Neuropathy target esterase in mouse whole blood as a biomarker of exposure to neuropathic organophosphorus compounds

The adult hen is the standard animal model for testing organophosphorus (OP) compounds for organophosphorus compound‐induced delayed neurotoxicity (OPIDN). Recently, we developed a mouse model for biochemical assessment of the neuropathic potential of OP compounds based on brain neuropathy target esterase (NTE) and acetylcholinesterase (AChE) inhibition. We carried out the present work to further develop the mouse model by testing the hypothesis that whole blood NTE inhibition could be used as a biochemical marker for exposure to neuropathic OP compounds. Because brain NTE and AChE inhibition are biomarkers of OPIDN and acute cholinergic toxicity, respectively, we compared NTE and AChE 20‐min IC50 values as well as ED50 values 1 h after single intraperitoneal (i.p.) injections of increasing doses of two neuropathic OP compounds that differed in acute toxicity potency. We found good agreement between the brain and blood for in vitro sensitivity of each enzyme as well for the ratios IC50(AChE)/IC50(NTE). Both OP compounds inhibited AChE and NTE in the mouse brain and blood dose‐dependently, and brain and blood inhibitions in vivo were well correlated for each enzyme. For both OP compounds, the ratio ED50(AChE)/ED50(NTE) in blood corresponded to that in the brain despite the somewhat higher sensitivity of blood enzymes. Thus, our results indicate that mouse blood NTE could serve as a biomarker of exposure to neuropathic OP compounds. Moreover, the data suggest that relative inhibition of blood NTE and AChE provide a way to assess the likelihood that OP compound exposure in a susceptible species would produce cholinergic and/or delayed neuropathic effects. Copyright © 2016 John Wiley & Sons, Ltd.The adult hen is the standard animal model for testing organophosphorus (OP) compounds for organophosphorus compound‐induced delayed neurotoxicity (OPIDN). Recently, we developed a mouse model for the biochemical assessment of the neuropathic potential of OP compounds based on brain neuropathy target esterase (NTE) and acetylcholinesterase (AChE) inhibition. The present work represents further development of the mouse model aimed at using whole blood NTE as a biomarker of exposure to neuropathic OP compounds and predicting OPIDN risk in susceptible species by comparing blood NTE and AChE inhibition.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/134102/1/jat3305.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/134102/2/jat3305_am.pd

Derivatives of 9-phosphorylated acridine as butyrylcholinesterase inhibitors with antioxidant activity and the ability to inhibit β-amyloid self-aggregation: potential therapeutic agents for Alzheimer’s disease

We investigated the inhibitory activities of novel 9-phosphoryl-9,10-dihydroacridines and 9-phosphorylacridines against acetylcholinesterase (AChE), butyrylcholinesterase (BChE), and carboxylesterase (CES). We also studied the abilities of the new compounds to interfere with the self-aggregation of β-amyloid (Aβ42) in the thioflavin test as well as their antioxidant activities in the ABTS and FRAP assays. We used molecular docking, molecular dynamics simulations, and quantum-chemical calculations to explain experimental results. All new compounds weakly inhibited AChE and off-target CES. Dihydroacridines with aryl substituents in the phosphoryl moiety inhibited BChE; the most active were the dibenzyloxy derivative 1d and its diphenethyl bioisostere 1e (IC50 = 2.90 ± 0.23 µM and 3.22 ± 0.25 µM, respectively). Only one acridine, 2d, an analog of dihydroacridine, 1d, was an effective BChE inhibitor (IC50 = 6.90 ± 0.55 μM), consistent with docking results. Dihydroacridines inhibited Aβ42 self-aggregation; 1d and 1e were the most active (58.9% ± 4.7% and 46.9% ± 4.2%, respectively). All dihydroacridines 1 demonstrated high ABTS•+-scavenging and iron-reducing activities comparable to Trolox, but acridines 2 were almost inactive. Observed features were well explained by quantum-chemical calculations. ADMET parameters calculated for all compounds predicted favorable intestinal absorption, good blood–brain barrier permeability, and low cardiac toxicity. Overall, the best results were obtained for two dihydroacridine derivatives 1d and 1e with dibenzyloxy and diphenethyl substituents in the phosphoryl moiety. These compounds displayed high inhibition of BChE activity and Aβ42 self-aggregation, high antioxidant activity, and favorable predicted ADMET profiles. Therefore, we consider 1d and 1e as lead compounds for further in-depth studies as potential anti-AD preparations

