and Leu-Pro-Gly-Pro, were studied in vitro in the blood of patients with disorders of lipid metabolism. The lipid-lowering impact of glyprolines and their ability to reduce the polymerization and to increase the depolymerization of fibrin in human blood were found. Possible mechanisms of lipolytic action of peptides by means of modulation of the lipid-dependent phospholipase A2 were proposed.

[Correction of impairments in functions of anticoagulation and insular systems of an organism by the regulatory peptide Leu-Pro-Gly-Pro].

It has been established that fivefold intranasal administration of the peptide Leu-Pro-Gly-Pro (1 mg/kg) to rats with developing refractory hyperglycemia leads to restoration and normalization of the functions of anticoagulation and insular systems. In the blood of experimental animals, there was a decrease in the sugar level and platelet aggregation and an increase in anticoagulant and all kinds of fibrinolytic (total, enzymatic, non-enzymatic, Hageman-dependent) activity.

[Cholesterol-lowering effect of the regulatory peptide Pro-Gly-Pro-Leu].

In the present paper anticoagulant-fibrinolytic effects of the peptide Pro-Gly-Pro-Leu in rats (370-500 g body weight) who consumed fatty foods with excess of saturated fatty acids (wheat flour and bread--35%, sugar--10%, margarine hydrogenated fats, mayonnaise, cheese--35% and offals--10%, cholesterol--1%, dry food--9%) has been established. The duration of the animals on the diet was 15 days. The experimental animals intranasally obtained peptide (200 microg/kg body weight per volume of 0.02 ml per 200 g body weight) 11 times (daily except weekends). Animals from the control group intranasally received instead of peptide its vehicle (0.85% solution of NaCl) at the same time and in the same amount. It has been shown that daily nasal administration of the regulatory tetrapeptide under fatty food intake for the entire period of the experiment has a positive effect on lipid metabolism. It warned the development of alimentary hypercholesterolemia, an increase in body weight, normalized disturbed lipid profile, blood cholesterol level. In addition, its administration also restored functional status of anticoagulation system and decreased elevated degree of blood coagulation to normal values. Possible mechanism of hypocholesterolemic activity of peptide can be explained by its ability to interact with receptors of blood or brain cells, and through a series of reactions mediated to reduce blood cholesterol levels. Thanks to the anti-platelet activity glyprolines effectively improves endothelial function and reduces the risk of blood clots in the blood vessels, providing improved rheological properties of blood and preventing the formation of atherosclerotic plaques in the arterial wall.

[A complex of heparin with the peptide Arg-Pro-Gly-Pro and its anticoagulative, fibrinolytic, and hyperglycemia effects].

Heparin was bound to the arginine-containing peptide Arg-Pro-Gly-Pro with the molar ratio of heparin to the peptide 1:1. The complex compound showed antiplatelet, anticoagulative, and fibrin-depolymerization activities. In an in vivo study, in type 2 diabetes progression, a 5-fold intranasal administration of the compound restored both impaired insular and anticlotting functions in rats. Furthermore, blood fibrinolytic and anticoagulative activities increased.

[Regulatory role of heparin compounds with low molecular blood ligands in plasma and thrombocyte hemostasis].

Analysis of the literature and our own research on the physiological effects of complex compounds of heparin with low molecular ligands (amino acids, regulatory peptides) is presented. It is proved that anticoagulative effects in blood flow were conditioned by the interaction of heparin with glioproline, immunopeptides, and other low molecular substances with formation of complex compounds. The presence of structural regions of binding of heparin and other components is established. It is indicated that in the blood of animals heparin complexes with low molecular ligands possess protective anticoagulative and antithrombotic effects. We made an attempt to reveal the possible mechanism of anticoagulative-fibrinolytic and antithrombotic action of complex compounds of heparin in the organism.

[Protective antithrombotic effects of proline-containing peptides in the animal body subjected to stress].

We discovered that simple proline-containing peptides Gly-Pro, Pro-Gly, Pro-Gly-Pro, and semax had an antistress protective effect on the organism appearing as anticoagulation system activation. Repeated intranasal injection of each of these peptides to rats prior to acute immobilization stress prevented a hypercoagulation response to prolonged stress lasting 60 min. At the same time there was increase of antithrombotic, anticoagulant, and fibrin depolymerization activity and recovery of enzymatic fibrinolytic activity. Dipeptides were found to have the greatest antistress effect. Our results showed that semax had a protective effect against enhanced blood coagulability resulting from repeated immobilization stress.

