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This paper describes tooth development in a basal squamate, Paroedura picta. Due to its reproductive strategy, mode of development and position within the reptiles, this gecko represents an excellent model organism for the study of reptile development. Here we document the dental pattern and development of non-functional (null generation) and functional generations of teeth during embryonic development. Tooth development is followed from initiation to cytodifferentiation and ankylosis, as the tooth germs develop from bud, through cap to bell stages. The fate of the single generation of non-functional (null generation) teeth is shown to be variable, with some teeth being expelled from the oral cavity, while others are incorporated into the functional bone and teeth, or are absorbed. Fate appears to depend on the initiation site within the oral cavity, with the first null generation teeth forming before formation of the dental lamina. We show evidence for a stratum intermedium layer in the enamel epithelium of functional teeth and show that the bicuspid shape of the teeth is created by asymmetrical deposition of enamel, and not by folding of the inner dental epithelium as observed in mammals.
- MeSH
- buněčná diferenciace MeSH
- ještěři embryologie MeSH
- modely u zvířat MeSH
- odontogeneze fyziologie MeSH
- zubní sklovina embryologie MeSH
- zuby embryologie MeSH
- zvířata MeSH
- Check Tag
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Xenograft models represent a promising tool to study the pathogenesis of hematological malignancies. To establish a reliable and appropriate in vivo model of aggressive human B-cell leukemia and lymphoma we xenotransplanted four p53-mutated cell lines and one ATM-mutated cell line into immunodeficient NOD/SCID IL2Rγ-null mice. The cell lines MEC-1, SU-DHL-4, JEKO-1, REC-1, and GRANTA-519 were transplanted intraperitoneally or subcutaneously and the engraftment was investigated using immunohistochemistry and flow cytometry. We found significant differences in engraftment efficiency. MEC-1, JEKO-1 and GRANTA-519 cell lines engrafted most efficiently, while SU-DHL-4 cells did not engraft at all. MEC-1 and GRANTA-519 massively infiltrated organs and the whole intraperitoneal cavity showing very aggressive growth. In addition, GRANTA-519 cells massively migrated to the bone marrow regardless of the transplantation route. The MEC-1 and GRANTA-519 cells can be especially recommended for in vivo study of p53-mutated chronic lymphocytic leukemia and ATM-mutated mantle cell lymphoma, respectively.
- MeSH
- ATM protein genetika MeSH
- biologické markery MeSH
- chronická lymfatická leukemie genetika metabolismus patologie MeSH
- genový knockout MeSH
- heterografty MeSH
- lidé MeSH
- lymfom z plášťových buněk genetika patologie MeSH
- modely nemocí na zvířatech MeSH
- mutace * MeSH
- myši inbrední NOD MeSH
- myši knockoutované MeSH
- myši SCID MeSH
- myši MeSH
- nádorové buněčné linie MeSH
- nádorový supresorový protein p53 genetika MeSH
- receptory interleukinů - společná gama-podjednotka genetika MeSH
- transplantace heterologní MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- mužské pohlaví MeSH
- myši MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Aristolochic acid (AA) causes aristolochic acid nephropathy, Balkan endemic nephropathy, and their urothelial malignancies. To identify enzymes involved in the metabolism of aristolochic acid I (AAI), the major toxic component of AA we used HRN (hepatic cytochrome P450 [Cyp] reductase null) mice, in which NADPH:Cyp oxidoreductase (Por) is deleted in hepatocytes. AAI was demethylated by hepatic Cyps in vitro to 8-hydroxy-aristolochic acid I (AAIa), indicating that less AAI is distributed to extrahepatic organs in wild-type (WT) mice. Indeed, AAI-DNA-adduct levels were significantly higher in organs of HRN mice, having low hepatic AAI demethylation capacity, than in WT mice. Absence of AAI demethylation in HRN mouse liver was confirmed in vitro; hepatic microsomes from WT, but not from HRN mice, oxidized AAI to AAIa. To define the role of hepatic Cyps in AAI demethylation, modulation of AAIa formation by CYP inducers was investigated. We conclude that AAI demethylation is attributable mainly to Cyp1a1/2. The higher AAI-DNA adduct levels in HRN than WT mice were the result of the lack of hepatic AAI demethylation concomitant with a higher activity of cytosolic NAD(P)H:quinone oxidoreductase (Nqo1), which activates AAI. Mouse hepatic Cyp1a1/2 also activated AAI to DNA adducts under hypoxic conditions in vitro, but in renal microsomes, Por and Cyp3a are more important than Cyp1a for AAI-DNA adduct formation. We propose that AAI activation and detoxication in mice are dictated mainly by AAI binding affinity to Cyp1a1/2 or Nqo1, by their turnover, and by the balance between oxidation and reduction of AAI by Cyp1a.
