The aim of this study was to reveal the effects of foodborne fluoxetine on morphological and condition profile, hematological profile, biochemical and oxidative stress indices on juvenile rainbow trout. The study was performed according to OECD Guideline No. 215. Fluoxetine was incorporated into Biomar 921 pellets at a dose of 0.047 mg/kg (environmental concentration), 0.577 mg/kg and 6.7 mg/kg. There was statistically significant change in hematological profile, including an increasing trend in neutrophil/lymphocyte ratio and a decreasing trend in the number of lymphocytes. Measurements of oxidative stress indicated decreased activity of the detoxifying enzyme glutathione-S-transferase in the liver and kidney. However, the measurement of GR, GPx, CAT, SOD activity, and TBARS showed no changes. Histopathological examination revealed damage to the proximal tubules of caudal kidney in exposed groups. This study confirms that fluoxetine has a significant effect on immune response.

• MeSH
• antidepresiva druhé generace toxicita   MeSH
• chemické látky znečišťující vodu toxicita   MeSH
• fluoxetin toxicita   MeSH
• imunita účinky léků   MeSH
• kontaminace potravin MeSH
• krevní obraz MeSH
• krmivo pro zvířata MeSH
• Oncorhynchus mykiss krev   imunologie   MeSH
• oxidační stres účinky léků   MeSH
• proximální tubuly ledvin účinky léků   MeSH
• zvířata MeSH
• Check Tag
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

The human proximal tubular HK-2 cell line is an immortalized cell line commonly used for studying proximal tubular toxicity. Even as their use is presently increasing, there unfortunately are no studies focused on functional changes in HK-2 cells associated with passaging. The aim of the present study, therefore, was to evaluate the functional stability of HK-2 cells during 13 weeks of continuous passaging after 6 and 24 h of treatment with model nephrotoxic compounds (i.e., acetaminophen, cisplatin, CdCl(2)). Short tandem repeat profile, the doubling time, cell diameter, glutathione concentration, and intracellular dehydrogenase activity were measured in HK-2 cells at each tested passage. The results showed that HK-2 cells exhibit stable morphology, cell size, and cell renewal during passaging. Mean doubling time was determined to be 54 h. On the other hand, we observed a significant effect of passaging on the susceptibility of HK-2 cells to toxic compounds. The largest difference in results was found in both cadmium and cisplatin treated cells across passages. We conclude that the outcomes of scientific studies on HK-2 cells can be affected by the number of passages even after medium-term cultivation and passaging for 13 weeks.

• MeSH
• antitumorózní látky toxicita   MeSH
• buněčné kultury metody   MeSH
• buněčné linie MeSH
• cisplatina toxicita   MeSH
• kadmium toxicita   MeSH
• lidé MeSH
• neopioidní analgetika toxicita   MeSH
• paracetamol toxicita   MeSH
• proximální tubuly ledvin účinky léků   patologie   MeSH
• viabilita buněk MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH

Lithium is mainly excreted into urine, and a large fraction of lithium filtered through glomeruli is reabsorbed in the proximal tubule. However, the mechanisms responsible for lithium reabsorption remain unclear. We previously reported that the reabsorption of lithium was biphasic in rats, and that foscarnet inhibited lithium reabsorption with a high affinity type. We herein evaluated the effects of acetazolamide and foscarnet on the renal excretion of lithium in rats treated with lithium chloride at 2 doses. In rats intravenously injected with a bolus of 25 mg/kg lithium chloride, acetazolamide facilitated the urinary excretion of lithium, and increased the fractional excretion of lithium from 0.446 to 0.953, near the theoretically maximum value. At a dose of 2.5 mg/kg lithium chloride, the fractional excretion of lithium was 0.241 in control rats, 0.420 in rats administered acetazolamide, and 0.976 in rats administered acetazolamide and foscarnet. These results showed the potent inhibition of lithium reabsorption by acetazolamide and foscarnet in rats. And, it was exhibited that the effects of acetazolamide on lithium reabsorption differed with the dosages of lithium administered.

