• Publikační typ
• abstrakt z konference MeSH

• Publikační typ
• abstrakt z konference MeSH

Boldine is an aporphine alkaloid widely consumed in the folk medicine of some regions. Its anticancer potential has been shown but not yet elucidated. We compared the antitumor effect of orally and parenterally applied boldine in mice bearing solid Ehrlich tumor. We also explored the effects of boldine on breast adenocarcinoma MCF-7 cells in vitro. Repeated i. p. injections of 30, 60, or 90mg boldine/kg, either alone or combined with doxorubicin, slowed tumor growth in vivo. The latter two doses also prolonged the post-therapeutic survival of the mice. When fed food supplemented with boldine at a dose of 90mg/kg, the tumor-bearing mice survived significantly longer, but there was no effect on tumor size. Interestingly, continuous p. o. administration did not produce detectable levels of boldine in plasma or tissue samples, in contrast to high but short-lived concentrations after i. p. injections. There was neither antagonism nor synergism between boldine and doxorubicin, except a possible synergism of i. p. boldine 90mg/kg combined with doxorubicin when compared with doxorubicin alone.Boldine was cytotoxic to MCF-7 cells and reduced their viability and proliferation in vitro. Exposure to boldine decreased bromodeoxyuridine incorporation and histone H3 phosphorylation but did not induce apoptosis. Boldine treatment resulted in p38, ERK, and JNK activation in the mitogen-activated protein kinase pathway in a dose-dependent manner. Since bioavailability in mice seems to be different from that reported in rats, pharmacokinetic studies in humans are needed to evaluate the role of boldine in the beneficial effects of Boldo infusions. Copyright Georg Thieme Verlag KG Stuttgart . New York.

• MeSH
• adenokarcinom * farmakoterapie   MeSH
• antioxidancia farmakologie   terapeutické užití   MeSH
• aporfiny farmakologie   terapeutické užití   MeSH
• doxorubicin MeSH
• experimentální nádory mléčných žláz * farmakoterapie   MeSH
• fytoterapie MeSH
• léky antitumorózní - screeningové testy MeSH
• lidé MeSH
• MFC-7 buňky MeSH
• myši MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• ženské pohlaví MeSH
• zvířata MeSH

The aim of the current study was to clarify the effect of high sucrose diet (HSD) on bile formation (BF) in rats with hereditary hypertriglyceridemia (HHTg). Potentially positive effects were studied for boldine, a natural choleretic agent. Administration of HSD to HHTg rats led to increased triglyceride deposition in the liver. HSD reduced BF as a consequence of decreased biliary secretion of bile acids (BA) and glutathione. Responsible mechanism was down-regulation of hepatic transporters for BA and glutathione, Bsep and Mrp2, respectively. Moreover, gene expressions of transporters for other constituents of bile, namely Abcg5/8 for cholesterol, Abcb4 for phospholipids, and Oatp1a4 for xenobiotics, were also reduced by HSD. Boldine partially attenuated cholestatic effect of HSD by promotion of biliary secretion of BA through up-regulation of Bsep and Ntcp, and by increase in biliary secretion of glutathione as a consequence of its increased hepatic disposition. This study demonstrates mechanisms of impaired BF during nonalcoholic fatty liver disease induced by HSD. Altered function of responsible transporters suggests also potential for changes in kinetics of drugs, which may complicate pharmacotherapy in subjects with high intake of sucrose, and with fatty liver disease. Sucrose induced alterations in BF may be alleviated by administration of boldine.

• MeSH
• aporfiny terapeutické užití   MeSH
• cholestáza farmakoterapie   patologie   MeSH
• hypertriglyceridemie farmakoterapie   genetika   patologie   MeSH
• konzumní sacharóza škodlivé účinky   MeSH
• krysa rodu rattus MeSH
• nealkoholová steatóza jater farmakoterapie   patologie   MeSH
• potkani transgenní MeSH
• potkani Wistar MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