- MeSH
- adukty DNA MeSH
- biotransformace MeSH
- cytochrom P-450 CYP1A1 metabolismus MeSH
- cytochrom P-450 CYP1A2 metabolismus MeSH
- játra enzymologie metabolismus MeSH
- karcinogeny farmakokinetika MeSH
- krysa rodu rattus MeSH
- kyseliny aristolochové farmakokinetika MeSH
- lidé MeSH
- metylace MeSH
- myši inbrední C57BL MeSH
- myši knockoutované MeSH
- myši MeSH
- NADPH-cytochrom c-reduktasa genetika metabolismus MeSH
- spektrometrie hmotnostní - ionizace laserem za účasti matrice MeSH
- vysokoúčinná kapalinová chromatografie MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- lidé MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
The roles of autophagic cell death and apoptosis induced by topoisomerase inhibitor irinotecan in colon cancer cells with deleted p53 were investigated during 48 h. We report that irinotecan-dependent cytotoxicity and proapoptotic activity were reduced in the present model while autophagy levels significantly increased. Upon p53 transfection, cell demise rates increased, with cells bearing the features of apoptosis and autophagic cell death. The subsequent studies into mechanisms of cell death process revealed the important role of Bax in mediating mitochondrial and lysosomal leakage which might serve as leading signals for both apoptosis and autophagic cell death. These results suggest that different modes of cell death in p53 null colon cancer cells treated with cytostatics (irinotecan) may be activated simultaneously. Moreover, their interactions possibly occur at several stages and aren't mutually exclusive. This might thus lead to a potential synergism with interesting therapeutic ramifications.
- MeSH
- apoptóza účinky léků fyziologie MeSH
- autofagie účinky léků fyziologie MeSH
- buňky HT-29 MeSH
- fytogenní protinádorové látky farmakologie terapeutické užití MeSH
- HCT116 buňky MeSH
- kamptothecin analogy a deriváty farmakologie terapeutické užití MeSH
- lidé MeSH
- nádorové buněčné linie MeSH
- nádorový supresorový protein p53 nedostatek genetika MeSH
- nádory tračníku farmakoterapie genetika metabolismus MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Cardiovascular malformations are the most common manifestation of diabetic embryopathy. The molecular mechanisms underlying the teratogenic effect of maternal diabetes have not been fully elucidated. Using genome-wide expression profiling, we previously demonstrated that exposure to maternal diabetes resulted in dysregulation of the hypoxia-inducible factor 1 (HIF-1) pathway in the developing embryo. We thus considered a possible link between HIF-1-regulated pathways and the development of congenital malformations. HIF-1α heterozygous-null (Hif1a(+/-)) and wild type (Wt) littermate embryos were exposed to the intrauterine environment of a diabetic mother to analyze the frequency and morphology of congenital defects, and assess gene expression changes in Wt and Hif1a(+/-) embryos. We observed a decreased number of embryos per litter and an increased incidence of heart malformations, including atrioventricular septal defects and reduced myocardial mass, in diabetes-exposed Hif1a(+/-) embryos as compared to Wt embryos. We also detected significant differences in the expression of key cardiac transcription factors, including Nkx2.5, Tbx5, and Mef2C, in diabetes-exposed Hif1a(+/-) embryonic hearts compared to Wt littermates. Thus, partial global HIF-1α deficiency alters gene expression in the developing heart and increases susceptibility to congenital defects in a mouse model of diabetic pregnancy.
- MeSH
- celogenomová asociační studie MeSH
- embryo savčí embryologie patologie MeSH
- faktor 1 indukovatelný hypoxií - podjednotka alfa * MeSH
- genetická predispozice k nemoci MeSH
- mutantní kmeny myší MeSH
- myši MeSH
- srdce embryologie MeSH
- svalové proteiny biosyntéza genetika MeSH
- těhotenství při diabetu genetika metabolismus patologie MeSH
- těhotenství MeSH
- vrozené srdeční vady embryologie genetika patologie MeSH
- vývojová regulace genové exprese * MeSH
- zvířata MeSH
- Check Tag
- myši MeSH
- těhotenství MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Plant clonal spread is ubiquitous and of great interest, owing both to its key role in plant community assembly and its suitability for plant behaviour research. However, mechanisms that govern spreading distance are not well known. Here we link spacer costs and below-ground competition in a simple model of growth in a homogeneous below-ground environment, in which optimal distance between ramets is based on minimizing the sum of these costs. Using this model, we predict a high prevalence of clonal growth that does not employ spacers in resource-poor environments and a nonlinear increase in spreading distance in response to increasing below-ground resource availability. Analysis of database data on clonal growth in relationship to below-ground resource availability revealed that patterns of the spread based on stolons is compatible with the model's predictions. As expected, model prediction failed for rhizomatous species, where spacer sizes are likely to be selected mainly to play roles other than spread. The model's simplicity makes it useful as a null model in testing hypotheses about the effects of environmental heterogeneity on clonal spread.
