Biomedical subjects

Petr Nachtigal

Publications and source records attributed to Petr Nachtigal.

10 recordsLinked to original sources

PubMed2006

Atorvastatin slows down the deterioration of inner ear function with age in mice.

Statins have revolutionized the treatment of hypercholesterolemia due to their ability to inhibit cholesterol biosynthesis. Their immunomodulatory and anti-inflammatory effects and positive effects on the treatment of atherosclerosis and its complications are well known. Here, we describe the effects of statins on the treatment of presbycusis in C57BL/6J mice. In this strain with accelerated aging, we demonstrate that animals treated with atorvastatin (10mg/kg per day in chow diet) for 2 months showed larger amplitudes of distortion product otoacoustic emissions (DPOAE) than did the non-treated control group. This finding indicates a better survival of outer hair cell function in the inner ear of C57BL/6J mice. The observed decreased expression of intercellular and vascular adhesion molecules in the aortic wall of atorvastatin-treated animals suggests that reducing endothelial inflammatory effects may contribute to the positive effect of atorvastatin on the amplitudes of DPOAE by influencing the blood supply to the inner ear. No such beneficial effect of statins was found in apoE(-/-) mice treated with atorvastatin under the same conditions. Our results suggest that statins could also slow down the age-related deterioration of hearing in man.

Acoustic Stimulation↗

PubMed2006

Expression and transport activity of breast cancer resistance protein (Bcrp/Abcg2) in dually perfused rat placenta and HRP-1 cell line.

Breast cancer resistance protein (BCRP/ABCG2) is a member of the ATP-binding cassette transporter family that recognizes a variety of chemically unrelated compounds. Its expression has been revealed in many mammal tissues, including placenta. The purpose of this study was to describe its role in transplacental pharmacokinetics using rat placental HRP-1 cell line and dually perfused rat placenta. In HRP-1 cells, expression of Bcrp, but not P-glycoprotein, was revealed at mRNA and protein levels. Cell accumulation studies confirmed Bcrp-dependent uptake of BODIPY FL prazosin. In the placental perfusion studies, a pharmacokinetic model was applied to distinguish between passive and Bcrp-mediated transplacental passage of cimetidine as a model substrate. Bcrp was shown to act in a concentration-dependent manner and to hinder maternal-to-fetal transport of the drug. Fetal-to-maternal clearance of cimetidine was found to be 25 times higher than that in the opposite direction; this asymmetry was partly eliminated by BCRP inhibitors fumitremorgin C (2 microM) or N-(4-[2-(1,2,3,4-tetrahydro-6,7-dimethoxy-2-isoquinolinyl)ethyl]-phenyl)-9,10-dihydro-5-methoxy-9-oxo-4-acridine carboxamide (GF120918; 2 microM) and abolished at high cimetidine concentrations (1000 microM). When fetal perfusate was recirculated, Bcrp was found to actively remove cimetidine from the fetal compartment to the maternal compartment even against a concentration gradient and to establish a 2-fold maternal-to-fetal concentration ratio. Based on our results, we propose a two-level defensive role of Bcrp in the rat placenta in which the transporter 1) reduces passage of its substrates from mother to fetus but also 2) removes the drug already present in the fetal circulation.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed2006

Atorvastatin has distinct effects on endothelial markers in different mouse models of atherosclerosis.

PURPOSE: Atherosclerosis is a progressive process that initially involves endothelial dysfunction. We investigated the effects of atorvastatin on both lipid parameters, and VCAM-1 and ICAM-1 expression in apoE-deficient or wild type C57BL/6J mice. METHODS: The C57BL/6J mice were fed with either chow or an atherogenic diet for 12 weeks. Male apoE-deficient mice were fed with the chow diet for 12 weeks. In 3 atorvastatin treated groups mice were fed the same diet as described above except atorvastatin was added to the diet at the dosage of 10 mg/kg per day for the last 8 weeks before euthanasia. RESULTS: Biochemical analysis showed that atorvastatin significantly decreased total cholesterol levels and VLDL in C57BL/6J mice fed with atherogenic diet but increased serum lipid levels in apoE-deficient mice. Stereological analysis of the immunohistochemical staining revealed that atorvastatin reduced endothelial expression of ICAM-1 and VCAM-1 only in C57BL/6J mice on chow diet. CONCLUSION: We have demonstrated that endothelial expression of both VCAM-1 and ICAM-1 does not correlate with cholesterol levels in these mice. Moreover, we showed that 8-week administration of atorvastatin decrease endothelial expression of VCAM-1 and ICAM-1 in C57BL/6J wild type mice beyond its lipid lowering effect but not in C57BL/6J wild type mice fed by atherogenic diet or in apoE-deficient mice.

Animals↗

PubMed2006

Endoglin expression in hyper-cholesterolemia and after atorvastatin treatment in apoE-deficient mice.