• MeSH
• acetazolamid farmakologie   MeSH
• antivirové látky farmakologie   MeSH
• chlorid lithný antagonisté a inhibitory   farmakokinetika   farmakologie   MeSH
• diuretika farmakologie   MeSH
• foskarnet farmakologie   MeSH
• krysa rodu rattus MeSH
• lékové interakce MeSH
• modely nemocí na zvířatech MeSH
• potkani Wistar MeSH
• proximální tubuly ledvin účinky léků   metabolismus   MeSH
• renální reabsorpce účinky léků   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

Exposure to aristolochic acid (AA) is associated with human nephropathy and urothelial cancer. The tumour suppressor TP53 is a critical gene in carcinogenesis and frequently mutated in AA-induced urothelial tumours. We investigated the impact of p53 on AAI-induced nephrotoxicity and DNA damage in vivo by treating Trp53(+/+), Trp53(+/-) and Trp53(-/-) mice with 3.5 mg/kg body weight (bw) AAI daily for 2 or 6 days. Renal histopathology showed a gradient of intensity in proximal tubular injury from Trp53(+/+) to Trp53(-/-) mice, especially after 6 days. The observed renal injury was supported by nuclear magnetic resonance (NMR)-based metabonomic measurements, where a consistent Trp53 genotype-dependent trend was observed for urinary metabolites that indicate aminoaciduria (i.e. alanine), lactic aciduria (i.e. lactate) and glycosuria (i.e. glucose). However, Trp53 genotype had no impact on AAI-DNA adduct levels, as measured by 32P-postlabelling, in either target (kidney and bladder) or non-target (liver) tissues, indicating that the underlying mechanisms of p53-related AAI-induced nephrotoxicity cannot be explained by differences in AAI genotoxicity. Performing gas chromatography-mass spectrometry (GC-MS) on kidney tissues showed metabolic pathways affected by AAI treatment, but again Trp53 status did not clearly impact on such metabolic profiles. We also cultured primary mouse embryonic fibroblasts (MEFs) derived from Trp53(+/+), Trp53(+/-) and Trp53(-/-) mice and exposed them to AAI in vitro (50 µM for up to 48 h). We found that Trp53 genotype impacted on the expression of NAD(P)H:quinone oxidoreductase (Nqo1), a key enzyme involved in AAI bioactivation. Nqo1 induction was highest in Trp53(+/+) MEFs and lowest in Trp53(-/-) MEFs; and it correlated with AAI-DNA adduct formation, with lowest adduct levels being observed in AAI-exposed Trp53(-/-) MEFs. Overall, our results clearly demonstrate that p53 status impacts on AAI-induced renal injury, but the underlying mechanism(s) involved remain to be further explored. Despite the impact of p53 on AAI bioactivation and DNA damage in vitro, such effects were not observed in vivo.

• MeSH
• cytochrom P-450 CYP1A1 genetika   MeSH
• exprese genu účinky léků   MeSH
• fibroblasty účinky léků   metabolismus   patologie   MeSH
• kultivované buňky MeSH
• kyseliny aristolochové metabolismus   toxicita   MeSH
• mutageny metabolismus   toxicita   MeSH
• myši inbrední C57BL MeSH
• myši knockoutované MeSH
• NAD(P)H dehydrogenasa (chinon) genetika   MeSH
• nádorový supresorový protein p53 genetika   MeSH
• poškození DNA * MeSH
• proximální tubuly ledvin účinky léků   metabolismus   patologie   MeSH
• vyšetření funkce ledvin MeSH
• zvířata MeSH
• Check Tag
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

Iron oxide nanoparticles (IONPs) have a great potential with regard to cell labelling, cell tracking, cell separation, magnetic resonance imaging, magnetic hyperthermia, targeted drug and gene delivery. However, a growing body of research has raised concerns about the possible unwanted adverse cytotoxic effects of IONPs. In the present study, the in vitro cellular uptake, antiproliferative activity, cytotoxicity, genotoxicity, prooxidant, microtubule-disrupting and apoptosis-inducing effect of Fe3O4@SiO2 and passivated Fe3O4@SiO2-NH2 nanoparticles on human renal proximal tubule epithelial cells (HK-2) have been studied. Both investigated silica coated IONPs were found to have cell growth-inhibitory activity in a time- and dose-dependent manner. Determination of cell cycle phase distribution by flow cytometry demonstrated a G1 and G2/M phase accumulation of HK-2 cells. A tetrazolium salt cytotoxicity assay at 24 h following treatment demonstrated that cell viability was reduced in a dose-dependent manner. Microscopy observations showed that both Fe3O4@SiO2 and Fe3O4@SiO2-NH2 nanoparticles accumulated in cells and appeared to have microtubule-disrupting activity. Our study also revealed that short term 1 h exposure to 25 and 100 μg/mL of silica coated IONPs causes genotoxicity. Compared with vehicle control cells, a significantly higher amount of γH2AX foci correlating with an increase in DNA double-strand breaks was observed in Fe3O4@SiO2 and Fe3O4@SiO2-NH2-treated and immunestained HK-2 cells. The investigated nanoparticles did not trigger significant ROS generation and apoptosis-mediated cell death. In conclusion, these findings provide new insights into the cytotoxicity of silica coated IONPs that may support their further safer use.

