Background and purpose: Carboxylesterases (CEs) metabolize a wide range of xenobiotic substrates including heroin, cocaine, meperidine and the anticancer agent CPT‐11. In this study, we have ...purified to homogeneity human liver and intestinal CEs and compared their ability with hydrolyse heroin, cocaine and CPT‐11.
Experimental approach: The hydrolysis of heroin and cocaine by recombinant human CEs was evaluated and the kinetic parameters determined. In addition, microsomal samples prepared from these tissues were subjected to chromatographic separation, and substrate hydrolysis and amounts of different CEs were determined.
Key results: In contrast to previous reports, cocaine was not hydrolysed by the human liver CE, hCE1 (CES1), either as highly active recombinant protein or as CEs isolated from human liver or intestinal extracts. These results correlated well with computer‐assisted molecular modelling studies that suggested that hydrolysis of cocaine by hCE1 (CES1), would be unlikely to occur. However, cocaine, heroin and CPT‐11 were all substrates for the intestinal CE, hiCE (CES2), as determined using both the recombinant protein and the tissue fractions. Again, these data were in agreement with the modelling results.
Conclusions and implications: These results indicate that the human liver CE is unlikely to play a role in the metabolism of cocaine and that hydrolysis of this substrate by this class of enzymes is via the human intestinal protein hiCE (CES2). In addition, because no enzyme inhibition is observed at high cocaine concentrations, potentially this route of hydrolysis is important in individuals who overdose on this agent.
In the winter period, water temperature is one of the main factors influencing the physiological state of fish. Its optimal and stable indicator during the whole winter period guarantees high yield ...of fish and its quality. To this date, the winter period is characterized by elevated temperatures with acute fluctuations. In this work, the main object of study is carp (Cyprinus carpio) at the age of six (young-of-the-year) and ten (one-year) months. The aim of this study was to determine how much the period of the optimal winter water temperatures decreased and how this affected the weight and fatness, hematological profiles, erythrocyte indices and basic biochemical parameters of carp muscle tissue. As a result of research, it was found that optimal winter water temperatures decreased by an average of two months, which affected the physiological state of carp. Consequently, there was a decrease in body weight and fatness. Dissolved oxygen level, pH, nitrites, nitrates and hardness were normal, while oxidation was increased. Muscle fat and protein levels decreased to critical levels, at the same time, moisture and ash levels were noted to increase. The total content of red blood cells decreased, however, the level of hemoglobin, mean corpuscular hemoglobin (MCH), mean cell hemoglobin concentration (MCHC) increased. With increasing hemoglobin content and concentration, mean corpuscular volume (MCV) decreased. After wintering, the number of white blood cells increased. The biochemical profile of carp blood showed a decrease in total protein in blood serum, albumin, triglycerides, cholesterol and glucose. After wintering, there was an increase in creatinine, phosphorus and calcium. Knowing how much the period of optimal winter temperatures has shortened, and how this affects the state of carp at the physiological level, will provide an opportunity to develop recommendations for improving wintering technologies. Considering the dynamics of climate change, the research in this area is promising.
Aim.
To study the structure of antihypertensive drugs prescription in pregnant women in routine practice in Kursk and Chisinau.
Material and methods.
The study design was observational descriptive ...cross-sectional. Authors conducted a survey of doctors in medical organizations in Kursk and Chisinau in 2017-2018.
Results.
Respondents from Kursk and Chisinau preferred methyldopa in prescriptions of central alpha-adrenergic receptor agonists. Doctors from Chisinau used clonidine in 14.3% of cases. The leading place in the group of calcium channel blockers belonged to short-acting nifedipine. Among beta-blockers in Kursk, doctors most often prescribed bisoprolol (43.3%), metoprolol (21.7%) and nebivolol (13.3%), while in Chisinau the preference was given to metoprolol (32.1%), atenolol (19.6%) and bisoprolol (16.1%). From the group of diuretics, Kursk doctors mainly prescribed hydrochlorothiazide (10%), indapamide (6.7%); in Chisinau, indapamide was the leader (19.6%), hydrochlorothiazide was used less frequently (7,1%). From the class of alpha-blockers, prazosin occupied the leading position among respondents in Kursk, and terazosin in Chisinau.
Conclusion.
The priority drug classes in both regions were calcium channel blockers, central alpha-adrenergic receptor agonists and beta-blockers. A small number of not recommended drugs prescriptions have been registered. In general, the prescribed treatment corresponded to the current guidelines and protocols for the management of patients with arterial hypertension during pregnancy.
CPT-11 is a potent antitumor agent that is activated by carboxylesterases (CE) and intracellular expression of CEs that can activate the drug results in increased cytotoxicity to the drug. As ...activation of CPT-11 (irinotecan-7-ethyl-10-4-(1-piperidino)-1-piperidinocarbonyloxycamptothecin) by human CEs is relatively inefficient, we have developed enzyme/prodrug therapy approaches based on the CE/CPT-11 combination using a rabbit liver CE (rCE). However, the in vivo application of this technology may be hampered by the development of an immune response to rCE. Therefore, we have developed a mutant human CE (hCE1m6), based on the human liver CE hCE1, that can activate CPT-11 approximately 70-fold more efficiently than the wild-type protein and can be expressed at high levels in mammalian cells. Indeed, adenoviral-mediated delivery of hCE1m6 with human tumor cells resulted in up to a 670-fold reduction in the IC(50) value for CPT-11, as compared to cells transduced with vector control virus. Furthermore, xenograft studies with human tumors expressing hCE1m6 confirm the ability of this enzyme to activate CPT-11 in vivo and induce antitumor activity. We propose that this enzyme should likely be less immunogenic than rCE and would be suitable for the in vivo application of CE/CPT-11 enzyme/prodrug therapy.