The aim of our study was to investigate whether two potent anti-inflammatory agents, dexamethasone and anakinra, an IL-1 receptor antagonist, may influence acute kidney injury (AKI) and associated drug excretory functions during endotoxemia (LPS) in rats. Ten hours after LPS administration, untreated endotoxemic rats developed typical symptoms of AKI, with reduced GFR, impaired tubular excretion of urea and sodium, and decreased urinary excretion of azithromycin, an anionic substrate for multidrug resistance-transporting proteins. Administration of both immunosuppressants attenuated the inflammatory response, liver damage, AKI, and increased renal clearance of azithromycin mainly by restoration of GFR, without significant influence on its tubular secretion. The lack of such an effect was related to the differential effect of both agents on the renal expression of individual drug transporters. Only dexamethasone increased the urinary clearance of bile acids, in accordance with the reduction of the apical transporter (Asbt) for their tubular reabsorption. In summary, our data demonstrated the potency of both agents used for the prevention of AKI, imposed by endotoxins, and for the restoration of renal drug elimination, mainly by the improvement of GFR. The influence of both drugs on altered tubular functions and the expression of drug transporters was differential, emphasizing the necessity of knowledge of transporting pathways for individual drugs applied during sepsis. The effect of anakinra suggests a significant contribution of IL-1 signaling to the pathogenesis of LPS-induced AKI.

• MeSH
• akutní poškození ledvin etiologie   prevence a kontrola   MeSH
• antagonista receptoru pro interleukin 1 farmakologie   terapeutické užití   MeSH
• antibakteriální látky farmakokinetika   MeSH
• antiflogistika farmakologie   terapeutické užití   MeSH
• azithromycin farmakokinetika   MeSH
• dexamethason farmakologie   terapeutické užití   MeSH
• eliminace ledvinami účinky léků   MeSH
• endotoxemie komplikace   farmakoterapie   MeSH
• endotoxiny farmakokinetika   MeSH
• hodnoty glomerulární filtrace účinky léků   MeSH
• imunosupresiva farmakologie   terapeutické užití   MeSH
• lipopolysacharidy MeSH
• potkani Wistar MeSH
• xenobiotika farmakokinetika   MeSH
• zvířata MeSH
• Check Tag
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Boldine, the major alkaloid from the Chilean Boldo tree, is used in traditional medicine to support bile production, but evidence to support this function is controversial. We analyzed the choleretic potential of boldine, including its molecular background. The acute- and long-term effects of boldine were evaluated in rats either during intravenous infusion or after 28-day oral treatment. Infusion of boldine instantly increased the bile flow 1.4-fold in healthy rats as well as in animals with Mrp2 deficiency or ethinylestradiol induced cholestasis. This effect was not associated with a corresponding increase in bile acid or glutathione biliary excretion, indicating that the effect is not related to stimulation of either bile acid dependent or independent mechanisms of bile formation and points to the osmotic activity of boldine itself. We subsequently analyzed bile production under conditions of changing biliary excretion of boldine after bolus intravenous administration and found strong correlations between both parameters. HPLC analysis showed that bile concentrations of boldine above 10 μM were required for induction of choleresis. Importantly, long-term pretreatment, when the bile collection study was performed 24-h after the last administration of boldine, also accelerated bile formation despite undetectable levels of the compound in bile. The effect paralleled upregulation of the Bsep transporter and increased biliary clearance of its substrates, bile acids. We consequently confirmed the ability of boldine to stimulate the Bsep transcriptional regulator, FXR receptor. In conclusion, our study clarified the mechanisms and circumstances surrounding the choleretic activity of boldine.

• MeSH
• ABC transportéry nedostatek   genetika   metabolismus   MeSH
• aplikace orální MeSH
• aporfiny aplikace a dávkování   metabolismus   farmakologie   MeSH
• buňky Hep G2 MeSH
• buňky MDCK MeSH
• cholagoga a choleretika aplikace a dávkování   metabolismus   farmakologie   MeSH
• ethinylestradiol farmakologie   MeSH
• genetická transkripce účinky léků   MeSH
• glutathion metabolismus   MeSH
• hepatobiliární exkrece MeSH
• intravenózní infuze MeSH
• játra účinky léků   metabolismus   MeSH
• kinetika MeSH
• lidé MeSH
• osmóza MeSH
• potkani inbrední LEW MeSH
• potkani transgenní MeSH
• potkani Wistar MeSH
• proteiny spojené s mnohočetnou rezistencí k lékům genetika   metabolismus   MeSH
• psi MeSH
• receptory cytoplazmatické a nukleární agonisté   genetika   metabolismus   MeSH
• signální transdukce účinky léků   MeSH
• transfekce MeSH
• upregulace MeSH
• žluč metabolismus   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• psi MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

