The aim of this study was to assess the impact of sulfamethoxazole (SMX) on oxidative stress indices in zebrafish (Danio rerio). The test was completed after 14 days. The tested concentrations were 50, 100 and 500 µg/L of SMX. Glutathione peroxidase, glutathione reductase, glutathione S-transferase and lipid peroxidation were investigated to determine the effects of SMX on oxidative stress in zebrafish. Lipid peroxidation gradually increased slightly (but non-significantly) at all tested concentrations during the test as compared to the control. The evaluation of oxidative stress biomarkers showed no significant changes in the activity of antioxidant enzymes in any experimental group exposed to SMX as compared to the control. The gradual increase in lipid peroxidation after 3 and 14 days in the SMX treated groups as compared to the control group indicates increasing cell membrane damage.

• MeSH
• antibakteriální látky toxicita   MeSH
• antioxidancia metabolismus   MeSH
• časové faktory MeSH
• dánio pruhované metabolismus   MeSH
• oxidační stres účinky léků   MeSH
• peroxidace lipidů účinky léků   MeSH
• sulfamethoxazol toxicita   MeSH
• zvířata MeSH
• Check Tag
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

The search for tacrine derivatives, as potential Alzheimer´s disease treatment, is still being at the forefront of scientific efforts. 7-MEOTA was found to be a potent, centrally active acetylcholinesterase inhibitor free of the serious side effects observed for tacrine. Unfortunately, a relevant argumentation about pharmacokinetics and potential toxicity is incomplete; information about tacrine derivatives absorption and especially CNS penetration are still rare as well as detailed toxicological profile in vivo. Although the structural changes between these compounds are not so distinctive, differences in plasma profile and CNS targeting were found. The maximum plasma concentration were attained at 18th min (tacrine; 38.20 ± 3.91 ng/ml and 7-MEOTA; 88.22 ± 15.19 ng/ml) after i.m. application in rats. Although the brain profiles seem to be similar; tacrine achieved 19.34 ± 0.71 ng/ml in 27 min and 7-MEOTA 15.80 ± 1.13 ng/ml in 22 min; the tacrine Kp (AUCbrain/AUCplasma) fit 1.20 and was significantly higher than 7-MEOTA Kp 0.10. Administration of tacrine and 7-MEOTA showed only mild elevation of some biochemical markers following single p.o. application in 24 hours and 7 days. Also histopathology revealed only mild-to-moderate changes following repeated p.o. administration for 14 days. It seems that small change in tacrine molecule leads to lower ability to penetrate through the biological barriers. The explanation that lower p.o. acute toxicity of 7-MEOTA depends only on differences in metabolic pathways may be now revised to newly described differences in pharmacokinetic and toxicological profiles.

• MeSH
• časové faktory MeSH
• cholinesterasové inhibitory aplikace a dávkování   farmakokinetika   toxicita   MeSH
• krysa rodu rattus MeSH
• mozek metabolismus   MeSH
• plocha pod křivkou MeSH
• potkani Wistar MeSH
• takrin aplikace a dávkování   analogy a deriváty   farmakokinetika   toxicita   MeSH
• tkáňová distribuce MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

The cytotoxicity of methacrylate-based biopolymers crosslinked by in situ photopolymerization has been attributed mainly to residual methacrylate monomers released due to incomplete polymerization. The residual monomers, primarily triethyleneglycol dimethacrylate or 2-hydroxyethyl methacrylate, may irritate adjacent tissue, or be released into the bloodstream and reach practically all tissues. Increased production of reactive oxygen species, which may be connected to concomitant glutathione depletion, has been the most noticeable effect observed in vitro following the exposure of cells to methacrylates. Radical scavengers such as glutathione or N-acetylcysteine represent the most important cellular strategy against methacrylate-induced toxicity by direct adduct formation, resulting in monomer detoxification. Reactive oxygen species may participate in methacrylate-induced genotoxic or pro-apoptotic effects and cell-cycle arrest via induction of corresponding molecular pathways in cells. A deeper understanding of the biological mechanisms and effects of methacrylates widely used in various bioapplications may enable a better estimation of potential risks and thus, selection of a more appropriate composition of polymer material to eliminate potentially harmful substances such as triethyleneglycol dimethacrylate.

