- MeSH
- Wound Healing * MeSH
- Humans MeSH
- Platelet-Rich Plasma MeSH
- Prospective Studies MeSH
- Plasma Skin Regeneration * MeSH
- Treatment Outcome MeSH
- Check Tag
- Humans MeSH
- Publication type
- Meeting Abstract MeSH
There are numerous studies supporting the contribution of oxidative stress to the pathogenesis of epilepsy. Prolonged oxidative stress is associated with the overexpression of ATP-binding cassette transporters, which results in antiepileptic drugs resistance. During our studies, three 1,2,4-triazole-3-thione derivatives were evaluated for the antioxidant activity and anticonvulsant effect in the 6 Hz model of pharmacoresistant epilepsy. The investigated compounds exhibited 2-3 times more potent anticonvulsant activity than valproic acid in 6 Hz test in mice, which is well-established preclinical model of pharmacoresistant epilepsy. The antioxidant/ROS scavenging activity was confirmed in both single-electron transfer-based methods (DPPH and CUPRAC) and during flow cytometric analysis of total ROS activity in U-87 MG cells. Based on the enzymatic studies on human carbonic anhydrases (CAs), acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), one can assume that the herein investigated drug candidates will not impair the cognitive processes mediated by CAs and will have minimal off-target cholinergic effects.
- MeSH
- Acetylcholinesterase metabolism MeSH
- Anticonvulsants chemical synthesis chemistry pharmacology MeSH
- Antioxidants chemical synthesis chemistry pharmacology MeSH
- Biphenyl Compounds antagonists & inhibitors MeSH
- Butyrylcholinesterase metabolism MeSH
- Cholinesterase Inhibitors chemical synthesis chemistry pharmacology MeSH
- Epilepsy drug therapy metabolism MeSH
- Carbonic Anhydrase Inhibitors chemical synthesis chemistry pharmacology MeSH
- Carbonic Anhydrases metabolism MeSH
- Humans MeSH
- Models, Molecular MeSH
- Molecular Structure MeSH
- Mice MeSH
- Cell Line, Tumor MeSH
- Oxidative Stress drug effects MeSH
- Picrates antagonists & inhibitors MeSH
- Reactive Oxygen Species metabolism MeSH
- Triazoles chemical synthesis chemistry pharmacology MeSH
- Cell Survival drug effects MeSH
- Dose-Response Relationship, Drug MeSH
- Structure-Activity Relationship MeSH
- Animals MeSH
- Check Tag
- Humans MeSH
- Mice MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
The Escherichia coli protein WrbA, an FMN-dependent NAD(P)H:quinone oxidoreductase, was crystallized under new conditions in the presence of FAD or the native cofactor FMN. Slow-growing deep yellow crystals formed with FAD display the tetragonal bipyramidal shape typical for WrbA and diffract to 1.2 Å resolution, the highest yet reported. Faster-growing deep yellow crystals formed with FMN display an atypical shape, but diffract to only ∼1.6 Å resolution and are not analysed further here. The 1.2 Å resolution structure detailed here revealed only FMN in the active site and no electron density that can accommodate the missing parts of FAD. The very high resolution supports the modelling of the FMN isoalloxazine with a small but distinct propeller twist, apparently the first experimental observation of this predicted conformation, which appears to be enforced by the protein through a network of hydrogen bonds. Comparison of the electron density of the twisted isoalloxazine ring with the results of QM/MM simulations is compatible with the oxidized redox state. The very high resolution also supports the unique refinement of Met10 as the sulfoxide, confirmed by mass spectrometry. Bond lengths, intramolecular distances, and the pattern of hydrogen-bond donors and acceptors suggest the cofactor may interact with Met10. Slow incorporation of FMN, which is present as a trace contaminant in stocks of FAD, into growing crystals may be responsible for the near-atomic resolution, but a direct effect of the conformation of FMN and/or Met10 sulfoxide cannot be ruled out.
