The Journal “Toksikologicheskiy vestnik” (Toxicological Review)
Four polymorphic GABRA2 gene variations: rs105733011, rs8168342, rs198286814, rs198837638 that can influence the formation of different biological effects of the organism when exposed to ethanol have been investigated. For rs105733011 polymorphism the frequency of occurrence of the CT genotype was found to be significantly higher (p < 0,05) among animals with «severe intoxication» – 37,0% than with «mild intoxication» – 14,0%. For rs198286814 polymorphism the tendency to the most frequent occurrence of the AG genotype in the group of animals with «severe intoxication» was established. Significant differences in the distribution of occurrence frequencies of the GG/AG genotypes in the studied groups for polymorphic loci rs8168342 and rs198837638 were not revealed. It was concluded that the rs105733011 polymorphism can be one of the genetic markers allowing to predict the degree of inhibitory action of ethanol in acute alcohol intoxication.
Keywords: intoxication, GARBA2 gene, genetic polymorphism, ethanol
An elemental analysis of the Tsarina Anastasia Romanovna hair fragments from the Moscow Kremlin necropolis has been carried out. The mass fractions of elements were determined by several methods: neutron activation analysis (using three facilities – the IBR-2 reactor, the IREN research facility, Joint Institute for Nuclear Research, Russia; and the WWR-K reactor, Institute of Nuclear Physics, Republic of Kazakhstan), inductively coupled plasma mass spectrometry, and atomic emission spectroscopy (Institute of Nuclear Physics, Republic of Kazakhstan). The results confirmed the hypothesis of mercury poisoning of the first Russian Tsarina Anastasia Romanovna.
Keywords: elemental composition, hair, Middle Ages, neutron activation analysis, inductively coupled plasma mass spectrometry, atomic emission spectroscopy
When modeling myeloablation cytostatic chemotherapy with cyclophosphamide in rats fulminant hyperammonemia was observed accompanied by an increase in the content of ammonia and glutamine, a decrease in the content of pyruvic and lactic acids in brain tissue. A positive correlation between the indicators of azotemia and the content of ammonia and glutamine in brain tissue was established. In loading test with ammonium acetate changes in the chemical composition of blood and brain tissue were more pronounced. The data obtained indicate the intensification of the intake of gastrointestinal ammonia into the brain from the blood, which leads to the depletion of the tissue pool of pyruvate with the introduction of cyclophosphane in doses used for myeloablation. Such changes create the conditions for disruption of energy supply of neurological functions during myeloablative cytotoxic chemotherapy using cyclophosphamide.
Keywords: cyclophosphamide, myeloablation regime, azotemia, brain, ammonia, glutamine, pyruvate, lactate
The effect of aryl hydrocarbon receptor agonists (FICZ and ITE), as well as lipopolysaccharide under the toxic action of benzo(a)pyrene in HepaRG human hepatoma cells was evaluated. Active forms of the key stress-activated kinase cascades and DNA repair system proteins were used as markers of the genotoxic action of benzo(a)pyrene. A mixture of lipopolysaccharide with benzo(a)pyrene increases benzo(a)pyrene cytotoxicity and reduces the activation of DNA repair system proteins below the control level. Aryl hydrocarbon receptor agonists (FICZ and ITE) exhibit a cytoprotective effect against benzo(a) pyrene, enhance Akt1 kinase activation, and downregulate activation of the p53 protein and Chk1 and Chk2 checkpoint kinases. Thus, FICZ and ITE reduce the genotoxicity of benzo(a)pyrene.
