Bulletin of Experimental Biology and Medicine最新文献

To develop the theoretical basis for neuronal antioxidant therapy, the study employed in vitro model of oxidative stress of cortical neurons in order to examine the repair mechanisms triggered in the damaged neurons by PGC-1α/NRF1/NRF2/TFAM signal pathway. The functions of proteins in this signal pathway were examined using online STRING software, which analyzed the network of protein-protein interactions (PPI). The hub genes in PGC-1α/NRF1/NRF2/TFAM signal pathway were analyzed with Cytoscape software. In vitro, the cortical neurons were treated with 25, 50, 75, or 100 μM H₂O₂. The inhibition rate of neurons with various concentrations of H₂O₂ was assessed by CCK8, thereupon the neuronal cells were exposed to H₂O₂ in optimal concentration of 75 μM for 24, 48, or 72 h. The time-dependent changes in the expression of PGC-1α, NRF1, NRF2, ATP-5α, and TFAM in neurons damaged by H₂O₂-induced oxidative stress were analyzed by Western blotting. The ROS level in damaged neurons, the value of mitochondrial membrane potential (MMP), permeability of mitochondrial permeability transition pores (MPTP), and apoptosis of neurons were analyzed by flow cytometry. Analysis of PPI network showed that transcriptional coactivator PGC-1α is the key regulator of energy metabolism in the cortical neurons, while NRF1 and NRF2 play important roles in mitochondrial biogenesis and in the response to oxidative stress. TFAM is required for basal transcription of mitochondrial DNA, and it is a hub gene in PGC-1α/NRF1/NRF2 pathway. Western blotting and flow cytometry showed that during the development of oxidative stress, PGC-1α activated the expression of NRF1, NRF2, and TFAM and simultaneously prevents MPP loss and MPTP opening. At this, NRF1/NRF2 diminished ROS level and reduced apoptosis, while TFAM enhanced expression of ATP-5α. Therefore, PGC-1α exerts the antioxidant and antiapoptotic effects in cortical neurons exposed to oxidative stress via activation of NRF1/NRF2/TFAM signal pathway.

We studied cardiac relaxation disorders on a rat model of DOX-induced cardiomyopathy (DOX, 2 mg/kg/week for 2 weeks). Left ventricular pressure and volume were synchronously recorded in vivo at baseline and under increased doses of dobutamine (DBA, 1-32 μg/kg/min). Left ventricular diastolic stiffness constants were calculated; the dose dependence of HR and isovolumic relaxation time (tau) was evaluated. In rats with cardiomyopathy, the diastolic stiffness constants increased with increasing the DBA doses, which was absent in the control; HR and tau showed opposite changes. The mean angular coefficient of linear trends in the dose dependence of stiffness constants on infusion was 2.98 × 10^-4 in rats with cardiomyopathy and -0.014 × 10^-4 in control animals. Thus, DOX cardiomyopathy led to an increase in the diastolic stiffness constants against the background of DBA treatment.

We studied the effects of 5- and 10-fold intragastric administration of a suspension and an extract of the cyanobacterium Leptolyngbya cf. ectocarpi on the parameters of protein (total protein, albumin, and urea), lipid (triglycerides and cholesterol), cholesterol, glucose, purine (uric acid), and lipoprotein (HDL and LDL) metabolism and on activities of liver transaminases (ALT and AST) in the serum of female C56Bl/6 mice. Changes in the metabolic profile of the mouse blood serum have been shown to be influenced by the frequency of administration and the intensity of lighting of the cyanobacterium culture.

Using high-cancer CBA mice we showed that regulation of the expression of β2 leukocyte integrins LFA-1 and Mac-1 on peripheral blood cells, serum levels of IL-6 and IL-10, and number of dopaminergic neurons in combination with CD8⁺ lymphocyte infiltration of the tumor and destruction of tumor nodes after preventive administration of a multiphytoadaptogen during the early ontogeny substantially affects the incidence and size of spontaneous hepatocarcinomas and increases the duration and quality of life.

A murine model of endometriosis was employed to evaluate the pharmacological efficacy of therapeutic compounds. Endometriosis was modeled by autotransplantation of uterine horn fragments onto the intestinal mesentery in three experimental paradigms: 1) with subcutaneous administration of estradiol; 2) a short-term protocol without estradiol; 3) a prolonged protocol without estradiol and with delayed administration of the test compound. In all animals, well-demarcated, rounded endometriotic lesions (endometriomas) were consistently observed at the implantation sites. Endoferin demonstrated its highest efficacy under the short-term, hormone-free protocol. The administration of exogenous estradiol interfered with the manifestation of the pharmacological activity of the test drug. Thus, a rapid in vivo method for assessing the therapeutic efficacy of candidate drugs was developed.

Although statins are among the most frequently prescribed drugs worldwide, their effect on the electrical activity of the heart, especially under chronic exposure, is poorly studied. We analyzed changes in the main repolarizing potassium currents in ventricular cardiomyocytes isolated from mice under chronic atorvastatin exposure. The mice received atorvastatin in drinking water at a dose of 10 mg/kg for 1 month. The whole-cell patch-clamp measurements showed an increase in the ultrarapid delayed rectifier potassium current I_Kur in the experimental group of mice (by ~40% in comparison with the control), with no changes in the transient outward potassium current I_to and the inward rectifier potassium current I_K1. No differences in the action potential configuration were revealed, which suggests possible changes in depolarizing currents under the influence of atorvastatin.

Outbred male Wistar rats underwent coronary artery occlusion (45 min) followed by reperfusion (120 min), and the infarct size to area at risk (IS/AAR) ratio was determined. For 8 days prior to coronary occlusion, rats were subcutaneously administered octreotide at doses of 20 and 40 μg/kg. In the control group rats, the levels of endogenous somatostatin were measured before occlusion and at the 120th minute of reperfusion. Preventive administration of 40 μg/kg octreotide reduced the levels of creatine kinase-MB (CK-MB) and infarct size by decreasing the necrosis area. Octreotide at a dose of 20 μg/kg produced no infarct-limiting effect. Control animals exhibited increased endogenous somatostatin levels by the end of reperfusion (in comparison with baseline), which negatively correlated with CK-MB levels.

Using in vivo microscopy, changes in the diameter of pial arterial microvessels were studied in rats with modeled moderate acute blood loss followed by whole-body cooling against the background of a single administration of tranexamic acid at a dose of 10 mg/kg. The antifibrinolytic agent enhanced vasoconstrictor responses of the arterioles during deep cooling, but had no significant effect at the stages of mild and moderate hypothermia.

Metabolic syndrome weakens the cardioprotective effect of adaptation to chronic continuous hypoxia (CCH). Here we studied the relationship between this weakening and leptin receptor expression. Wistar rats were maintained on a high-fat high-carbohydrate diet for 84 days to model metabolic syndrome and subjected to CCH for 21 days at 12% O₂. Ischemia/reperfusion was modeled by occlusion of the left coronary artery (45 min) followed by reperfusion (2 h). The Ca²⁺-retention capacity of myocardial mitochondria was assessed. Metabolic syndrome increased leptin receptor expression in the myocardium by 46% and reduced the cardioprotective effect of CCH. Metabolic syndrome reduced Ca2+-retention capacity in both non-adapted and adapted to CCH rats. Leptin receptor expression showed an inverse correlation with Ca²⁺-retention capacity (r = -0.63, p < 0.0001) and a direct correlation with the level of creatine kinase-MB (r = 0.32; p = 0.03). It is assumed that increased expression of leptin receptor in the myocardium of rats with metabolic syndrome plays an important role in weakening of the mechanisms of cardioprotective effects of adaptation to CCH.

The serum levels of oxidative stress marker, ischemia-modified albumin (IMA) were studied in healthy young (18-49 years), middle-aged (51-68 years), elderly and older (73-99 years) people. The content of IMA was measured using albumin cobalt binding assay. In addition, the IMA/albumin ratio (IMAR) was calculated. The content of IMA was elevated in the elderly individuals in comparison with the other two age groups (p < 0.05). Similar changes were observed for IMAR (p < 0.01). A positive correlation was established between the levels of IMA, IMAR, and age in the total group of volunteers (r = 0.308, p < 0.05 and r = 0.412, p < 0.01, respectively). The results show that oxidative modification of serum albumin increases with age.