Ellipticine is an antineoplastic agent, which forms covalent DNA adducts mediated by cytochromes P450 (CYP) and peroxidases. We evaluated the role of hepatic versus extra-hepatic metabolism of ellipticine, using the HRN (Hepatic Cytochrome P450 Reductase Null) mouse model, in which cytochrome P450 oxidoreductase (POR) is deleted in hepatocytes, resulting in the loss of essentially all hepatic CYP function. HRN and wild-type (WT) mice were treated i.p. with 1 and 10 mg/kg body weight of ellipticine. Multiple ellipticine-DNA adducts detected by (32)P-postlabelling were observed in organs from both mouse strains. Highest total DNA binding levels were found in liver, followed by lung, kidney, urinary bladder, colon and spleen. Ellipticine-DNA adduct levels in the liver of HRN mice were up to 65% lower relative to WT mice, confirming the importance of CYP enzymes for the activation of ellipticine in livers, recently shown in vitro with human and rat hepatic microsomes. When hepatic microsomes of both mouse strains were incubated with ellipticine, ellipticine-DNA adduct levels with WT microsomes were up to 2.9-fold higher than with those from HRN mice. The ratios of ellipticine-DNA adducts in extra-hepatic organs between HRN and WT mice of up to 4.7 suggest that these organs can activate ellipticine and that more ellipticine is available in the circulation. These results and the DNA adduct patterns found in vitro and in vivo demonstrate that both CYP1A or 3A and peroxidases participate in activation of ellipticine to reactive species forming DNA adducts in the mouse model used in this study.
- MeSH
- adukty DNA analýza metabolismus MeSH
- cytochrom P-450 CYP1A1 metabolismus MeSH
- cytochrom P-450 CYP3A metabolismus MeSH
- DNA metabolismus účinky léků MeSH
- elipticiny metabolismus toxicita MeSH
- hepatocyty enzymologie účinky léků MeSH
- injekce intraperitoneální MeSH
- izotopové značení metody MeSH
- jaterní mikrozomy enzymologie účinky léků MeSH
- játra enzymologie účinky léků MeSH
- myši inbrední C57BL MeSH
- myši knockoutované MeSH
- myši MeSH
- NADPH-cytochrom c-reduktasa genetika metabolismus nedostatek MeSH
- protinádorové látky metabolismus toxicita MeSH
- radioizotopy fosforu MeSH
- umlčování genů MeSH
- vztah mezi dávkou a účinkem léčiva MeSH
- zvířata MeSH
- Check Tag
- mužské pohlaví MeSH
- myši MeSH
- zvířata MeSH
Kinin-vasoactive peptides activate two G-protein-coupled receptors (R), B(1)R (inducible) and B(2)R (constitutive). Their complex role in cardiovascular diseases could be related to differential actions on oxidative stress. This study investigated impacts of B(1)R or B(2)R gene deletion in mice on the cardiac function and plasma antioxidant and oxidant status. Echocardiography-Doppler was performed in B(1)R (B(1)R(-/-)) and B(2)R (B(2)R(-/-)) deficient and wild type (WT) adult male mice. No functional alteration was observed in B(2)R(-/-) hearts. B(1)R(-/-) mice had significantly lowered fractional shortening and increased isovolumetric contraction time. The diastolic E and A waves velocity ratio was similar in all mice groups. Thus B(1)R(-/-) mice provide a model of moderate systolic dysfunction, whereas B(2)R(-/-) mice displayed a normal cardiac phenotype. Plasma antioxidant capacity (ORAC) was significantly decreased in both B(1)R(-/-) and B(2)R(-/-) mice whereas the vitamin C levels were decreased in B(2)R(-/-) mice only. Plasma ascorbyl free radical was significantly higher in B(1)R(-/-) compared to WT and B(2)R(-/-) mice. Therefore, the oxidative stress index, ascorbyl free radical to vitamin C ratio, was increased in both B(1)R(-/-) and B(2)R(-/-) mice. Hence, B(1)R and B(2)R deficiency are associated with increased oxidative stress, but there is a differential imbalance between free radical production and antioxidant defense. The interrelationship between the differential B(1)R and B(2)R roles in oxidative stress and cardiovascular diseases remain to be investigated.