Keywords: polyaromatic hydrocarbons, benzo(a)pyrene, aryl hydrocarbon receptor, HepaRG, NF-kappaB, genotoxicity
One of the urgent tasks of clinical toxicology is the development of therapy aimed at stoichiometric and/or catalytic detoxification of organophosphorus compounds in the bloodstream, which will prevent the poison’s entering the neuromuscular and neuronal synapses and help to avoid irreversible consequences of poisoning. An auxiliary option for the detoxification of organophosphorus compounds in the bloodstream may be a directed effect on albumin, the main transport protein of the blood, by means of molecules modulating its binding and/or esterase properties. The aim of the present study is to evaluate the effect of fatty acids on the binding and esterase activity of human albumin to organophosphorus compounds by molecular modeling methods on the example of paroxone and oleic acid. According to the data obtained, an increased concentration of fatty acids in the blood reduces the likelihood of paraoxon binding to albumin and pseudo-esterase reaction.
Keywords: human serum albumin, organophosphorus compounds, fatty acids, molecular modeling
The paper presents data on changes in model biomembranes (liposomes, erythrocyte shadows, erythrocytes) used as test objects to determine those ranges of concentrations of biologically active substances in which there is no violation of the structure or function of experimental objects. Melaphene, plant growth regulator used in small doses in seed pre-treatment, and antioxidant phenosan derivatives, phenoxane and IHFANs, have been used as biologically active substances. It was shown by DSC that phenosan derivatives at concentrations equal to 10-5 M and higher destroy the microdomain organization in the bilayers of phospholipid multilamellar liposomes and reshape protein microdomains in the shadows of red blood cells. Melaphene in small and large concentrations changes polymodal the microdomain organization in the bilayers of phospholipid multilamellar liposomes without destroying the structure and does not affect the protein microdomains in the shadows. An increase in the membrane permeability in isolated intact erythrocytes in the presence of melaphene in large and small concentrations has been revealed by means of spectral anaslysis. The method of small-angle diffraction scattering showed the absence of the effect of melaphene in a wide range of concentrations on the thickness of phospholipid bilayers and the order of their packaging in multilamellar liposomes.
Keywords: phospholipids, multilamellar liposomes, biologically active substances, erythrocyte shadows, erythrocytes, DSC, small-angle diffraction scattering
The article on the basis of an analysis of the literature discusses promising areas for the development of antidote prophylaxis and treatment of acute cyanide poisoning. The chemical compounds mediating anticyanide activity by stimulating the main detoxification mechanisms of endogenous cyanide: sulfangen, cobinamide, α-ketoglutaric acid claimed to be potential cyanide antidotes, effective and safe for intramuscular and intraosseous injections, inhalation and oral administration.
Keywords: antidotes, detoxification, cobinamide, toxicity, sulfangen, cyanide, α, -ketoglutaric acid
Receptors associated with trace amines, 1st subtype (TAAR1), are the promising targets for the development of new pharmacological approaches to the treatment of various neuropsychiatric disorders. Currently TAAR1 agonists are undergoing clinical trials as new pharmacologically active agents with antipsychotic action. At the same time, the expression of TAAR1 and the physiological significance of these receptors as regulators of the activity of catecholaminergic structures in the Central nervous system suggest that the activation of TAAR1 can have a therapeutic effect in patients suffering from mental diseases such as obsessive-compulsive disorder and attention deficit hyperactivity disorder, which are accompanied by violations of impulsive and compulsive control. This paper is an attempt to critically evaluate the currently existing data set obtained during testing of TAAR1 ligands in in vivo studies over the past 5 years. The analysis suggests that TAAR1 agonists may provide and have a limited anti-compulsive effect when used in the clinic.
Keywords: TAAR1, ADHD, OCD, dopamine, serotonin, preclinical studies
The resorptive effects of 0.01 M cerium nanodioxide sol upon single intraperitoneal administration to rats have been studied. The acute exposure to nanoparticles was found to have a dose-dependent general toxic effect on the body (weight loss, inflammatory changes in the abdominal organs, modification of individual behavior, hematological changes, metabolic imbalance), which develops on the background of POL activation. The prooxidant effect of cerium dioxide nanoparticles is demonstratively manifested at relatively high exposure levels (80–8 mg / kg). The threshold dose for the general toxic effect (Limch integr) is equal to 0.8 mg / kg.
Keywords: cerium dioxide nano, rats, acute toxicity, prooxidant action, antioxidant action