Вакцинопрофилактика пневмококковой инфекции у детей

Pneumococcal infection remains one of the leading reasons for infant mortality from vaccine-preventable infections. Today vaccination is the most effective way to prevent diseases caused by antibiotic-resistant pneumococci. In the article, authors present current approaches to vaccinal prevention of pneumococcal diseases. The plan of action for carrying out active immunoprophylaxis of pneumococcal infection is explained in detail for both healthy children and patients from risk groups for severe pneumococcal diseases development. The published work is based on key points of the guidelines of the Ministry of Health of the Russian Federation on vaccinal prevention of pneumococcal infection (developed and approved by the professional association of pediatricians «The Union of Pediatricians of Russia»).Пневмококковая инфекция остается одной из ведущих причин детской смертности от вакциноуправляемых инфекций. Вакцинация на сегодняшний день является наиболее эффективным направлением профилактики заболеваний, вызываемых устойчивыми к антибактериальным препаратам пневмококкам. В статье коллективом авторов представлены актуальные подходы к вакцинопрофилактике болезней пневмококковой этиологии. Подробно разъяснен алгоритм действий при проведении активной иммунопрофилактики пневмококковой инфекции как здоровых детей, так и пациентов из групп риска по развитию тяжелых форм пневмококковых заболеваний. Публикация основана на ключевых позициях методических рекомендаций Министерства здравоохранения РФ по вакцинопрофилактике пневмококковой инфекции (разработанных и утвержденных профессиональной ассоциацией детских врачей «Союз педиатров России»).КОНФЛИКТ ИНТЕРЕСОВАвторы статьи подтвердили отсутствие конфликта интересов, о котором необходимо сообщить

Mineral and chemical compositions of sedimentary and volcano-sedimentary rocks drilled in DSDP Legs 43 and 44

Sedimentary cover on the bottom of the Northwest Atlantic Ocean is underlain by Late Jurassic - Cretaceous tholeiite-basalt formation. It consists of come sedimentary formations with different lithologic features and age. Their composition, stratigraphic position and, distribution are described on materials of deep-sea drilling. Mineralogical and geochemical studies of DSDP Leg 43 and Leg 44 holes lead to new ideas about composition and genesis of some sediment types of and their associations. High metal contents in the chalk formation of black clays on the Bermuda Rise probably result from exhalations. Connection of red-colored and speckled deposits with hiatuses in sedimentation is shown. Main stages of geological history of the North American Basin are reflected in accumulation of the followed formations: ancient carbonate formation (Late Jurassic - Early Cretaceous), formation of black clays rich in organic matter (Cretaceous), formation of speckled clays (Late Cretaceous), siliceous-clayey turbidite formation (Eocene), hemipelagic and pelagic clayey formation (Neogene), and terrigenous turbidite formation (Pleistocene)

Study of Compatibility of Components of A New Combined Drug for Treatment of Alcoholic Intoxication and Its Hepatoprotective Effect on A Model of Alcoholic Liver Injury