• MeSH
• acetylcystein farmakologie   MeSH
• biokompatibilní materiály chemie   toxicita   MeSH
• glutathion metabolismus   MeSH
• kyseliny polymethakrylové chemie   toxicita   MeSH
• lidé MeSH
• methakryláty chemie   toxicita   MeSH
• polyethylenglykoly chemie   toxicita   MeSH
• reaktivní formy kyslíku metabolismus   MeSH
• scavengery volných radikálů farmakologie   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

The development of acetylcholinesterase reactivators, i.e., antidotes against organophosphorus poisoning, is an important goal of defense research. The aim of this study was to compare cytotoxicity and chemical structure of five currently available oximes (pralidoxime, trimedoxime, obidoxime, methoxime, and asoxime) together with four perspective oximes from K-series (K027, K074, K075, and K203). The cytotoxicity of tested substances was measured using two methods - colorimetric 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide assay and impedance based real-time cytotoxicity assay - in three different cell lines (HepG2, ACHN, and NHLF). Toxicity was subsequently expressed as toxicological index IC50. The tested compounds showed different cytotoxicity ranging from 0.92 to 40.06 mM. In HepG2 cells, K027 was the least and asoxime was the most toxic reactivator. In ACHN and NHLF cell lines, trimedoxime was the compound with the lowest adverse effects, whereas the highest toxicity was found in methoxime-treated cells. The results show that at least five structural features affect the reactivators' toxicity such as the number of oxime groups in the molecule, their position on pyridinium ring, the length of carbon linker, and the oxygen substitution or insertion of the double bond into the connection chain. Newly synthetized oximes with IC50 ≥ 1 mM evaluated in this three cell lines model might appear suitable for further testing.

• MeSH
• alternativy testů na zvířatech MeSH
• buňky Hep G2 MeSH
• fibroblasty účinky léků   MeSH
• inhibiční koncentrace 50 MeSH
• LD50 MeSH
• lidé MeSH
• molekulární struktura MeSH
• oximy chemie   toxicita   MeSH
• preklinické hodnocení léčiv MeSH
• reaktivátory cholinesterázy chemie   toxicita   MeSH
• viabilita buněk účinky léků   MeSH
• vztahy mezi strukturou a aktivitou MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH

The aim of current study was to evaluate the effect of the most common anthocyanidins (cyanidin, delphinidin, malvidin, pelargonidin, and peonidin) on the transcriptional activity of steroid and nuclear receptors. The activities of steroid receptors - progesterone receptor (PR), estrogen receptor (ER), androgen receptor (AR), glucocorticoid receptor (GR), and nuclear receptors - vitamin D receptor (VDR), retinoid X receptor (RXR), retinoic acid receptor (RAR), pregnane X receptor (PXR), and thyroid receptor (TR) were assessed using either stable transfected luciferase gene reporter cell lines or transiently transfected cell lines. The cytotoxicity assays and gene reporter assays were performed after the 24-h treatment of cells with increasing range of concentrations (10 nM to 50 µM) of selected anthocyanidins. The results of experiments indicate that none of the examined anthocyanidins in all tested concentrations caused remarkable changes of transcriptional activity of studied steroid receptors, but their increasing concentrations slightly inhibited transcriptional activity of nuclear receptors induced by model agonists.

• MeSH
• anthokyaniny farmakologie   MeSH
• genetická transkripce účinky léků   MeSH
• lidé MeSH
• nádorové buňky kultivované MeSH
• receptory cytoplazmatické a nukleární genetika   MeSH
• steroidní receptory genetika   MeSH
• viabilita buněk účinky léků   MeSH
• vztah mezi dávkou a účinkem léčiva MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH

CONTEXT: Acetaminophen (APAP) hepatotoxicity is often studied in primary cultures of hepatocytes of various species, but there are only few works comparing interspecies differences in susceptibility of hepatocytes to APAP in vitro. OBJECTIVES: The aim of our work was to compare hepatotoxicity of APAP in rat and mouse hepatocytes in primary cultures. MATERIALS AND METHODS: Hepatocytes isolated from male Wistar rats and C57Bl/6J mice were exposed to APAP for up to 24 h. We determined lactate dehydrogenase (LDH) activity in culture medium, activity of cellular dehydrogenases (WST-1) and activity of caspases 3 in cell lysate as markers of cell damage/death. We assessed content of intracellular reduced glutathione, production of reactive oxygen species (ROS) and malondialdehyde (MDA). Respiration of digitonin-permeabilized hepatocytes was measured by high resolution respirometry and mitochondrial membrane potential (MMP) was visualized (JC-1). RESULTS: APAP from concentrations of 2.5 and 0.75 mmol/L induced a decrease in viability of rat (p < 0.001) and mouse (p < 0.001) hepatocytes (WST-1), respectively. In contrast to rat hepatocytes, there was no activation of caspase-3 in mouse hepatocytes after APAP treatment. Earlier damage to plasma membrane and faster depletion of reduced glutathione were detected in mouse hepatocytes. Mouse hepatocytes showed increased glutamate + malate-driven respiration in state 4 and higher susceptibility of the outer mitochondrial membrane (OMM) to APAP-induced injury. CONCLUSION: APAP displayed dose-dependent toxicity in hepatocytes of both species. Mouse hepatocytes in primary culture however had approximately three-fold higher susceptibility to the toxic effect of APAP when compared to rat hepatocytes.

