Neonatal hyperbilirubinemia or jaundice is associated with kernicterus, resulting in permanent neurological damage or even death. Conventional phototherapy does not prevent hyperbilirubinemia or eliminate the need for exchange transfusion. Here we investigated the potential of therapeutic bile acids ursodeoxycholic acid (UDCA) and obeticholic acid (OCA, 6-α-ethyl-CDCA), a farnesoid-X-receptor (FXR) agonist, as preventive treatment options for neonatal hyperbilirubinemia using the hUGT1*1 humanized mice and Ugt1a-deficient Gunn rats. Treatment of hUGT1*1 mice with UDCA or OCA at postnatal days 10-14 effectively decreased bilirubin in plasma (by 82% and 62%) and brain (by 72% and 69%), respectively. Mechanistically, our findings indicate that these effects are mediated through induction of protein levels of hUGT1A1 in the intestine, but not in liver. We further demonstrate that in Ugt1a-deficient Gunn rats, UDCA but not OCA significantly decreases plasma bilirubin, indicating that at least some of the hypobilirubinemic effects of UDCA are independent of UGT1A1. Finally, using the synthetic, non-bile acid, FXR-agonist GW4064, we show that some of these effects are mediated through direct or indirect activation of FXR. Together, our study shows that therapeutic bile acids UDCA and OCA effectively reduce both plasma and brain bilirubin, highlighting their potential in the treatment of neonatal hyperbilirubinemia.
- MeSH
- bilirubin krev MeSH
- ileum účinky léků metabolismus MeSH
- isoxazoly farmakologie MeSH
- játra účinky léků metabolismus MeSH
- kyselina chenodeoxycholová analogy a deriváty terapeutické užití MeSH
- kyselina ursodeoxycholová terapeutické užití MeSH
- myši MeSH
- novorozenecká hyperbilirubinemie krev farmakoterapie MeSH
- potkani Gunn MeSH
- receptory cytoplazmatické a nukleární agonisté metabolismus MeSH
- výsledek terapie MeSH
- žlučové kyseliny a soli terapeutické užití MeSH
- zvířata MeSH
- Check Tag
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Butyrate produced by the intestinal microbiota is essential for proper functioning of the intestinal immune system. Total dependence on parenteral nutrition (PN) is associated with numerous adverse effects, including severe microbial dysbiosis and loss of important butyrate producers. We hypothesised that a lack of butyrate produced by the gut microbiota may be compensated by its supplementation in PN mixtures. We tested whether i.v. butyrate administration would (a) positively modulate intestinal defence mechanisms and (b) counteract PN-induced dysbiosis. Male Wistar rats were randomised to chow, PN, and PN supplemented with 9 mM butyrate (PN+But) for 12 days. Antimicrobial peptides, mucins, tight junction proteins, and cytokine expression were assessed by RT-qPCR. T-cell subpopulations in mesenteric lymph nodes (MLN) were analysed by flow cytometry. Microbiota composition was assessed in caecum content. Butyrate supplementation resulted in increased expression of tight junction proteins (ZO-1, claudin-7, E-cadherin), antimicrobial peptides (Defa 8, Rd5, RegIIIγ), and lysozyme in the ileal mucosa. Butyrate partially alleviated PN-induced intestinal barrier impairment and normalised IL-4, IL-10, and IgA mRNA expression. PN administration was associated with an increase in Tregs in MLN, which was normalised by butyrate. Butyrate increased the total number of CD4+ and decreased a relative amount of CD8+ memory T cells in MLN. Lack of enteral nutrition and PN administration led to a shift in caecal microbiota composition. Butyrate did not reverse the altered expression of most taxa but did influence the abundance of some potentially beneficial/pathogenic genera, which might contribute to its overall beneficial effect.
- MeSH
- biodiverzita MeSH
- butyráty farmakologie MeSH
- fenotyp MeSH
- fylogeneze MeSH
- ileum účinky léků patologie MeSH
- kolon účinky léků patologie MeSH
- lymfatické uzliny účinky léků metabolismus MeSH
- lymfocyty účinky léků metabolismus MeSH
- messenger RNA genetika metabolismus MeSH
- modely u zvířat MeSH
- muciny biosyntéza MeSH
- Panethovy buňky účinky léků metabolismus MeSH
- parenterální výživa * MeSH
- peptidy genetika metabolismus MeSH
- permeabilita MeSH
- potkani Wistar MeSH
- potravní doplňky * MeSH
- proteiny těsného spoje metabolismus MeSH
- regulace genové exprese účinky léků MeSH
- střeva patologie MeSH
- střevní mikroflóra * účinky léků MeSH
- tenké střevo účinky léků MeSH
- zvířata MeSH
- Check Tag
- mužské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
The Campylobacter jejuni-host interaction may be affected by the host's gut microbiota through competitive exclusion, metabolites, or modification of the immune response. To understand this interaction, C. jejuni colonization and local immune responses were compared in chickens with different gut microbiota compositions. Birds were treated with an antibiotic cocktail (AT) (experiments 1 and 2) or raised under germfree (GF) conditions (experiment 3). At 18 days posthatch (dph), they were orally inoculated either with 104 CFU of C. jejuni or with diluent. Cecal as well as systemic C. jejuni colonization, T- and B-cell numbers in the gut, and gut-associated tissue were compared between the different groups. Significantly higher numbers of CFU of C. jejuni were detected in the cecal contents of AT and GF birds, with higher colonization rates in spleen, liver, and ileum, than in birds with a conventional gut microbiota (P < 0.05). Significant upregulation of T and B lymphocyte numbers was detected in cecum, cecal tonsils, and bursa of Fabricius of AT or GF birds after C. jejuni inoculation compared to the respective controls (P < 0.05). This difference was less clear in birds with a conventional gut microbiota. Histopathological gut lesions were observed only in C. jejuni-inoculated AT and GF birds but not in microbiota-colonized C. jejuni-inoculated hatchmates. These results demonstrate that the gut microbiota may contribute to the control of C. jejuni colonization and prevent lesion development. Further studies are needed to identify key players of the gut microbiota and the mechanisms behind their protective role.