The aim of the work is the development of a combined drug for use in alcohol intoxication based on the physicochemical properties and chemical compatibility of active pharmaceutical ingredients and excipients, and the study of the hepatoprotective effect in alcoholic hepatitis in rats. Materials and methods. During the studies, physical and physicochemical methods were used, a Specord 200 spectrophotometer (Germany), analytical scales Sartorius (SARTORIUS, Germany), class A volumetric glassware and reagents that meet the requirements of the State Pharmacopoeia of Ukraine (SPhU). Alcoholic hepatitis in rats was reproduced by intragastric administration of an aqueous 40% ethanol solution at a dose of 7 ml/kg for 1 week. Results. A new combined agent is proposed for use in alcohol intoxication in the form of an effervescent powder for the preparation of an oral solution, which contains glycine, L-glutamic acid, acetylsalicylic acid, ascorbic acid, fructose / sorbitol and sodium bicarbonate and citric acid to accelerate the dissolution of medicinal substances. To study the compatibility of the components, experimental studies of hygroscopicity, chemical interaction / chemical stability and an assessment of the redox potential of the proposed active pharmaceutical ingredients were carried out. To study the stability of the API, studies were carried out on sugaramine condensation due to the choice of amino acids and ascorbic acid in the composition of drugs. Based on the research results, it was decided to divide the API into 2 packages, separating sodium bicarbonate and glycine, which can interact with ascorbic acid / acetylsalicylic acid and ascorbic acid, respectively. In an in vivo experiment, it was found that the use of the new drug is accompanied by the normalization of the antioxidant-prooxidant status of the liver due to a likely decrease in the TBA-AP level and an increase in the RG index in the liver homogenate relative to the control group. Conclusions. Evaluation of the physicochemical properties of API allowed us to propose a new combined drug (TS-PP) for use in alcohol intoxication in the form of an effervescent powder for the preparation of oral solution. In alcoholic hepatitis in rats, it was found that the use of the studied drug largely prevents the formation of the effects of the toxic effects of ethanol on the rat organism, which is manifested by inhibition of destruction of hepatocyte membranes, a decrease in the level of LPO products, restoration of the RG index and improvement of the protein synthesizing function of the liver due to the complex effect of amino acids and ascorbic acid contained in the produc

Conjugates of Tacrine with Salicylamide as Promising Multitarget Agents for Alzheimer’s Disease

New conjugates of tacrine and salicylamide with alkylene spacers were synthesized and evaluated as potential multifunctional agents for Alzheimer’s disease (AD). The compounds exhibited high acetylcholinesterase (AChE, IC50 to 0.224 μM) and butyrylcholinesterase (BChE, IC50 to 0.0104 μM) inhibitory activities. They were also rather poor inhibitors of carboxylesterase, suggesting a low tendency to exert potential unwanted drug-drug interactions in clinical use. The conjugates were mixed-type reversible inhibitors of both cholinesterases and demonstrated dual binding to the catalytic and peripheral anionic sites of AChE in molecular docking that, along with experimental results on propidium iodide displacement, suggest their potential to block AChE-induced β-amyloid aggregation. The new conjugates exhibited high ABTS.+-scavenging activity. N-(6-(1,2,3,4-Tetrahydroacridin-9-ylamino)hexyl)salicylamide is a lead compound that also demonstrates metal chelating ability toward Cu2+, Fe2+ and Zn2+. Thus, the new conjugates have displayed the potential to be multifunctional anti-AD agents for further development.Conjugates of tacrine and salicylamide were synthesized as potential multifunctional anti-AD agents. The compounds have high anticholinesterase (IC50 AChE to 0.22 μM, IC50 BChE to 0.01 μM) and low anti-CES activity, displaced propidium iodide from the AChE PAS, being in agreement with the results of molecular docking. The conjugates exhibited ABTS+-scavenging (TEAC to 0.9) and metal-chelating activity.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/172840/1/cmdc202200080_am.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/172840/2/cmdc202200080.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/172840/3/cmdc202200080-sup-0001-misc_information.pd

Conjugates of Tacrine and Salicylic Acid Derivatives as New Promising Multitarget Agents for Alzheimer’s Disease