• MeSH
• biologické markery metabolismus   MeSH
• buněčná membrána účinky léků   metabolismus   MeSH
• druhová specificita MeSH
• glutathion metabolismus   MeSH
• hepatocyty cytologie   účinky léků   metabolismus   MeSH
• jaterní mitochondrie účinky léků   enzymologie   metabolismus   MeSH
• kultivované buňky MeSH
• membránový potenciál mitochondrií účinky léků   MeSH
• mitochondriální membrány účinky léků   metabolismus   MeSH
• myši inbrední C57BL MeSH
• neopioidní analgetika škodlivé účinky   MeSH
• oxidace-redukce MeSH
• oxidační stres účinky léků   MeSH
• paracetamol škodlivé účinky   MeSH
• peroxidace lipidů účinky léků   MeSH
• potkani Wistar MeSH
• reaktivní formy kyslíku agonisté   metabolismus   MeSH
• viabilita buněk účinky léků   MeSH
• zvířata MeSH
• Check Tag
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• srovnávací studie MeSH

OBJECTIVES: Highly toxic organophosphorus compounds (V- and G-nerve agents) were originally synthesized for warfare or as agricultural pesticides. Data on their acute toxicity are rare and patchy. Therefore, there is a need for integrated summary comparing acute toxicity of organophosphates using different administration routes in the same animal model with the same methodology. Based on original data, a summary of in vivo acute toxicity of selected V- and G-nerve agents (tabun, sarin, soman, VX, Russian VX) and organophosphates paraoxon (POX) and diisopropyl fluorophosphate (DFP) in rats has been investigated. MATERIALS AND METHODS: Male Wistar rats were exposed to organophosphates in several administration routes (i.m., i.p., p.o, s.c., p.c.). The acute toxicity was evaluated by the assessment of median lethal dose (LD50, mg kg(-1)) 2, 4, and 24 hours post exposure. RESULTS: V-agents were the most toxic presented with LD50 ranged from 0.0082 mg kg(-1) (VX, i.m.) to 1.402 mg kg(-1) (Russian VX, p.o.), followed by G-agents (LD50 = 0.069 mg kg(-1)/soman, i.m./ - 117.9 mg kg(-1)/sarin, p.c./), organophosphate POX and DFP (LD50 = 0.321 mg kg(-1)/POX, i.m./ - 420 mg kg(-1)/DFP, p.c./). Generally, i.m. administration was the most toxic throughout all tested agents and ways of administration (LD50 = 0.0082 mg kg(-1)/VX/ - 1.399 mg kg(-1)/DFP/) whereas p.c. way was responsible for lowest acute toxicity (LD50 = 0.085 mg kg(-1)/VX/ - 420 mg kg(-1)/DFP/). CONCLUSION: The acute toxicity of selected organophosphorus compounds is summarized throughout this study. Although the data assessed in rats are rather illustrative prediction for human, it presents a valuable contribution, indicating the toxic potential and harmfulness of organophosphates.

• MeSH
• aplikace kožní MeSH
• aplikace orální MeSH
• chemické bojové látky chemie   toxicita   MeSH
• injekce intramuskulární MeSH
• injekce subkutánní MeSH
• LD50 MeSH
• molekulární struktura MeSH
• organofosforové sloučeniny chemie   toxicita   MeSH
• pesticidy chemie   toxicita   MeSH
• potkani Wistar MeSH
• testy akutní toxicity MeSH
• zvířata MeSH
• Check Tag
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Sulfur mustard (SM) is a chemical warfare agent with cytotoxic effect and a tight link to oxidative stress (OS). Depletion of antioxidants is considered as a cause of detrimental consequence and belongs to the important steps leading to cell death. The oxidative injury appearing after SM exposure is not well understood. Nevertheless, identification of the pathological processes would be a good opportunity to establish an efficient therapy. Here, we focused our effort on an estimation of reactive oxygen species homeostasis and apoptotic processes in Wistar rats exposed to 0-160 mg/kg of SM. We assayed antioxidant activity, thiobarbituric acid reactive substances, reduced glutathione/oxidized glutathione, metallothionein, glutathione reductase, glutathione peroxidase, glutathione S-transferase, caspase 3, and glucose in the livers, kidneys, and muscles of the animals. Significant OS, depletion of low-molecular-mass antioxidants, increase in caspase activity, and some other processes related to SM action were determined. Moreover, we infer a principal role of OS in the tested organs.