• MeSH
• apoptóza účinky léků   MeSH
• buněčné linie MeSH
• buněčný cyklus účinky léků   MeSH
• dvouřetězcové zlomy DNA MeSH
• epitelové buňky účinky léků   MeSH
• geny p53 MeSH
• histony genetika   MeSH
• lidé MeSH
• magnetické nanočástice toxicita   MeSH
• mikrotubuly účinky léků   MeSH
• oxid křemičitý toxicita   MeSH
• oxid železnato-železitý toxicita   MeSH
• poškození DNA * MeSH
• povrchové vlastnosti MeSH
• proximální tubuly ledvin cytologie   MeSH
• reaktivní formy kyslíku MeSH
• testy genotoxicity MeSH
• virová transformace buněk MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Cadmium is a heavy metal causing toxicity especially in kidney cells. The toxicity is linked also with enhanced oxidative stress leading to cell death. On the other hand, our recent experiments have shown that an increase of total intracellular dehydrogenases activity can also occur in kidney cells before declining until cell death. The aim of the present study, therefore, was to evaluate this transient enhancement in cell viability after cadmium treatment. The human kidney HK-2 cell line was treated with CdCl(2) at concentrations 0-200 microM for 2-24 h and intracellular dehydrogenase activity was tested. In addition, we measured reactive oxygen species (ROS) production, glutathione levels, mitochondrial membrane potential, and C-Jun-N-terminal kinase (JNK) activation. We found that significantly increased dehydrogenase activity could occur in cells treated with 25, 100, and 200 microM CdCl(2). Moreover, the results showed an increase in ROS production linked with JNK activation following the enhancement of dehydrogenase activity. Other tests detected no relationship with the increased in intracellular dehydrogenase activity. Hence, the transient increase in dehydrogenase activity in HK-2 cells preceded the enhancement of ROS production and our finding provides new evidence in cadmium kidney toxicity.

• MeSH
• aktivace enzymů účinky léků   fyziologie   MeSH
• buněčné linie MeSH
• kadmium toxicita   MeSH
• lidé MeSH
• membránový potenciál mitochondrií účinky léků   fyziologie   MeSH
• oxidační stres účinky léků   fyziologie   MeSH
• oxidoreduktasy metabolismus   MeSH
• proximální tubuly ledvin účinky léků   metabolismus   MeSH
• reaktivní formy kyslíku metabolismus   MeSH
• viabilita buněk účinky léků   fyziologie   MeSH
• vztah mezi dávkou a účinkem léčiva MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH

• MeSH
• chronická renální insuficience farmakoterapie   metabolismus   patofyziologie   MeSH
• diabetes mellitus 2. typu farmakoterapie   MeSH
• diabetické nefropatie patofyziologie   MeSH
• glifloziny MeSH
• glomerulus patofyziologie   MeSH
• hemodynamika účinky léků   MeSH
• hypoglykemika farmakologie   terapeutické užití   MeSH
• krevní glukóza metabolismus   účinky léků   MeSH
• krevní tlak MeSH
• lidé MeSH
• natriuréza MeSH
• proximální tubuly ledvin patofyziologie   MeSH
• sodík metabolismus   MeSH
• transportér 2 pro sodík a glukózu MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• přehledy MeSH

Dapagliflozin je představitel nové skupiny perorálních antidiabetik založených na inhibici SGLT2 receptoru v proximálním tubulu ledvin. Navozená glykosurie pak vede ke snížení glykémie, poklesu hmotnosti i krevního tlaku. Účinnost a bezpečnost dapagliflozinu v monoterapii i kombinační léčbě je prokázána řadou klinických studií. Metaanalýza dosud provedených studií fáze III navíc prokázala neutrální vliv dapagliflozinu na MACE (kombinovaný výsledný ukazatel: úmrtí z kardiovaskulárních příčin, nefatální infarkt myokardu a cévní mozková příhoda) a snížení počtu hospitalizací pro srdeční selhání. Účinnost dapagliflozinu byla navíc potvrzena recentně publikovanou rozsáhlou studií „z reálné klinické praxe“.

Dapagliflozin is a representative of a new group of peroral antidiabetics based on inhibition of the SGLT2 receptor in the proximal renal tubule. Induced glycosuria then leads to a decrease in blood glucose, weight loss and blood pressure. The efficacy and safety of dapagliflozin in both monotherapy and combination therapy has been demonstrated in a number of clinical trials. Moreover, the meta-analysis of the Phase III studies has shown a neutral effect of dapagliflozin on MACE (combined endpoint: cardiovascular death, non-fatal myocardial infarction and stroke) and reduced hospitalization for heart failure. In addition, the efficacy of dapagliflozin has been confirmed recently by a large-scale „real clinical practice“ trial.

