Hepatotoxic Effects of Acetaminophen. Protective Properties of Tryptophan Derivatives

Rat intoxication with acetaminophen (APAP) (500–1500 mg/kg body weight, intragastrically) caused a considerable dose dependent decrease in reduced glutathione (GSH) level in both liver cell cytoplasm and mitochondria (at the dose 1500 mg/kg body weight by 60% and 33%, respectively). The decrease in cytoplasmic GSH level was more pronounced than in mitochondria. Despite of significant mitochondrial GSH depletion we did not observe any inactivation of the mitochondrial enzymes: succinate dehydrogenase, α-ketoglutarate dehydrogenase, glutathione peroxidase, and also any decrease in the respiratory activity of liver mitochondria isolated from APAP-intoxicated rats. We have investigated hepatoprotector properties of tryptophan derivatives, melatonin and N-acetyl-nitrosotryptophan (a nitric oxide donor). The pineal gland hormone, melatonin, a known antioxidant (10 mg/kg body weight), did not prevent intramitochondrial GSH, but decreased the APAP hepatotoxicity evaluated as the decrease in the activity of marker enzymes of hepatic damage, ALT and AST and total bilirubin content in blood plasma of intoxicated rats, whereas NNT did not exhibit any hepatoprotective effects

Rat Liver Mitochondria Impairment under Acute Carbon Tetrachloride-Induced Intoxication. Effects of Melatonin

The aim of the present work was to investigate the mechanisms of oxidative damage of rat liver mitochondria in vitro, under hypochlorous acid (HOCl) induced oxidative stress, and in vivo, under acute carbon tetrachloride-induced intoxicationin rats. Hypochlorous acid (50–300 µM), the main inflammatory agent, inhibited liver mitochondria respiratory activityand caused uncoupling in the respiratory and phosporylation processes. The toxic damage of rat liver after 24 h of acute carbon tetrachloride induced intoxication (4 g/kg, intragastrically) was accompanied by a significant reduction in succinate- and glutamate-depen-dent respiration rate in state 3 (by 65%, p< 0.001, and by 50%, p< 0.01, respectively). The respiration control ratio approached 1, reflecting the loss of respirationcontrol. The phosphorylation coefficient significantly decreased due to uncoupling of the oxidation and phosphorylation processes. The mitochondrial alterations were associated with oxidation of intramitochondrial GSH by 25% (p< 0.05), the marked inhibition of succinate dehydrogenase (complex II) by 35% (p< 0.05), and the rise of blood plasma nitric oxide level by 45% (p< 0.05). The impairment of mitochondrial respiratory function may result from the inhibition of enzymatic activities in the respiratory chain and the damage of mitochondrial membrane during intoxication and plays a key role in the development of the CCl4-induced hepatotoxicity. Melatonin administration under CCl4-induced intoxication (three times at a dose of 10 mg/kg)increased the rate of succinate oxidation in state 3 by 30% (p< 0.05) and reversed the increase in glutathione peroxidase activity. Melatonin prevented an elevation of nitric oxide level in the blood plasma of intoxicated animals but did not protect mitochondrial functions under acute intoxication

Benfotiamine improves functional recovery of the infarcted heart via activation of pro-survival G6PD/Akt signaling pathway and modulation of neurohormonal response

Benfotiamine (BFT) is a transketolase activator that directs glucose to the pentose phosphate pathway. The present study investigated whether BFT improves the recovery after myocardial infarction (MI) and explored underlying mechanisms of protection. Non-diabetic and streptozotocin-induced type 1 diabetic mice were supplemented with BFT (70 mg/kg/day in drinking water) for 4 weeks and then subjected to MI or sham operation. Cardiac function was monitored by echocardiography. At two weeks post-MI, intra-ventricular pressure was measured by Millar tip-catheter and hearts were collected for biochemical, immunohistochemical and expressional analyses. No treatment effect was observed in sham-operated mice. Post-MI mortality was higher in diabetic mice and hemodynamic studies confirmed the worsening effect of diabetes on functional recovery. Furthermore, diabetic mice demonstrated increased cardiomyocyte apoptosis, reduced reparative angiogenesis, larger scars, enhanced oxidative stress, and blunted activation of the pro-survival VEGF receptor-2/Akt/Pim-1 signaling pathway. BFT improved post-MI survival, functional recovery and neovascularization and reduced cardiomyocyte apoptosis and neurohormonal activation in diabetic as well as in non-diabetic mice. In addition, BFT stimulated the activity of pentose phosphate pathway enzymes, leading to reduction of oxidative stress, phosphorylation/activation of VEGF receptor-2 and Akt and increased Pim-1, pBad and Bcl-2 levels. These effects were contrasted on silencing glucose-6-phosphate dehydrogenase, the key enzyme in pentose phosphate pathway, or inhibiting Akt. BFT benefits post-MI recovery through stimulation of pro-survival mechanisms and containment of neurohormonal response. These results may have implications for the treatment of myocardial ischemia