• MeSH
• antioxidancia metabolismus   MeSH
• chemické bojové látky toxicita   MeSH
• glutathion metabolismus   MeSH
• játra účinky léků   MeSH
• kosterní svaly účinky léků   MeSH
• krysa rodu rattus MeSH
• látky reagující s kyselinou thiobarbiturovou metabolismus   MeSH
• ledviny účinky léků   MeSH
• oxidační stres účinky léků   MeSH
• oxidoreduktasy metabolismus   MeSH
• potkani Wistar MeSH
• yperit toxicita   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Sulfur mustard (SM) is an important chemical warfare agent. The mechanism of SM toxicity still has not been fully recognized. However, oxidative stress and following the damaging of macromolecules in the human body is considered one of the crucial steps in SM toxicity. Rats intoxicated with pure (i.e., distilled) SM were used as a model organism. The doses, 0 (control), 5, 20, and 80 mg/kg of body weight, were applied intradermally. A hormone with strong antioxidant potency, melatonin, was applied (25 and 50 mg/kg, subcutaneously) into the other group of rats exposed with the same doses of SM. Total plasma protein, ferric-reducing antioxidant power (FRAP), thiobarbituric-acid-reactive substances (TBARS), and plasma protein carbonyls were assayed in blood plasma. A significant decrease of total plasma proteins was found for control, and the lowest dose of SM was treated with melatonin. Melatonin was also able to enhance the production of low-molecular-weight antioxidants, as the SM-intoxicated rats had significantly (P ≤ 0.01) increasing FRAP levels after intoxication with SM in doses of 20 and 80 mg/kg, when compared to the control treated with melatonin. Melatonin also decreased TBARS level, representing reduced lipid peroxidation (LPO). However, LPO seems to be of less importance for SM toxic impact. The more reliable parameter was the level of total plasma protein carbonyls. The carbonyl levels were significantly increased due to SM, and the carbonylation was slowed due to melatonin intake. In conclusion, melatonin seems to be a prospective compound in reducing SM toxicity impact in the rat.

• MeSH
• antioxidancia aplikace a dávkování   terapeutické užití   MeSH
• chemické bojové látky toxicita   MeSH
• injekce intradermální MeSH
• injekce intraperitoneální MeSH
• krevní proteiny metabolismus   MeSH
• krysa rodu rattus MeSH
• látky reagující s kyselinou thiobarbiturovou metabolismus   MeSH
• melatonin aplikace a dávkování   terapeutické užití   MeSH
• otrava krev   metabolismus   prevence a kontrola   MeSH
• oxidační stres účinky léků   MeSH
• potkani Wistar MeSH
• yperit toxicita   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

The ability of two combinations of oximes (HI-6+trimedoxime, HI-6+K203) to reduce soman-induced acute neurotoxic signs and symptoms was compared with the neuroprotective efficacy of the oxime HI-6 alone, using a functional observational battery. Soman-induced neurotoxicity and the neuroprotective effects of HI-6 alone and HI-6 combined with trimedoxime or K203 in rats poisoned with soman at a sublethal dose (90 μg/kg intramuscularly, i.m.; 80% of LD₅₀ value) were monitored by the functional observational battery at 24 hours following soman administration. The results indicate that both tested oxime mixtures combined with atropine were able to allow soman-poisoned rats to survive 24 hours following soman challenge, while 4 nontreated soman-poisoned rats and 1 soman-poisoned rat treated with oxime HI-6 alone combined with atropine died within 24 hours following soman poisoning. While the oxime HI-6 alone combined with atropine treatment was able to eliminate a few soman-induced neurotoxic signs and symptoms, both oxime mixtures showed higher neuroprotective efficacy in soman-poisoned rats. Especially, the combination of HI-6 with trimedoxime was able to eliminate most soman-induced neurotoxic signs and symptoms and markedly reduce acute neurotoxicity of soman in rats. Thus, both tested mixtures of oximes combined with atropine were able to increase the neuroprotective effectiveness of antidotal treatment of acute soman poisonings, compared to the individual oxime.

• MeSH
• chování zvířat účinky léků   MeSH
• kombinovaná farmakoterapie MeSH
• krysa rodu rattus MeSH
• molekulární struktura MeSH
• neuroprotektivní látky aplikace a dávkování   chemie   terapeutické užití   MeSH
• neurotoxické syndromy etiologie   patofyziologie   prevence a kontrola   MeSH
• oximy aplikace a dávkování   chemie   terapeutické užití   MeSH
• pohybová aktivita účinky léků   MeSH
• potkani Wistar MeSH
• pyridinové sloučeniny aplikace a dávkování   chemie   terapeutické užití   MeSH
• soman otrava   MeSH
• trimedoxim aplikace a dávkování   chemie   terapeutické užití   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH