The roles of hyperglycaemia and oxidative stress in the rise and collapse of the natural protective mechanism against vascular endothelial cell dysfunction in diabetes.

Vascular endothelial cell (VEC) dysfunction in diabetes has been associated with hyperglycaemia-induced intra- and extracellular glycation of proteins and to overproduction of glucose-derived free radicals. VEC protect their intracellular environment against an increased influx of glucose in face of hyperglycaemia by reducing the expression and plasma membrane abundance of their glucose transporter-1 (GLUT-1). We investigated the hypothesis that glucose-derived free radicals induce this down-regulatory mechanism in VEC, but proved the contrary. In fact, pro-oxidants significantly increased the expression and plasma membrane abundance of GLUT-1 and the rate of glucose transport in VEC while abolishing high-glucose-induced down-regulation of the hexose transport system. The resulting uncontrolled influx of glucose followed by overproduction of glucose-derived ROS further up-regulates the rate of glucose transport, and vice versa. This perpetuating glycoxidative stress finally leads to the collapse of the auto-regulatory protective mechanism and accelerates the development of dysfunctional endothelium in blood vessels.

[Carbohydrate metabolism in the brain in comatose states]. / Uglevodnyi obmen v golovnom mozge pri komatoznykh sostoianiiakh.

The article confirms an earlier discovered phenomenon that during comas and in post-coma periods the brain releases glucose and consumes lactate. It is suggested that the phenomenon is based on glucogenesis taking place in the brain from non-carbohydrate glucose precursors, which is phylogenetically predetermined and biologically expedient.

[Carbohydrate metabolism in the brain in comatose states. Mechanisms of gluconeogenesis]. / Uglevodnyi obmen v golovnom mozge pri komatoznykh sostoianiiakh. Mekhanizmy gliukoneogeneza.

Glucose release and lactate uptake by the brain during coma is discussed. A hypothesis of autonomous gluconeogenesis in the brain is suggested. To substantiate the hypothesis use is made of the literature data on the presence in the brain of stimuli, and its provision with substrates and gluconeogenetic enzyme apparatus. Special attention is paid to the problem of gluconeogenesis energy supply during hypoxia, using proton or sodium potentials.

Benzothiazole derivatives augment glucose uptake in skeletal muscle cells and stimulate insulin secretion from pancreatic ß-cells via AMPK activation.

Adenosine monophosphate-activated protein kinase (AMPK) has been identified as one of the major targets for antidiabetic drugs. This study describes two AMPK-activating agents 2-(benzo[d]thiazol-2-ylmethylthio)-6-ethoxybenzo[d]thiazole and 2-(propylthio)benzo[d]thiazol-6-ol, that increase the rate of glucose uptake in L6 myotubes and also augment glucose-stimulated insulin secretion in INS-1E ß-cells and rat islets. We believe that such unique bi-functional compounds can be further used for the development of a new class of antidiabetic drugs.

Cyclooxygenase-2 (PTGS2) inhibitors augment the rate of hexose transport in L6 myotubes in an insulin- and AMPKalpha-independent manner.