Neuropeptides, Trophic Factors, and Other Substances Providing Morphofunctional and Metabolic Protection in Experimental Models of Diabetic Retinopathy

Vision is the most important sensory modality for many species, including humans. Damage to the retina results in vision loss or even blindness. One of the most serious complications of diabetes, a disease that has seen a worldwide increase in prevalence, is diabetic retinopathy. This condition stems from consequences of pathological metabolism and develops in 75% of patients with type 1 and 50% with type 2 diabetes. The development of novel protective drugs is essential. In this review we provide a description of the disease and conclude that type 1 diabetes and type 2 diabetes lead to the same retinopathy. We evaluate existing experimental models and recent developments in finding effective compounds against this disorder. In our opinion, the best models are the long-term streptozotocin-induced diabetes and Otsuka Long-Evans Tokushima Fatty and spontaneously diabetic Torii rats, while the most promising substances are topically administered somatostatin and pigment epithelium-derived factor analogs, antivasculogenic substances, and systemic antioxidants. Future drug development should focus on these

Technical innovations as a means of increasing the efficiency of technological equipment in modern production conditions

This article presents a study of the possibilities of technological equipment in municipal engineering, as well as technical innovations to improve its efficiency. The authors review the research on a hydraulic mode and resistances in a working body of a technological equipment. The research results are determined by the introduction of new technical solutions aimed at increasing the efficiency in the work of the Vodokanal enterprises. Improvement of technological equipment is as a result of the improved working conditions in the process of the water disposal system operation

Extensible Battle Management Language as a Transformation Enabler

This paper addresses a new approach to the longstanding problem of interoperating military command and control with combat simulations. There is great potential benefit in such a capability, both for more effective training and as a “what if ” capability during military operations. We describe the Battle Management Language, an unambiguous means of describing military operations to people, simulations, and robotic forces. The process that developed the BML and its extension into the realm of Web services are described. The new capability is projected to be an enabler for the ongoing Transformation activities in the US Department of Defense. Integrated with the Command and Control Information Exchange Data Model (C2IEDM), BML as extended through We

04E-SIW-064 – Page 1 of 11 Developing Extensible Battle Management Language to Enable Coalition

ABSTRACT: Command and Control (C2) communication in a network centric environment is postulated to be data intensive. However, the most critical C2 information, the commander’s intent, orders and directives, does not currently flow as data. It is communicated as “free text ” elements within messages or as stand-alone files. While suitable for interpersonal communication, it is inadequate for use with simulations, or for the future forces that have robotic components. As commanders increasingly rely upon simulation-based decision aids (and therefore use their C2 devices to control simulations) a solution for this “free text ” problem must be found. Battle Management Language (BML) was developed as a solution to this problem. BML is defined as the unambiguous language used to: 1) command and control forces and equipment conducting military operations and, 2) provide for situational awareness and a shared, common operational picture. It can be seen as a representation of a digitized commander’s intent to be used for real troops, for simulated troops, and for future robotic forces. Based on this concept, the U.S. Army developed a prototype of BML demonstrating an actual National Training Center (NTC) Brigade Operations Order. The US Defense Modeling and Simulation Office’s (DMSO) Extensible M&amp;S Framework (XMSF) initiative has started with this BML prototype (consisting of a future US Army C2 System and a US Army Entity Level Simulation) is transforming it into a joint and coalition solution (using a Join