[Fibrinolytic and hypoglycemic effects of the Pro-Gly-Pro-Leu peptide during development of insulin-dependent diabetes in rats].

Repeated (over 7 days) intranasal introduction of the Pro-Gly-Pro-Leu peptide into animals at a dose of 1 mg/kg before injection of the diabetogenic metabolite alloxan provided effective protection of an organism against development of insulin-dependent diabetes mellitus and prevented development of hypercoagulating alterations in the system of hemostasis. An increasing in the anticoagulating and fibrinolytic activities in rat blood plasma was detected. The peptide under study also showed antidiabetogenic action: repeated intranasal introduction of the Pro-Gly-Pro-Leu peptide into animals for 7 days inhibited development of diabetes symptoms in rats pretreated with alloxan.

[The protective effect of the arginine-heparin complex under simulation of insulin-dependent diabetes].

Daily intramuscular injections of the arginine-heparin complex for 5 days before injection of diabetogenic metabolite alloxan did not cause insulin-dependent diabetes in animals for 3 weeks. As a result of these injections, the anticoagulant fibrinolytic pattern of the anticoagulant system was activated and the platelet aggregation decreased. This effect held for 7 days after injection.

[Comparative studies of anticoagulant and fibrinolytic effects of glyprolines Gly-Pro and Gly-Pro-Arg in conditions of immobilization stress].

It has been shown that proline-containing peptides Gly-Pro and Gly-Pro-Arg in vitro had anticoagulant and nonenzymatic fibrinolytic activity. It was established that after intranasal introduction of these peptides to a rat, anticoagulant and fibrinolytic activity of enzymatic and nonenzymatic nature increased in the rat blood. The peptide protective effect against hypercoagulation induced by immobilization stress was found after repeated intranasal introduction of each peptide into the animal.

[Antidiabetogenic action of Pro-Gly-Arg and Pro-Gly-Pro-Arg peptides after their intranasal chronic administration to animals].

It was shown that chronic (over 7 days) intranasal injection of the Pro-Gly-Arg tripeptide to rats in the dose 1 mg/kg before the injection of a diabetogenic dose of alloxan, promotes effective defense against development of insulin dependent diabetes mellitus. At the same time, the tetra-peptide Pro-Gly-Pro-Arg did not show a hypoglycemic affect during diabetes mellitus provocation. Administration of Pro-Gly-Arg and Pro-Gly-Pro-Arg peptides also activates anticoagulation potential.

[Comparative study of hemostatic properties of the complex and mixture of high molecular weight heparin and adenosine triphosphate].

Anticoagulant and nonenzymatic fibrinolytic activities increased in blood plasma of 6-7-month-old rats after repeated intramuscular administration of the heparin-adenosine triphosphate complex (G-ATP). The mixture of heparin and ATP had no fibrin depolymerizing activity in vitro. Repeated intramuscular administration of the mixture had anticoagulant effect although it was 1.5-1.6 times less pronounced compared to the complex. A higher anticoagulant and fibrinolytic efficiency of the G-ATP complex compared to the mixture is concluded.

[Antiplatelet effect of adenosine triphosphate administration to animals under different experimental conditions].

A significant and considerable decrease in abnormally high platelet aggregation has been demonstrated after intramuscular administration of sodium adenosine triphosphate (ATP) to rats with depressed anti-coagulant system (in aging rats at the age of 11-12 months) and to rats with experimental diabetes both preliminarily and at the background of progressing diabetes. The elimination of one of thrombotic risk factors (decreasing elevated platelet aggregation) points to possible antithrombotic activity of ATP under these experimental conditions.

[Effect of chronic intramuscular administration of low molecular weight heparin-collagen complex on hemostatic indices and development of alloxan-induced diabetes].

Repeated intramuscular administration of low molecular weight heparin-collagen complex proved to increase fibrinolytic activity and to decrease platelet aggregation in the blood of rats (11 months) with depressed anticoagulant system. Administration of diabetogenic alloxan dose induced no diabetes mellitus in such animals.

[Comparison of anticoagulant effects of regulatory proline-containing oligopeptides. Specificity of glyprolines, semax, and selank and potential of their practical application].