AIMS/HYPOTHESIS: Some cyclooxygenase-2 (COX2, also known as prostaglandin-endoperoxide synthase 2 [PTGS2]) inhibitors have been shown to increase insulin sensitivity in man or induce hypoglycaemic episodes when overconsumed or taken in combination with oral hypoglycaemic drugs. These side-effects and their impact on patients are not always recognised in routine clinical practice. We investigated whether these side-effects of COX2 (PTGS2) inhibitors result from stimulation of the glucose transport system in skeletal muscle cells. MATERIALS AND METHODS: L6 myotube cultures were used to study effects of COX2 (PTGS2) inhibitors on the glucose transport system and their relationship to PTGS2 expression, insulin action and AMP-activated protein kinase alpha (AMPKalpha) activity. RESULTS: The inhibitors niflumic acid, nimesulide and rofecoxib increased the rate of hexose uptake in L6 myotubes in the absence of insulin and in a dose- and time-dependent manner. They did this by increasing the total cell content of member 4 of the solute carrier family 2 (SCLC2A4, previously known as glucose transporter 4 [GLUT4]) (but not SCLC2A1 [previously known as GLUT1]) mRNA and protein and the amount of it in the plasma membrane. AMPKalpha was not involved in the latter effect since the inhibitors did not activate it. In addition, none of the inhibitors modulated the rate of hexose transport in vascular endothelial and smooth muscle cells expressing PTGS2 and SCLC2A1. Prostaglandin-endoperoxide synthase 1 (also known as cyclooxygenase 1) inhibitors (acetylsalicylic acid and indomethacin) did not alter the rate of hexose uptake and SCLC2A4 subcellular distribution in L6 myotubes. CONCLUSIONS/INTERPRETATION: This study suggests that certain COX2 (PTGS2) inhibitors can alter glucose homeostasis in vivo by stimulating glucose uptake in skeletal muscles that express PTGS2.

Delayed autoregulation of glucose transport in vascular endothelial cells.

AIMS/HYPOTHESIS: We aimed to characterise the development of autoregulation of glucose transport in vascular endothelial cells and its relationship to 12-lipoxygenase (12-LO) expression. METHODS: Bovine aortic endothelial cells were exposed to 5.5 and 23.0 mmol/l glucose for up to 48 h. The rates of glucose transport, GLUT-1 and 12-LO expression and of 12-hydroxyeicosatetraenoic acid (12-HETE) production were determined. RESULTS: We showed high glucose-dependent downregulation of glucose transport and transporter in vascular endothelial cells within 36-48 h. A similar time-dependent increase in the expression of 12-LO and the generation of its product 12-HETE was also observed. This downregulatory process was prevented when lipoxygenase activity was inhibited. CONCLUSIONS/INTERPRETATION: Vascular endothelial cells, which were previously thought to be "glucose-blind", do in fact downregulate GLUT-1 expression and the rate of glucose transport in response to extended exposure to high glucose concentrations. This slow development of glucose-induced downregulation in vascular endothelial cells is related to the slower basal rate of glucose transport in these cells and the slow induction of 12-LO. These data are interesting in view of current hypotheses that attribute vascular endothelial cell dysfunction in diabetes to the lack of a glucose-induced autoregulatory response.

[The treatment of nocturnal enuresis in children]. / Lechenie nochnogo énuireza u detei.

367 children with nocturnal enuresis (NE) were divided into randomly selected groups. Two groups were treated with amitriptylin (the 1st group) or imipramine (the 2nd one). In the third group the treatment was differentiated and depended on coexist clinical sleep disturbances. In such cases there were used according to indications amitriptylin (including in combination with cyclodol), imipramine, diazepam. Additionally nootropic drugs (pyracetam, pantogam) were also administrated. In 3 month after the treatment 68.3% of the patients of the 3rd group still had complete remission. These results were better then in the 1st (20.9%) and in the 2nd (45.6%) groups of patients in which the treatment of NE was not depended on coexist disturbances.

[Organization of intensive therapy of eclampsia and eclamptic coma]. / Voprosy organizatsii intensivnoi terapii pri éklampsii i éklampticheskoi komie.

This is an overview of counselling, medical and methodological assistance given to obstetric facilities of the Moscow region during 10 years. It is concluded that regional obstetric-gynecologic centers should be established, which incorporate an intensive care unit and a mobile resuscitation team.

Eicosanoids participate in the regulation of cardiac glucose transport by contribution to a rearrangement of actin cytoskeletal elements.