Human carboxylesterase 1 (hCE1) exhibits broad substrate specificity and is involved in xenobiotic processing and endobiotic metabolism. We present and analyze crystal structures of hCE1 in complexes ...with the cholesterol-lowering drug mevastatin, the breast cancer drug tamoxifen, the fatty acyl ethyl ester (FAEE) analogue ethyl acetate, and the novel hCE1 inhibitor benzil. We find that mevastatin does not appear to be a substrate for hCE1, and instead acts as a partially non-competitive inhibitor of the enzyme. Similarly, we show that tamoxifen is a low micromolar, partially non-competitive inhibitor of hCE1. Further, we describe the structural basis for the inhibition of hCE1 by the nanomolar-affinity dione benzil, which acts by forming both covalent and non-covalent complexes with the enzyme. Our results provide detailed insights into the catalytic and non-catalytic processing of small molecules by hCE1, and suggest that the efficacy of clinical drugs may be modulated by targeted hCE1 inhibitors.
The article is aimed at studying the substance and directions for the use of crowd technologies in the context of large industrial integrated holdings. A range of business tasks that can be ...successfully accomplished by using crowd technologies (crowdsourcing) has been defined, instrumentarium and stages of the staff working process in line with crowdsourcing technology have been analyzed. A general description and goal of crowdsourcing strategies have been provided. The advantages of crowdsourcing have been determined as follows: minimizing the labor and research costs on accomplishment of emerging tasks; obtaining innovative ideas; determining problem areas; displaying business transparency and willingness to cooperate; increasing consumer loyalty, company value; ability to mobilize additional resources through public platforms, etc.
CPT-11 (irinotecan, 7-ethyl-10-4-(1-piperidino)-1-piperidinocarbonyloxycamptothecin) is an anticancer prodrug that has been approved for the treatment of colon cancer. It is a member of the ...camptothecin class of drugs and activation to the active metabolite SN-38, is mediated by carboxylesterases (CE). SN-38 is a potent topoisomerase I poison and is highly effective at killing human tumor cells, with IC
50 values in the low nM range. However, upon high dose administration of CPT-11 to cancer patients, a cholinergic syndrome is observed, that can be rapidly ameliorated by atropine. This suggests a direct interaction of the drug or its metabolites with acetylcholinesterase (AChE). Kinetic studies indicated that CPT-11 was primarily responsible for AChE inhibition with the 4-piperidinopiperidine moiety, the major determinant in the loss of enzyme activity. Structural analogs of 4-piperidinopiperidine however, did not inhibit AChE, including a benzyl piperazine derivate of CPT-11. These results suggest that novel anticancer drugs could be synthesized that do not inhibit AChE, or alternatively, that novel AChE inhibitors could be designed based around the camptothecin scaffold.
This work presents an extreme biomimetics route for the creation of nano- structured biocomposites utilizing a chitinous template of poriferan origin. The specific thermal stability of the ...nanostructured chitinous template allowed for the formation under hydrothermal conditions of a novel germanium oxide- chitin composite with a defined nanoscale structure. Using a variety of analytical techniques （FTIR, Raman, energy dispersive X-ray （EDX）, near-edge X-ray absorption fine structure （NEXAFS）, and photoluminescence （PL） spectroscopy, EDS-mapping, selected area for the electron diffraction pattern （SAEDP）, and transmission electron microscopy （TEM））, we showed that this bioorganic scaffold induces the growth of GeO2 nanocrystals with a narrow （150-300 nm） size distri- bution and predominantly hexagonal phase, demonstrating the chitin template＇s control over the crystal morphology. The formed GeO2-chitin composite showed several specific physical properties, such as a striking enhancement in photo- luminescence exceeding values previously reported in GeOR-based biomaterials. These data demonstrate the potential of extreme biomimetics for developing new-generation nanostructured materials.
Atomically sharp domain walls in ferroelectrics are considered as an ideal platform to realize easy-to-reconfigure nanoelectronic building blocks, created, manipulated and erased by external fields. ...However, conductive domain walls have been exclusively observed in oxides, where domain wall mobility and conductivity is largely influenced by stoichiometry and defects. Here, we report on giant conductivity of domain walls in the non-oxide ferroelectric GaV
S
. We observe conductive domain walls forming in zig-zagging structures, that are composed of head-to-head and tail-to-tail domain wall segments alternating on the nanoscale. Remarkably, both types of segments possess high conductivity, unimaginable in oxide ferroelectrics. These effectively 2D domain walls, dominating the 3D conductance, can be mobilized by magnetic fields, triggering abrupt conductance changes as large as eight orders of magnitude. These unique properties demonstrate that non-oxide ferroelectrics can be the source of novel phenomena beyond the realm of oxide electronics.
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