PURPOSE: Endoglin (CD105) is a marker of activated endothelium and a modulator of TGF-beta signaling. We hypothesized whether endothelial expression of endoglin is changed in hypercholesterolemia as well as whether its expression is affected by atorvastatin treatment in apoE-deficient mice. METHODS: ApoE-deficient mice were fed with the chow diet for either 4 weeks or for 12 weeks respectively. In two treated groups, mice were fed with chow diet except atorvastatin was added to the diet for the last 4 weeks or for the last 8 weeks respectively, before euthanasia. RESULTS: Administration of atorvastatin did not affect lipid parameters after 4 weeks treatment, however increased all lipid parameters after 8 weeks of treatment. Stereological analysis of immunohistochemical staining revealed that atorvastatin significantly decreased endoglin expression in endothelium after 4 weeks of treatment but increased it after 8 weeks of treatment. CONCLUSIONS: This study demonstrates that endoglin is expressed by aortic endothelium showing similar staining patterns like other markers involved in the process of atherosclerosis. In addition, we showed that endoglin expression in endothelium could be affected by the administration of atorvastatin beyond its lipid lowering effects in apoE-deficient mice.

Animals↗

PubMed2005

MDOC and atorvastatin have potential antiinflammatory effects in vascular endothelium of apoE-/- mouse model of atherosclerosis.

Members of the immunoglobulin superfamily of endothelial adhesion molecules, vascular cell adhesion molecule (VCAM-1) and intercellular cell adhesion molecule (ICAM- 1), strongly participate in leukocyte adhesion to the endothelium and play an important role in all stages of atherogenesis. The aim of this study was to detect and quantify the changes of endothelial expression of VCAM-1, and ICAM-1 in the vessel wall after the short-term administration of simvastatin, atorvastatin, and micro dispersed derivatives of oxidised cellulose (MDOC) in apolipoprotein-E-deficient (apoE(-/-)) mice atherosclerotic model. Hyperlipidemic apoE(-/-) mice (n = 32) received normal chow diet or diet containing simvastatin or atorvastatin 10 mg/kg/day or MDOC 50 mg/kg/day. Total cholesterol, VLDL, LDL, HDL and TAG were measured and the endothelial expression of VCAM-1 and ICAM-1 was visualized and quantified by means of immunohistochemistry and stereology, respectively. Total cholesterol levels was insignificantly lowered only in MDOC treated mice but not in mice treated with statins. ICAM-1 endothelial expression was not affected by neither simvastatin nor MDOC treatment. However, significant diminution of VCAM-1 endothelial expression was observed in both atorvastatin and MDOC treated mice. These results provide new information of potential hypolipidemic substance MDOC and its potential anti-inflammatory effects. Furthermore, we have confirmed anti-inflammatory effects of atorvastatin independent of plasma cholesterol lowering. Thus, the results of this study show potential benefit of both MDOC and atorvastatin treatment in apoE(-/-) mouse model of atherosclerosis suggesting their possible combination might be of interest.

Administration, Oral↗

PubMed2005

Vimentin expression during altered spermatogenesis in rats.

The collapse of vimentin caused by some xenobiotics correlates with the loss of structural integrity of the seminiferous epithelium. In this study, we investigated the effect of busulphan (an anticancer drug with toxic effects on dividing germ cells) on vimentin filament distribution in rat seminiferous epithelium and compared it with changes found in testes of unilaterally cryptorchid rats. In the seminiferous epithelium, the vimentin labelling was observed only in the Sertoli cells, showing a stage-specific arrangement of the filaments. Both busulphan treatment and cryptorchism caused altered distribution of vimentin filaments in the Sertoli cells. In both models, the apical vimentin filaments collapsed towards the nuclei and were disorganized in the basal region of the Sertoli cells while the germ cells were diminished in the epithelium. After the busulphan effect subsided (4 weeks after administration), spermatogenesis began to restore and vimentin filaments began to organize in basal and perinuclear regions of Sertoli cells among the spermatogonia and spermatocytes. Vimentin labelling of the sloughed material in the lumen of cryptorchid testes (but not in busulphan treated animals) was observed. We conclude that the Sertoli cell vimentin filaments play an important role in the maintenance of spermatogenesis, their damage is associated with the seminiferous epithelium disintegration and their restoration with a recovery of spermatogenesis after the unfavourable conditions subside.

Animals↗

PubMed2005

The changes in the endothelial expression of cell adhesion molecules and iNOS in the vessel wall after the short-term administration of simvastatin in rabbit model of atherosclerosis.

Cell adhesion molecules P-selectin, VCAM-1 and ICAM-1 play an important role in the pathogenesis of atherosclerosis. High levels of nitric oxide (NO) produced by inducible NO synthase (iNOS) have been associated with atherosclerotic processes. Simvastatin is an HMG-CoA reductase inhibitor responsible for many clinical benefits. The aim of this study was to detect and quantify changes in endothelial expression of P-selectin, VCAM-1, ICAM-1 and iNOS in the vessel wall after the shortterm administration of simvastatin in a rabbit model of atherosclerosis. Eighteen New Zealand White rabbits were randomly divided into three groups (n=6). In the cholesterol group, rabbits consumed an atherogenic diet (0.4% cholesterol) for eight weeks. In the simvastatin group, rabbits consumed an atherogenic diet for six weeks and then consumed an atherogenic diet supplemented with simvastatin (10 mg kg(-1)) for two weeks. Biochemical analysis showed that administration of simvastatin led to an almost two-fold lowering of the total serum cholesterol, VLDL, LDL and HDL, but not triglycerides, compared with the cholesterol-fed rabbits only. Stereological analysis of the immunohistochemical staining revealed that administration of simvastatin (10 mg kg(-1) daily) in an atherogenic diet decreased the endothelial expression of P-selectin, ICAM-1 and iNOS in both aortic arch and carotid artery compared with the cholesterol fed-rabbits only. We conclude that simvastatin has beneficial effects on endothelial function by decreasing expression of P-selectin, ICAM-1 and iNOS in endothelial cells in the very early stages of atherogenesis.

Animals↗

PubMed2004

Analysis of accumulation of 99mTc-octreotide and 99mTc-EDDA/HYNIC-Tyr3-octreotide in the rat kidneys.

The aim of this study was to compare renal handling and distribution of (99m)Tc-octreotide and (99m)Tc-EDDA/HYNIC-Tyr(3)-octreotide (HYNIC-TOC) in rats. In kidney perfusion experiments, the renal clearance value of (99m)Tc-octreotide was three times lower than that of (99m)Tc-EDDA/HYNIC-TOC. The predominant renal excretion of (99m)Tc-EDDA/HYNIC-TOC was associated with a high and long-term renal accumulation up to 48 hrs. Microautoradiographic results indicated that (99m)Tc-EDDA/HYNIC-TOC was retained mainly in the renal medulla within the cells of the collecting ducts and in the surrounding tissue. Lower positivity was found in the proximal and distal tubular cells. We conclude that the mechanism of renal accumulation of somatostatin analogues renal accumulation is complex and that proximal tubular reabsorption is probably not the main mechanism for uptake of (99m)Tc-EDDA/HYNIC-TOC in the kidneys. The presence of the somatostatin receptors, differences in the tonicity level within kidneys and other possible mechanisms could participate in their renal accumulation.

Animals↗

PubMed2004

Application of stereological methods for the quantification of VCAM-1 and ICAM-1 expression in early stages of rabbit atherogenesis.

Early stages of atherogenesis are characterized by the overexpression of cell adhesion molecules with the subsequent accumulation of macrophages, smooth muscle cells and proliferation of extracellular matrix in arterial intima. The quantification of atherogenic changes is necessary for the objective evaluation of the atherogenic process. The purpose of this study was to introduce stereological methods that may be used for the quantification of immunohistochemical staining, namely intercellular cell adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1). Twenty-four New Zealand White rabbits were subdivided into the three groups. Eighteen rabbits received a 0.4% cholesterol diet for 1, 2 and 3 months, respectively. Stereological principles of the systematic uniform random sampling and the point-counting method were applied for the quantification. Stereological analysis showed that VCAM-1 and ICAM-1 were upregulated during the consumption of high cholesterol diet and that VCAM-1, but not ICAM-1, has a considerable role in the formation of early atherosclerotic lesions. Stereological methods proved to be useful for the quantification of immunohistochemistry and can be used for an objective characterization of atherogenic changes in atherosclerosis.

Animals↗

PubMedDate not supplied

Expression and functional activity of breast cancer resistance protein (BCRP, ABCG2) transporter in the human choriocarcinoma cell line BeWo.

1. Breast cancer resistance protein (BCRP, ABCG2) is a drug efflux transporter that is believed to affect the drug disposition of several drugs and xenobiotics. In the present study, we evaluated the localization and functional expression of BCRP in the human choriocarcinoma cell line BeWo, an in vitro model of the human trophoblast, and compared it with the expression of P-glycoprotein (MDR1, ABCB1) as the most widely studied placental transporter. In addition, the expression of BCRP at the mRNA level was compared with that of MDR1 in the human term placenta. 2. Western blotting analysis revealed high endogenous expression of BCRP protein in BeWo cells. Using indirect immunofluorescence microscopy, we found that the BCRP transporter appears to be localized predominantly at the apical plasma membrane. Functional studies showed a significant effect of the BCRP inhibitors GF120918 (5 micromol/L) and Ko143 (1 micromol/L) on mitoxantrone accumulation and, thus, confirmed efflux activity of BCRP in BeWo cells. 3. Using absolute mRNA quantification with real-time reverse transcription-polymerase chain reaction, we found high expression of BCRP in BeWo cells, whereas no transcript of MDR1 (P-glycoprotein), the most extensively studied drug transporter, was detected. 4. In the human placenta, BCRP was localized predominantly in the syncytiotrophoblast layer; however, immunopositivity for the BXP-21 antibody was also observed in fetal vessels of the chorionic villi. The number of BCRP transcripts in the human term placenta was found to be more than 10-fold higher compared with the expression of MDR1. 5. In conclusion, we suggest that BeWo cells could serve as a suitable in vitro model to study trans-trophoblast transport of BCRP substrates and that placental BCRP can play an important role in preventing the accumulation of potentially toxic xenobiotics in the trophoblast cells.

ATP Binding Cassette Transporter, Subfamily B, Mem↗