- MeSH
- X-Ray Diffraction MeSH
- Flavin-Adenine Dinucleotide chemistry metabolism MeSH
- Flavin Mononucleotide chemistry metabolism MeSH
- Crystallization MeSH
- Crystallography, X-Ray MeSH
- NAD(P)H Dehydrogenase (Quinone) chemistry metabolism MeSH
- Oxidation-Reduction MeSH
- Escherichia coli Proteins chemistry metabolism MeSH
- Repressor Proteins chemistry metabolism MeSH
- Protein Binding MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Research Support, U.S. Gov't, Non-P.H.S. MeSH
In order to learn more about the molecular basis for the inhibition of DNA replication produced by antitumor platinum drugs, we investigated DNA polymerization using DNA templates site-specifically modified with the 1,2-GG intrastrand cross-link of dinuclear bifunctional [{trans-PtCl(NH(3))(2)}(2){l-spermidine-N1,N8}](3+)(BBR3571) or conventional mononuclear cisplatin. These cross-links which have the same nature, but differ in the size and character of the conformational alteration induced in double-helical DNA, were analyzed for bypass ability with reverse transcriptase of human immunodeficiency virus type 1 and Klenow fragment of DNA polymerase I deficient in exonuclease activity. We found that the 1,2-GG intrastrand CL of BBR3571 inhibited DNA translesion synthesis markedly more than the same adduct of cisplatin. This result was explained by a larger size of the cross-link of BBR3571 and by a flexibility induced in DNA by this cross-link which can make the productive binding of this adduct at the polymerase site more difficult.
Besides its classical function as an orchestrator of calcium and phosphorus homeostasis, vitamin D also affects insulin secretion and tissue efficiency. A number of studies have consistently reported the inverse relationship between vitamin D deficiency and type 2 diabetes. Activation of certain metabolic pathways and down-stream transcription factors may protect from glucolipotoxicity and their targeted activation -e.g. by vitamin D - might explain the detrimental role of vitamin D deficiency in diabetes. The aim of the study was to quantify gene and protein expression of selected enzymes involved in the protection from glucolipotoxicity, specifically glyoxalase 1 (GLO1), and other enzymes with antioxidant activity - hemoxygenase (HMOX), thiamin pyrophosphokinase (TPK1) and transketolase (TKT), under normo- and hyperglycemic conditions and upon addition of vitamin D in peripheral blood mononuclear cells (PBMCs) and human umbilical vein endothelial cells (HUVEC). The results of our study indicate that the active form of vitamin D regulates gene expression of enzymes opposing the harmful effect of glucolipotoxicity whose activities appear to be suppressed by hyperglycemia. However, we were unable to confirm this effect on protein expression. While we cannot speculate on the effect of vitamin D on diabetes itself our results support its role in the protection against existing glucolipotoxicity therefore possibly translating into the prevention of development of diabetic complications.
- MeSH
- Human Umbilical Vein Endothelial Cells drug effects enzymology MeSH
- Homeostasis drug effects MeSH
- Insulin secretion MeSH
- Cells, Cultured MeSH
- Lactoylglutathione Lyase genetics metabolism MeSH
- Leukocytes, Mononuclear drug effects enzymology MeSH
- Humans MeSH
- Gene Expression Regulation MeSH
- Thiamin Pyrophosphokinase genetics metabolism MeSH
- Transketolase genetics metabolism MeSH
- Vitamin D pharmacology MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- MeSH
- Antipsychotic Agents pharmacology chemistry MeSH
- Humans MeSH
- Piperazines pharmacology chemistry MeSH
- Check Tag
- Humans MeSH
Chemická látka 1,4-butandiol je řazena mezi průmyslová rozpouštědla, využívá se též jako základ pro výrobu plastických hmot, elastomerů a fólií. Ve 20. století byla tato substance v České republice často zneužívána pro své prosexuální a relaxační účinky jako rekreační droga, jako anabolikum a prostředek ke zvýšení tělesné výkonnosti. Článek prezentuje kazuistiku, která popisuje dlouhodobé pravidelné zneužívání této látky a shrnuje její vliv na lidský organismus.
The chemical substance 1,4 butanediol belongs among industrial solvents. It is also used as a base in production of plastic and elastomer substances and films. The substance was used for its prosexual and calming effect as a "recreational drug" and also as an anabolic agent and a substance to enhance physical performance. The case-report describes long-term and regular use of this substance and its impact to a human organism.
- Keywords
- tekutá extáze, tekuté mýdlo, GHB,
- MeSH
- Substance Withdrawal Syndrome MeSH
- Butylene Glycols * pharmacokinetics poisoning adverse effects MeSH
- Delirium chemically induced MeSH
- Hydroxybutyrates poisoning adverse effects MeSH
- Cognitive Dysfunction chemically induced MeSH
- Middle Aged MeSH
- Humans MeSH
- Designer Drugs MeSH
- Sodium Oxybate analysis metabolism MeSH
- Sleep Wake Disorders chemically induced MeSH
- Substance-Related Disorders * diagnosis therapy MeSH
- Dietary Supplements MeSH
- Check Tag
- Middle Aged MeSH
- Humans MeSH
- Male MeSH
- Publication type
- Case Reports MeSH