Intact actin microfilaments are required for insulin-regulated glucose transporter isoform 4 (GLUT4) translocation to the plasma membrane. Lipoxygenase (LO) metabolites have recently been shown to contribute to the regulation of actin cytoskeleton rearrangement. In the present investigation, ventricular cardiomyocytes were used to study the effects of two structurally different LO inhibitors (esculetin and nordihydroguaiaretic acid) on insulin signalling events, glucose uptake, GLUT4 translocation and the actin network organization. Insulin stimulation increased glucose uptake 3-fold in control cells, whereas LO inhibition completely blocked this effect. This was paralleled by a slight reduction in the insulin-induced tyrosine phosphorylation of insulin receptor substrate (IRS)-1 and IRS-2. However, inhibition of 12-LO did not affect the association of phosphatidylinositol 3-kinase with IRS-1 and the phosphorylation of Akt/protein kinase B in response to insulin. Addition of 12(S)-hydroxyeicosatetraenoic acid almost completely restored the insulin action in cells exposed to nordihydroguaiaretic acid. Insulin stimulation increased cell surface GLUT4 2-fold in control cells, whereas LO inhibition abrogated the insulin-stimulated GLUT4 translocation. LO inhibition induced a prominent disassembly of actin fibres compared with control cells. In conclusion, we show here that 12(S)-hydroxyeicosatetraenoic acid plays a role in the organization of the actin network in cardiomyocytes. LO inhibition blocks GLUT4 translocation without affecting downstream insulin signalling. These data suggest that LO metabolites participate in the regulation of glucose transport by contributing to a rearrangement of actin cytoskeletal elements.

Residual pneumoperitoneum: a cause of postoperative pain after laparoscopic cholecystectomy.

After laparoscopic cholecystectomy, residual gas is inevitably retained in the peritoneal cavity. An active attempt is not always made to remove it. Using a double-blind prospective protocol in 40 healthy patients, we evaluated the effect of residual pneumoperitoneum on post-laparoscopic cholecystectomy pain intensity. On completion of surgery, prior to removal of the surgical instruments, the patients were randomly divided into two groups: in the active aspiration (AA) group an active attempt was made to remove as much gas as possible from the peritoneal cavity, while in the nonactive aspiration (NAA) group no such effort was made. Postoperative pain was assessed hourly over a 4-h period with a visual analog scale (VAS) and a patient-controlled analgesia (PCA) device. During the first postoperative hour, the NAA patients made significantly (P < 0.05) more demands (mean +/- SD) for morphine than those in the AA group (31.3 +/- 26.2 vs 15.3 +/- 15.7) and also received a borderline significantly (P = 0.056) larger dose (mean +/- SD) of PCA morphine (3.9 +/- 1.9 mg vs 2.7 +/- 1.3 mg). The VAS scores (mean +/- SD) over the 4-h study period were similar in both groups, being high during the first postoperative hour (AA = 5.1 +/- 2.1 vs NAA = 6.1 +/- 2.2) and then decreasing. We conclude that residual pneumoperitoneum is a contributing factor in the etiology of postoperative pain after laparoscopic cholecystectomy.

Amelioration of TNBS-induced colon inflammation in rats by phospholipase A2 inhibitor.

The pathophysiology of inflammatory bowel disease (IBD) involves the production of diverse lipid mediators, namely eicosanoids, lysophospholipids, and platelet-activating factor, in which phospholipase A2 (PLA2) is the key enzyme. Accordingly, it has been postulated that control of lipid mediator production by inhibition of PLA2 would be useful for the treatment of IBD. This hypothesis was tested in the present study by examining the therapeutic effect of a novel extracellular PLA2 inhibitor (ExPLI), composed of carboxymethylcellulose-linked phosphatidylethanolamine (CMPE), on trinitrobenzenesulfonic acid-induced colitis. Intraperitoneal administration of CMPE suppressed the colitis as measured by mortality rate, intestinal permeability, plasma PLA2 activity, intestinal myeloperoxidase activity, and histological morphometry. Current therapeutic approaches for inflammatory conditions focus on the selective control of a lipid mediator(s) (e.g., prostaglandins or leukotrienes). The present study supports the concept that inclusive control of lipid mediator production by PLA2 inhibition is a plausible approach to the treatment of colitis and introduces the ExPLIs as a prototype of a novel NSAID for the treatment of intestinal inflammation.