A series of previously synthesized conjugates of tacrine and salicylamide was extended by varying the structure of the salicylamide fragment and using salicylic aldehyde to synthesize salicylimine derivatives. The hybrids exhibited broad-spectrum biological activity. All new conjugates were potent inhibitors of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) with selectivity toward BChE. The structure of the salicylamide moiety exerted little effect on anticholinesterase activity, but AChE inhibition increased with spacer elongation. The most active conjugates were salicylimine derivatives: IC50 values of the lead compound 10c were 0.0826 µM (AChE) and 0.0156 µM (BChE), with weak inhibition of the off-target carboxylesterase. The hybrids were mixed-type reversible inhibitors of both cholinesterases and displayed dual binding to the catalytic and peripheral anionic sites of AChE in molecular docking, which, along with experimental results on propidium iodide displacement, suggested their potential to block AChE-induced β-amyloid aggregation. All conjugates inhibited Aβ42 self-aggregation in the thioflavin test, and inhibition increased with spacer elongation. Salicylimine 10c and salicylamide 5c with (CH2)8 spacers were the lead compounds for inhibiting Aβ42 self-aggregation, which was corroborated by molecular docking to Aβ42. ABTS•+-scavenging activity was highest for salicylamides 5a–c, intermediate for salicylimines 10a–c, low for F-containing salicylamides 7, and non-existent for methoxybenzoylamides 6 and difluoromethoxybenzoylamides 8. In the FRAP antioxidant (AO) assay, the test compounds displayed little or no activity. Quantum chemical analysis and molecular dynamics (MD) simulations with QM/MM potentials explained the AO structure–activity relationships. All conjugates were effective chelators of Cu2+, Fe2+, and Zn2+, with molar compound/metal (Cu2+) ratios of 2:1 (5b) and ~1:1 (10b). Conjugates exerted comparable or lower cytotoxicity than tacrine on mouse hepatocytes and had favorable predicted intestinal absorption and blood-brain barrier permeability. The overall results indicate that the synthesized conjugates are promising new multifunctional agents for the potential treatment of AD

Conjugates of Tacrine and Salicylic Acid Derivatives as New Promising Multitarget Agents for Alzheimer’s Disease

A series of previously synthesized conjugates of tacrine and salicylamide was extended by varying the structure of the salicylamide fragment and using salicylic aldehyde to synthesize salicylimine derivatives. The hybrids exhibited broad-spectrum biological activity. All new conjugates were potent inhibitors of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) with selectivity toward BChE. The structure of the salicylamide moiety exerted little effect on anticholinesterase activity, but AChE inhibition increased with spacer elongation. The most active conjugates were salicylimine derivatives: IC50 values of the lead compound 10c were 0.0826 µM (AChE) and 0.0156 µM (BChE), with weak inhibition of the off-target carboxylesterase. The hybrids were mixed-type reversible inhibitors of both cholinesterases and displayed dual binding to the catalytic and peripheral anionic sites of AChE in molecular docking, which, along with experimental results on propidium iodide displacement, suggested their potential to block AChE-induced β-amyloid aggregation. All conjugates inhibited Aβ42 self-aggregation in the thioflavin test, and inhibition increased with spacer elongation. Salicylimine 10c and salicylamide 5c with (CH2)8 spacers were the lead compounds for inhibiting Aβ42 self-aggregation, which was corroborated by molecular docking to Aβ42. ABTS•+-scavenging activity was highest for salicylamides 5a–c, intermediate for salicylimines 10a–c, low for F-containing salicylamides 7, and non-existent for methoxybenzoylamides 6 and difluoromethoxybenzoylamides 8. In the FRAP antioxidant (AO) assay, the test compounds displayed little or no activity. Quantum chemical analysis and molecular dynamics (MD) simulations with QM/MM potentials explained the AO structure–activity relationships. All conjugates were effective chelators of Cu2+, Fe2+, and Zn2+, with molar compound/metal (Cu2+) ratios of 2:1 (5b) and ~1:1 (10b). Conjugates exerted comparable or lower cytotoxicity than tacrine on mouse hepatocytes and had favorable predicted intestinal absorption and blood-brain barrier permeability. The overall results indicate that the synthesized conjugates are promising new multifunctional agents for the potential treatment of AD