Experimental and theoretical demonstration of different effect of certain regulatory peptides (RPs) on blood coagulation is available. The problem of the role of RPs in hemostatic processes becomes particularly significant since, first, the peptides are widespread in nature both in animal and plant tissues, second, there is a relationship between the peptide structure and function and, third, both natural and synthetic peptides are used in practical medicine to correct functions of some factors of the hemostatic system. Many peptide inhibitors of the primary and plasma hemostasis potentiating anticoagulant effects in the body have been described.

[Hemostaseological description of the heparin-adenosine triphosphate (ATP) complex].

Biochemical methods confirmed the presence of the heparin-ATP complex. Acid sulfonate and carboxyl groups proved to mediate heparin-ATP complex formation. The technique for preparation of the heparin complex at a 1 : 20 weight ratio of the components and different pH was developed. Intramuscular administration of resulting complex increased anticoagulant and fibrinolytic activities of animal (rat) plasma. The obtained data indicate the presence of physiologically active heparin-ATP complex providing for anticoagulant effects in the body.

[Effect of the heparin-lysine complex on the hemostatic and insular systems]. / Vliianie kampleksa geparin-lizin na gemostaticheskuiu i insuliarnuiu sistemu.

We studied the effect of chronic intraperitoneal administration of heparin-lysine complex on the state of the hemostatic and insular systems in young and senescent animals (rats). This complex exerted a positive effect on physiological function of the coagulant, anticoagulant, and fibrinolytic components of the hemostatic system in the norm and in developing experimental alloxan diabetes. In this case, both the complex and its components, lysine and heparin, had a pronounced antidiabetogenic effect.

[Antidiabetic and anticoagulant properties of the heparin-glutamic acid complex]. / Antidiabetogennye i protivosvertyvaiushchie svoistva soedineniia geparina s glutaminovoi kislotoi.

Natural heparin complexes proved to activate the anticoagulation system. The obtained experimental data convincingly confirm that glutamic acid alone, and particularly in a complex with heparin, has a considerable preventive potential and efficiently protects experimental animals with induced diabetes mellitus.

[Highly stable regulatory oligopeptides: experience and applications]. / Vysokostabil'nye reguliatornye oligopeptidy: opyt i perspektivy primeneniia.

The most stable regulatory peptides (RP) including the new family of RP (glyprolines) and derivatives of hybrid peptide MEHFPGP are characterized. High ability of glyprolines to penetrate into the blood-stream through the gastrointestinal tract is demonstrated. Antiulcer, antithrombotic and antidiabetic activities of glyprolines were discovered in experiments on white rats. The activity of oligopeptides PGP, PG and GP is compared. Mechanisms of glycoprolines activities and feasibility of their administration with connective tissue food proteins are discussed. Thus, glyprolines are perspective drugs for treatment of gastric ulcer, correction of hemostasis and thrombosis suppression prepared for preclinical trial.

[Role of neuraminidase in pathogenesis of influenza]. / Rol' neiraminidazy v patogeneze grippozonoi infektsii.

The influenza neuraminidase (NA) possesses, both in vivo and in vitro, the anticoagulant and fibrinolytic activity. A computerized comparative analysis of the influenza NA viruses, type A, showed nine regions of amino-acid sequences compatible with the tissue activator of human plasminogen. The mentioned regions are highly conservative for each NA subtype irrespective of a source or a year, when an influenza strain was isolated. The role of NA in pathogenesis of influenza infection is under consideration.

[ Influenza virus proteins modulate hemostasis in vitro and in vivo ]. / Belki virusa grippa moduliruiut gemostaz in vitro i in vivo.

We studied the effect of influenza virus proteins--hemagglutinin, neuraminidase, nucleoprotein, and membrane protein--on hemostasis in vitro and in vivo. The obtained data demonstrated that the envelope proteins hemagglutinin and neuraminidase increased the plasma fibrinolytic and anticoagulant activities and the activity of human tissue plasminogen activator. Among the core proteins of influenza virus, membrane protein proved to have the highest activity; in contrast to hemagglutinin and neuraminidase, it inhibited fibrinolysis, increased the coagulation activity of the plasma, and decreased the activity of human tissue plasminogen activator. Combined action of hemagglutinin and neuraminidase increased the plasma fibrinolytic and anticoagulant activities exceeding their individual effects. Combined action of an envelope protein hemagglutinin and membrane protein also increased the plasma fibrinolytic and anticoagulant activities although to a lesser extent as compared to hemagglutinin alone. The obtained data indicate that the viral proteins are physiologically active and can induce hemostatic changes specific for influenza.