• Klíčová slova
• Dapagliflozin,
• MeSH
• benzhydrylové sloučeniny MeSH
• diabetes mellitus 2. typu * farmakoterapie   komplikace   patologie   MeSH
• glifloziny MeSH
• glukosidy MeSH
• glykovaný hemoglobin MeSH
• hmotnostní úbytek MeSH
• hypoglykemika * farmakologie   škodlivé účinky   terapeutické užití   MeSH
• kardiovaskulární nemoci farmakoterapie   MeSH
• klinické zkoušky, fáze III jako téma MeSH
• lidé MeSH
• proximální tubuly ledvin účinky léků   MeSH
• transportér 2 pro sodík a glukózu * MeSH
• Check Tag
• lidé MeSH

Fluoride has toxic potential particularly for teeth, bones, and kidney. This study was aimed to investigate the NaF exposure effects on the growth of ameloblasts and kidney proximal tubular cells. Adult male healthy rats were used as experiment models, divided into control and NaF-induced groups. The expression of amelogenin, Bcl-2, and caspase-3 were significantly different in the control and NaF-induced group (P < 0.05). There was no correlation among these proteins in the control group but significant correlation in the NaF-induced group (r = 0.694). There was a significant correlation in proximal tubular cells, as seen from the increase of caspase-3 in the NaF-induced group (r = 0.715).

• MeSH
• ameloblasty cytologie   účinky léků   metabolismus   MeSH
• epitelové buňky metabolismus   MeSH
• fluorid sodný farmakologie   MeSH
• imunohistochemie MeSH
• kaspasa 3 metabolismus   MeSH
• krysa rodu rattus MeSH
• proliferace buněk účinky léků   MeSH
• protoonkogenní proteiny c-bcl-2 metabolismus   MeSH
• proximální tubuly ledvin cytologie   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

Fixní kombinace dapagliflozin/metformin spojuje výhody dvou perorálních antidiabetik s různým mechanismem účinku v léčbě pacientů s diabetes mellitus 2. typu. Dapagliflozin je vysoce selektivní inhibitor glukózového transportéru SGLT2 v proximálním renálním tubulu, jeho podání vede ke snížení reabsorpce glukózy, ke zvýšení glykosurie a ke snížení hodnoty renálního prahu pro glukózu. Zvýšená glykosurie vede ke snížení glykemie. Druhá součást fixní kombinace – metformin – patří mezi biquanidy, snižuje endogenní hepatální produkci glukózy, střevní absorpci glukózy a zlepšuje inzulinovou senzitivitu zvýšením periferního vychytávání glukózy a jejího využití. Snižuje jak glykemii nalačno, tak postprandiální glykemii. Fixní kombinace obou látek přímo zasahuje do patofyziologie diabetu 2. typu a představuje účinnou léčbu ověřenou řadou klinických studií.

The fixed combination of dapagliflozin/metformin associates the advantages of two oral antidiabetic drugs with different mechanism of action in the treatment of type 2 diabetes mellitus. Dapagliflozin is a highly selective sodium glucose transporter 2 inhibitor (SGLT2) in the proximal renal tubules, leading to decrease of glucose reabsorption, increase of urinary glucose excretion while lowering the renal threshold for glucose. Increased glucuresis leads to reduction of glycaemia. Metformin, the second integral part of the combination, ranks among the biquanides, acting by decreasing endogenous hepatic glucose production, decreasing intestinal absorption of glucose while improving insulin sensitivity by increasing peripheral glucose uptake and utilisation. It reduces fasting and postprandial glycaemia. The fixed combination of both drugs directly impacts the pathophysiology of type 2 diabetes mellitus and represents an effective therapy, already proven by a whole line of clinical studies.

• MeSH
• adherence k farmakoterapii MeSH
• algoritmy MeSH
• biguanidy * aplikace a dávkování   farmakokinetika   farmakologie   škodlivé účinky   terapeutické užití   MeSH
• diabetes mellitus 2. typu * farmakoterapie   MeSH
• fixní kombinace léků * MeSH
• glifloziny MeSH
• glykovaný hemoglobin MeSH
• klinické zkoušky, fáze III jako téma MeSH
• kombinovaná farmakoterapie MeSH
• krevní glukóza MeSH
• lékové formy MeSH
• lidé MeSH
• metaanalýza jako téma MeSH
• metformin * aplikace a dávkování   farmakokinetika   farmakologie   škodlivé účinky   terapeutické užití   MeSH
• multicentrické studie jako téma MeSH
• postprandiální období MeSH
• proximální tubuly ledvin účinky léků   MeSH
• renální glykosurie MeSH
• transportér 2 pro sodík a glukózu * aplikace a dávkování   farmakokinetika   farmakologie   škodlivé účinky   terapeutické užití   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• hodnotící studie MeSH