- MeSH
- antibakteriální látky farmakologie MeSH
- B-lymfocyty imunologie mikrobiologie MeSH
- bursa Fabricii účinky léků imunologie mikrobiologie MeSH
- Campylobacter jejuni účinky léků imunologie patogenita MeSH
- cékum účinky léků imunologie mikrobiologie MeSH
- gnotobiologické modely imunologie MeSH
- ileum účinky léků imunologie mikrobiologie MeSH
- interakce hostitele a patogenu imunologie MeSH
- játra účinky léků imunologie mikrobiologie MeSH
- kampylobakterové infekce imunologie mikrobiologie veterinární MeSH
- kur domácí MeSH
- mikrobiální interakce imunologie MeSH
- nemoci drůbeže imunologie mikrobiologie MeSH
- počet mikrobiálních kolonií MeSH
- slezina účinky léků imunologie mikrobiologie MeSH
- střevní mikroflóra imunologie MeSH
- T-lymfocyty imunologie mikrobiologie MeSH
- zvířata MeSH
- Check Tag
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
This study was undertaken to evaluate possible antiallergic effects of an extract of pigments from green sea urchin (Strongylocentrotus droebachiensis) shells. Effects were studied on animal models - guinea pig ileum contraction, rabbit eyes allergic conjunctivitis, and rabbit local skin irritation. The extract significantly reduced, in a dose-dependent manner, the histamine-induced contractions of the isolated guinea pig ileum with ID50 =1.2 µg/mL (in equivalents of spinochrome B), had an inhibitory effect on the model of ocular allergic inflammation surpassing the reference drug olopatadine, and did not show any irritating effect in rabbits. The extract predominantly contained polyhydroxy-1,4-naphthoquinone which would be responsible for the pharmacological activity. The active compounds of the extract were evaluated in silico with molecular docking. Molecular docking into H1R receptor structures obtained from molecular dynamic simulations showed that all spinochrome derivatives bind to the receptor active site, but spinochrome monomers fit better to it. The results of the present study suggest possibilities for the development of new agents for treating allergic diseases on the base of pigments from sea urchins shells.
- MeSH
- alergická konjunktivitida farmakoterapie MeSH
- antialergika chemie izolace a purifikace farmakologie MeSH
- biologické pigmenty chemie MeSH
- dibenzoxepiny farmakologie MeSH
- histamin farmakologie MeSH
- ileum účinky léků MeSH
- králíci MeSH
- kůže účinky léků MeSH
- modely nemocí na zvířatech MeSH
- morčata MeSH
- naftochinony chemie izolace a purifikace farmakologie MeSH
- simulace molekulového dockingu MeSH
- skořápky zvířat chemie MeSH
- Strongylocentrotus chemie MeSH
- vztah mezi dávkou a účinkem léčiva MeSH
- zvířata MeSH
- Check Tag
- králíci MeSH
- morčata MeSH
- mužské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem 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
This study aimed to investigate the effects of intravenous anesthetics on hepatosplanchnic microcirculation in laparotomized mechanically ventilated rats using Sidestream Dark-field (SDF) imaging. Thirty male Wistar rats were divided into 5 groups (n = 6 each). All rats were initially anesthetized with 60 mg/kg pentobarbital (i.p.) for instrumentation. This was followed by either ketamine, propofol, thiopental, midazolam or saline+fentanyl (iv bolus over 5 min and then maintenance over 90 min). SDF imaging of the liver and distal ileum microcirculation was performed at the baseline and at t = 5, 35, 65 and 95 min. In propofol group there was increase of functional sinusoidal density (FSD) following induction (+25%, P < 0.05) and maintenance at t = 95 min (+10.3%, P < 0.05), in ketamine and midazolam group decrease of FSD was observed after induction (-20.4%, P < 0.05; -10.1%, P < 0.05) and during maintenance at t = 65 min (-11.6%, P < 0.05; -11.4%, P < 0.05) when compared to baseline. Following induction with propofol functional capillary density (FCD) of ileal longitudinal muscle layer increased (+10.6%, P < 0.05) and returned to baseline values during maintenance. Ketamine and midazolam decreased FCD of longitudinal layer after induction (-24.6%, P < 0.05; -21.1%, P < 0.05) and remained decreased during maintenance at t = 95 min (-10.8%, P < 0.05; -15.5%, P < 0.05). In thiopental and control group, changes in microcirculatory parameters were not significant throughout the study. In conclusion, intravenous anesthetics affect the hepatosplanchnic microcirculation differentially, propofol has shown protective effect on the liver and intestinal microcirculation.
