Metabolism of a New Antiaggregant, Indolinone Derivative.

Cytochrome p450-mediated metabolism of GRS (indolinone antiaggregant) and its effects on activities of cytochrome p450 isoenzymes were studied. Inhibition of 6 isomers of cytochrome p450 in human liver microsomes was studied with the use of specific substrates. It was found that human liver cytochrome p450 enzymes could not induce degradation of GRS and that GRS was not an inductor or inhibitor of cytochrome p450 family members 1A2, 2C9, 2C19, 2D6, 2C8, and 3A4. Hence, clinical use of the prospective antiaggregant would not involve the risk of uncontrolled fluctuations in GRS concentrations in the organism because of interactions between the drugs.

Co-Transplantation of Pancreatic Islet Cells and Mesenchymal Bone Marrow Precursors on Titanium Nickelide Scaffolds in Alloxan-Induced Diabetes Mellitus.

We studied therapeutic activity of co-transplantation of allogeneic pancreatic islet cells and mesenchymal bone marrow progenitors on TiNi scaffolds in Wistar rats with experimental alloxan-induced diabetes mellitus. In preliminary experiments with co-culturing of cells in different proportions followed by their transplantation on tissue-engineered constructs, the optimum ratio of these cells was determined - 3:1. Regeneration was assessed by biochemical methods by the blood levels of glucose and glycosylated hemoglobin on days 15, 30, and 5. In the group with combined cell transplantation on TiNi scaffold, normalization of the studied biochemical parameters occurred earlier than after monotherapy with allogenic islet cells and was associated with an increase in animal lifespan. Normalization of the parameters of bone marrow hemopoiesis, in particular, the number of myelokaryocytes and erythroblasts was also noted.

[Oxidative stress in adipose tissue as a primary link in pathogenesis of insulin resistance].

Obesity is a leading risk factor of diabetes mellitus type 2, impairments of lipid metabolism and cardiovascular diseases. Dysfunctions of the accumulating weight of the visceral fat are primarily linked to pathogenesis of systemic insulin resistance. The review considers modern views about biochemical mechanisms underlying formation of oxidative stress in adipocytes at obesity, as one of key elements of impairments of their metabolism triggering formation of systemic insulin resistance.

[THE ROLE OF THE ENDOGENOUS CANNABINOID SYSTEM IN THE FORMATION OF THE GENERAL ADAPTATION SYNDROME].

Nonopioid stress-induced analgesia is the consequence of activation of CB1 receptors by the increased level of 2-arachidonoyl glycerol, anandamide in the periaqueductal gray matter in the midbrain. The activation of cannabinoid CB1 receptors inhibits stress-induced ulcerogenesis due to the strengthening of the antioxidant defense of the gastric mucosa. CB1 receptor antagonists promote an increase in ACTH and corticosterone concentrations in the blood of intact animals, the knockout of the gene encoding the CB1 receptor exhibits the same effect. Antagonists of CB1 receptors enhance the stressor elevation of ACTH and corticosterone levels in the blood of experimental animals. It was found an increase in stress-induced elevation of corticosterone and ACTH levels in the blood of mice with a knockout of the gene encoding the CB1 receptor. An increase in the endogenous anandamide level or disturbance of the reuptake of endogenous cannabi-noids after application of pharmacological agents promotes reducing corticosterone level in stressed animals. Consequently, endogenous cannabinoids inhibit basal and suppress stress-induced activity of the hypothalamic-pituitary-adrenal axis. The indicated regulation is carried out on the level of the hypothalamus, pituitary and adrenal cortex. Stimulation of central cannabinoid receptors leads to an activation of the sympathetic system. The activation of peripheral CB1 receptors leads to inhibition of norepinephrine release from sympathetic terminals and epinephrine release from the adrenal glands. The endogenous CB1 receptor agonists play an anxiolytic role and prevent the occurrence of pathological anxiety.

Activity of sphingomyelinase in rat liver in acute and chronic toxic hepatitis: proportion between peroxidative and phospholipase pathways of lipid bilayer modification.

We showed that sphingomyelinase activity in the liver increased only during the acute phase of toxic hepatitis. Peroxidative modification of hepatocyte membrane bilayer prevailed during the acute phase, while after transformation of the process to the chronic phase phospholipase pathway predominated.

Functional activity of sphingomyelin cycle in rat liver in chronic toxic hepatitis.

Activities of sphingomyelinase and ceramidase decreased in the liver in chronic toxic hepatitis and the balance between the levels of proapoptotic ceramide and antiapoptotic sphyngosine-1-phosphate shifts towards the latter substance. Pronounced changes in the qualitative and quantitative composition of fatty acids in the sphingomyelin cycle effector molecules were revealed.

Negative chronotropic effect of cannabinoids and their water-soluble emulsion is related to activation of cardiac CB1 receptors.

Intravenous injection of cannabinoids dissolved in cremophore EL:ethanol:NaCl mixture and water-soluble emulsion of the same cannabinoids caused identical negative chronotropic effects in chloralose-narcotized rats. Selective CB1 and CB2 receptor antagonist HU-210 also induced a negative chronotropic effect in rats, while pre-injection of CB1 receptor antagonist SR 141716A completely abolished this effect of HU-210. Selective CB2 receptor antagonist SR 144528 had no effect on HU-210-induced bradycardia. Preinjection of ganglioblocker hexamethonium also did not abolish the negative chronotropic effect of HU-210 and ACPA. Perfusion of isolated rat heart with Krebs-Henseleit solution containing HU-210 in a final concentration of 100 nM reduced heart rate. It was shown that the negative chronotropic effect of cannabinoids is mediated through activation of cardiac CB1 receptors.

Influence of venezuelan equine encephalitis, influenza and mumps vaccine viral strains on morphological patterns and viability of human tumor cells in vitro.

PURPOSE: To study the cytolytic and cytostatic effects in some human tumor cells lines after their infection with vaccine viral stains. MATERIALS AND METHODS: Cultures of human tumor cell lines (Hep-2, P3HR-1 and K-562) were exposed to vaccine viral strains of mumps, influenza and venezuelan equine encephalitis (VEE) to determine the impact of these strains on cell mitotic activity, nuclear abnormalities in interphase, extent of cell vacuole dystrophy and cell viability. RESULTS: Vaccine strains of the VEE and mumps viruses induced definite cytolytic effect in all studied cell lines, whereas the influenza virus showed such ability only in the Hep-2 cell line. Moreover, the VEE virus induced cytostatic effect in Hep-2, K-562, P3HR-1 cell lines; the mumps virus in Hep-2 and P3HR-1; and the influenza virus in Hep-2 and K- 562 cell lines. CONCLUSION: Vaccine strains of both the VEE and mumps viruses were able to induce definite cytolytic effect in all studied cell lines. However, further investigations are required to develop novel immunological methods for human tumor treatment.

Activity of phospholipase A2 with different localization in liposomes.

Damages to liposomal membranes resulted from intensification of lipid peroxidation with iron ions in the presence of ascorbate or treatment with the membrane disintegrator tetrachloromethane led to activation of phospholipase A2, which depended on the enzyme localization in liposomes. Activity of phospholipase A2 located on the inner liposome surface increased less significantly compared to the enzyme bound to the outer surface.