- MeSH
- antioxidancia metabolismus MeSH
- biologické markery krev MeSH
- dysfunkce levé srdeční komory krev genetika metabolismus patofyziologie MeSH
- funkce levé komory srdeční * MeSH
- kontrakce myokardu * MeSH
- kyselina dehydroaskorbová analogy a deriváty krev MeSH
- myokard metabolismus MeSH
- myši inbrední C57BL MeSH
- myši kmene 129 MeSH
- myši knockoutované MeSH
- myši MeSH
- oxidační stres * MeSH
- pulzní dopplerovská echokardiografie MeSH
- receptor bradykininu B1 nedostatek genetika MeSH
- receptor bradykininu B2 nedostatek genetika MeSH
- zvířata MeSH
- Check Tag
- mužské pohlaví MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Tibial pseudarthrosis often features deficient bone formation, excessive bone resorption, and extensive pathological fibrosis, particularly in individuals with Neurofibromatosis type I (NF1). It was hypothesized that overactive NF1-Ras-JNK signalling may underlie the pathological fibrosis, and that this could be treated via a JNK antagonist. CC-930, a small molecule JNK inhibitor, was trialed in closed fractures in wild type mice CC-930 (25 mg/kg/twice daily) was dosed throughout fracture healing (D2–21) and during the latter stages of repair (D11–21). All fractures healed by D21, regardless of treatment, with some of the CC-930 (D11–21) treatment group showing early bridging. CC-930 (D11–21) was tested in an Nf1-null fracture model where Nf1 was inactivated by Ad-Cre virus injection in Nf1flox/flox mice; these mice also possessed a Cre-responsive tdTomato transgene. CC-930 resulted in a significant decrease in non-unions (93% vehicle vs. 64% CC-930, p < 0.01). Local treatment with the bone anabolic rhBMP-2 (10 μg) increased union and callus bone volume, but also increased the fibrotic tissue at the fracture site. Fractures treated with a combination of rhBMP-2 (10 μg) and CC-930 were all partially or fully bridged by D21 (p < 0.01 vs. vehicle) and there was a significant decrease in fibrosis vs. rhBMP-2 alone (p < 0.01). In untreated Nf1-null fractures, the tdTomato transgene was expressed in fibrous tissue at the fracture site, but not in the newly forming bone. These data suggest that JNK inhibition may be an effective therapeutic approach for reducing pathological fibrosis in NF1 tibial pseudarthrosis, however other adjunctive strategies may be required to augment bone formation.
- MeSH
- fraktury tibie farmakoterapie MeSH
- hojení fraktur MeSH
- JNK mitogenem aktivované proteinkinasy antagonisté a inhibitory MeSH
- kostní morfogenetický protein 2 aplikace a dávkování farmakologie MeSH
- modely nemocí na zvířatech MeSH
- myši inbrední C57BL MeSH
- neurofibromatóza 1 * komplikace MeSH
- pseudoartróza diagnostické zobrazování patologie prevence a kontrola MeSH
- Publikační typ
- práce podpořená grantem MeSH
Pulmonary artery banding (PAB) is used as a surgical palliation to reduce excessive pulmonary blood flow caused by congenital heart defects. Due to the lack of microscopic studies dealing with the tissue remodeling caused by contemporary PAB materials, this study aimed to assess histologic changes associated with PAB surgery by analyzing local tissue reaction to the presence of Gore-Tex strips fixed around the pulmonary artery. Gore-Tex strips were used for PAB in a growing porcine model. After 5 weeks, histologic samples with PAB (n = 5) were compared with healthy pulmonary arterial segments distal to the PAB or from a sham-treated animal (n = 1). Stereology was used to quantify the density of the vasa vasorum and the area fraction of elastin, smooth muscle actin, macrophages, and nervi vasorum within the pulmonary arterial wall. The null hypothesis stated that samples did not differ histopathologically from adjacent vascular segments or sham-treated samples. The PAB samples had a greater area fraction of macrophages, a lower amount of nervi vasorum, and a tendency toward decreased smooth muscle content compared with samples that had no PAB strips. There was no destruction of elastic membranes, no medionecrosis, no pronounced inflammatory infiltration or foreign body reaction, and no vasa vasorum deficiency after the PAB. All the histopathologic changes were limited to the banded vascular segment and did not affect distal parts of the pulmonary artery. The study results show the tissue reaction of palliative PAB and suggest that Gore-Tex strips used contemporarily for PAB do not cause severe local histologic damage to the banded segment of the pulmonary arterial wall after 5 weeks in a porcine PAB model.
- MeSH
- arteria pulmonalis patologie chirurgie MeSH
- hemodynamika MeSH
- ligace MeSH
- modely nemocí na zvířatech MeSH
- následné studie MeSH
- prasata MeSH
- svaly hladké cévní patologie MeSH
- vrozené srdeční vady patologie chirurgie MeSH
- výkony cévní chirurgie metody MeSH
- zvířata MeSH
- Check Tag
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- srovnávací studie MeSH