- MeSH
- analýza krevních plynů MeSH
- anestetika intravenózní farmakologie MeSH
- fentanyl farmakologie MeSH
- ileum krevní zásobení účinky léků MeSH
- játra krevní zásobení účinky léků MeSH
- ketamin farmakologie MeSH
- krysa rodu rattus MeSH
- midazolam farmakologie MeSH
- mikrocirkulace účinky léků MeSH
- potkani Wistar MeSH
- propofol farmakologie MeSH
- thiopental farmakologie MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- mužské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Klíčová slova
- slizniční zhojení,
- MeSH
- biologická terapie metody trendy využití MeSH
- Crohnova nemoc farmakoterapie MeSH
- gastroenterologie metody trendy MeSH
- hodnocení léčiv MeSH
- ileum patologie účinky léků MeSH
- lidé MeSH
- metaanalýza jako téma MeSH
- monoklonální protilátky aplikace a dávkování škodlivé účinky terapeutické užití MeSH
- multicentrické studie jako téma MeSH
- nežádoucí účinky léčiv MeSH
- statistika jako téma MeSH
- střevní sliznice účinky léků MeSH
- stupeň závažnosti nemoci MeSH
- TNF-alfa antagonisté a inhibitory aplikace a dávkování terapeutické užití MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- kongresy MeSH
The quaternary benzo[c]phenanthridine alkaloid sanguinarine (SG) is the main component of Sangrovit, a natural livestock feed additive. Dihydrosanguinarine (DHSG) has recently been identified as a SG metabolite in rat. The conversion of SG to DHSG is a likely elimination pathway of SG in mammals. This study was conducted to evaluate the toxicity of DHSG in male Wistar rats at concentrations of 100 and 500 ppm DHSG in feed for 90 days (average doses of 14 and 58 mg DHSG/kg body weight/day). No significant alterations in body or organ weights, macroscopic details of organs, histopathology of liver, ileum, kidneys, tongue, heart or gingiva, clinical chemistry or hematology markers in blood in the DHSG-treated animals were found compared to controls. No lymphocyte DNA damage by Comet assay, formation of DNA adducts in liver by 32P-postlabeling, modulation of cytochrome P450 1A1/2 or changes in oxidative stress parameters were found. Thus, repeated dosing of DHSG for 90 days at up to 500 ppm in the diet (i.e. approximately 58 mg/kg/day) showed no evidence of toxicity in contrast to results published in the literature. In parallel, DHSG pharmacokinetics was studied in rat after oral doses 9.1 or 91 mg/kg body weight. The results showed that DHSG undergoes enterohepatic cycling with maximum concentration in plasma at the first or second hour following application. DHSG is cleared from the body relatively quickly (its plasma levels drop to zero after 12 or 18 h, respectively).
- MeSH
- adukty DNA MeSH
- benzofenantridiny farmakokinetika krev toxicita MeSH
- biochemická analýza krve MeSH
- časové faktory MeSH
- financování organizované MeSH
- ileum patologie účinky léků MeSH
- isochinoliny farmakokinetika krev toxicita MeSH
- játra patologie účinky léků MeSH
- kometový test MeSH
- krmivo pro zvířata MeSH
- krysa rodu rattus MeSH
- náhodné rozdělení MeSH
- orgánová specificita MeSH
- oxidační stres účinky léků MeSH
- pilotní projekty MeSH
- plocha pod křivkou MeSH
- poškození DNA účinky léků MeSH
- potkani Wistar MeSH
- systém (enzymů) cytochromů P-450 účinky léků MeSH
- testy genotoxicity MeSH
- tkáňová distribuce MeSH
- velikost orgánu účinky léků MeSH
- vztah mezi dávkou a účinkem léčiva MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- mužské pohlaví MeSH
- zvířata MeSH
- Klíčová slova
- imuregen,
- MeSH
- dieta metody MeSH
- finanční podpora výzkumu jako téma MeSH
- ileum účinky léků MeSH
- myši MeSH
- oligonukleotidy aplikace a dávkování farmakologie MeSH
- polynukleotidy aplikace a dávkování farmakologie MeSH
- střevní sliznice účinky léků MeSH
- zvířata MeSH
- Check Tag
- myši MeSH
- ženské pohlaví MeSH
- zvířata MeSH