The purpose of the present study was to compare the activity of two different clinically available iron chelators on the development of acute liver injury after administration of the bacterial endotoxin (lipopolysaccharide [LPS]) in rats. Lipopolysaccharide was administered either alone or after pretreatment with dexrazoxane (DEX) or deferoxamine (DFO). Control groups received only saline or its combination with either chelator. After 8 h, untreated LPS rats developed liver injury, with signs of inflammation and oxidative stress. Lipopolysaccharide reduced plasma iron concentrations in association with increased production of hepcidin and the reduced liver expression of ferroportin. Administration of chelating agents to LPS animals showed distinct effects. Although both drugs were able to reduce liver iron content, together with corresponding changes in hepcidin and ferroportin expressions, only DFO showed a protective effect against liver injury despite relatively small liver concentrations. In sharp contrast, DEX failed to improve any hallmark of liver injury and even worsened the GSH/GSSG ratio, the indicator of oxidative stress in the tissue. High-performance liquid chromatography-mass spectrometry analysis showed marked liver accumulation of iron-chelating metabolite of DEX (ADR-925), whereas the parent compound was undetectable. Further downregulation of transporters involved in bile formation was observed after DFO in the LPS group as well as in healthy animals. Neither chelator imposed significant liver injury in healthy animals. In conclusion, we demonstrated marked differences in the modulation of endotoxemic liver impairment between two iron chelators, implicating that particular qualities of chelating agents may be of crucial importance.

• MeSH
• chelátory železa terapeutické užití   MeSH
• deferoxamin terapeutické užití   MeSH
• dexrazoxan terapeutické užití   MeSH
• endotoxemie komplikace   MeSH
• krysa rodu rattus MeSH
• nemoci jater farmakoterapie   etiologie   MeSH
• potkani Wistar MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• srovnávací studie MeSH

• Publikační typ
• abstrakt z konference MeSH

• Publikační typ
• abstrakt z konference MeSH

Epigallocatechin gallate (EGCG) has been shown to be protective in various experimental models of liver injury, although opposite effects have also been reported. Since its effect on biliary physiology has not been thoroughly investigated, the present study evaluated effect of EGCG on bile flow and bile acid homeostasis in rats. Compared to controls, EGCG treatment decreased bile flow by 23%. Hepatic paracellular permeability and biliary bile acid excretion were not altered by EGCG administration, but biliary glutathione excretion was reduced by 70%. Accordingly, the main glutathione transporter on the hepatocyte canalicular membrane, multidrug resistance-associated protein 2 (Mrp2), was significantly decreased at the protein level. EGCG administration also doubled plasma bile acid levels compared to controls. While protein levels of the main hepatic bile acid transporters were unchanged, the rate-limiting enzyme in the bile acid synthesis, Cyp7a1, was significantly increased by EGCG. Enhanced bile acid synthesis in these animals was also confirmed by a 2-fold increase in plasma marker 7α-hydroxy-4-cholesten-3-one. In contrast, EGCG markedly downregulated major bile acid transporters (Asbt and Ostα) and regulatory molecules (Shp and Fgf15) in the ileum. When EGCG was coadministered with ethinylestradiol, a potent cholestatic agent, it did not show any additional effect on the induced cholestasis. This study shows ability of EGCG to raise plasma bile acid concentrations, mainly through Cyp7a1 upregulation, and to decrease bile production through reduction in Mrp2-mediated bile acid-independent bile flow. In conclusion, our data demonstrate that under certain conditions EGCG may induce cholestasis.

• MeSH
• ABC transportéry genetika   MeSH
• cholestáza chemicky indukované   MeSH
• cholestenony metabolismus   MeSH
• cholesterol-7-alfa-hydroxylasa genetika   metabolismus   MeSH
• down regulace účinky léků   MeSH
• ethinylestradiol farmakologie   MeSH
• glutathion metabolismus   MeSH
• hepatocyty účinky léků   metabolismus   MeSH
• homeostáza účinky léků   MeSH
• ileum účinky léků   metabolismus   MeSH
• katechin analogy a deriváty   toxicita   MeSH
• krysa rodu rattus MeSH
• permeabilita MeSH
• potkani Wistar MeSH
• upregulace účinky léků   MeSH
• žlučové kyseliny a soli biosyntéza   metabolismus   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH