Introduction: Endoglin is a 180 kDa transmembrane glycoprotein that was demonstrated to be present in two different forms, namely membrane endoglin (Eng) and soluble endoglin (sEng). Increased sEng levels in the circulation have been detected in atherosclerosis, arterial hypertension, and type II diabetes mellitus. sEng is now considered an important biomarker of cardiometabolic disorders. We aimed to evaluate the potentially harmful effects of high sEng levels in combination with other risk factors of cardiometabolic disorders. Results: We demonstrated the harmful effects of sEng with respect to the development of endothelial dysfunction and liver disorders. Long-term hypercholesterolemia combined with high levels of sEng resulted in the aggravation of endothelial and vessel wall dysfunction in the aorta, with possible alterations of the membrane endoglin/eNOS. In addition, long-term exposure to high levels of sEng during aging results in alteration of vasoconstriction properties of the aorta, reduced eNOS phosphorylation, decreased Eng expression, and altered Eng signaling. sEng also activates the expression of BM4, resulting in the development of arterial hypertension. Moreover, high levels of human sEng result in increased hepatic deposition of cholesterol due to reduced conversion into BA, as well as redirects the metabolism of triglycerides (TAG) to its accumulation in the liver via reduced TAG elimination by -oxidation combined with reduced hepatic efflux. Finally, sEng was shown to be reduced after Lipoprotein apheresis (after each procedure and in long term perspective) in patients with Familial hypercholesterolemia. Conclusion: In conclusion, we propose that sEng can be considered a risk factor for the development of vascular dysfunction and liver alteration, suggesting it might be the potential therapeutical target for pharmacological intervention in these cardiometabolic disorders.

• Publikační typ
• abstrakt z konference MeSH

• Publikační typ
• abstrakt z konference MeSH

Zdokonalení diagnostiky karcinomu prsu, jednéz nejčastějších příčin smrti, může přinést významné zvýšení šancí použité chemoterapie na úspěch. Projekt je zaměřen na hodnocení změn spekter regulačních chemokinů v séru nemocných s karcinomem prsu s cílem sledovat odezvu těchto molekul během neoadjuvantní chemoterapie a korelovat tato data s výsledkem léčby. Současně budou data porovnávána s chemokiny na odpovídajícím myším modelu, kde bude navíc sledován protinádorový a toxikologický účinek dvou nových slibných protinádorových látek, boldinu a alfa tomatinu. Referenční látkou bude doxorubicin, standardně používaný v léčebných režimech malignit prsní žlázy. Společně s použitím in vitro celulárních modelů lze předpokládat přispění výsledků projektu k poznání patofyziologie nádorů prsu, jakož i možných nových mechanizmů a jejich ovlivnění prostřednictvím nových nadějných látek. To je důležité v kontextu s možnou dispozicí těchto látek jako komponent potravy resp. potravinových doplňků.; Improvement of the diagnostics of breast cancer, one of the most common cause of death, may bring better chances of chemotherapy to be successful. Thus, the present project aims at evaluation of changes in regulatory chemokines during neoadjuvant chemotherapy and their correlation with therapy outcomes. These data will be compared with chemokines detected in corresponding mouse model, where the anticancer and toxicological effects of two new plant-derived anticancer agents, boldine and alpha-tomatine will be evaluated as well. Doxorubicin, a standard drug in clinical regimens, will serve as a reference. Together with data from in vitro cellular models, we expect contribution of our results to the understanding of the pathophysiology of breast cancers,of possible new therapeutic mechanisms and their modulation through new agents. This information is also important in the context of the availability of these two compounds as food components or food additives.

• MeSH
• aporfiny aplikace a dávkování   farmakokinetika   škodlivé účinky   terapeutické užití   MeSH
• chemokiny analýza   MeSH
• ELISA MeSH
• farmakokinetika MeSH
• fytogenní protinádorové látky farmakokinetika   MeSH
• lékové interakce MeSH
• lidé MeSH
• myši MeSH
• nádory prsu patofyziologie   MeSH
• nádory závislé na hormonech farmakoterapie   MeSH
• neoadjuvantní terapie MeSH
• nežádoucí účinky léčiv MeSH
• tomatin analogy a deriváty   farmakokinetika   škodlivé účinky   terapeutické užití   MeSH
• Check Tag
• lidé MeSH
• myši MeSH

• Konspekt
• Farmacie. Farmakologie
• NLK Obory
• farmacie a farmakologie
• gynekologie a porodnictví
• onkologie
• NLK Publikační typ
• závěrečné zprávy o řešení grantu IGA MZ ČR

• MeSH
• farmakologie * MeSH
• kanabinoidy MeSH
• rostlinné extrakty MeSH
• výzkum * MeSH
• Publikační typ
• rozhovory MeSH

• MeSH
• akademie a ústavy * dějiny   organizace a řízení   MeSH
• klinická farmakologie * metody   pracovní síly   výchova   MeSH
• lidé MeSH
• výzkum MeSH
• Check Tag
• lidé MeSH

• O autorovi
• Ústav farmakologie LF UK Hradec Králové

Sarcomas are malignant mesenchymal tumors of variable aggressiveness characterized by a substantial invasive and metastatic potential. In this review we discuss current results of pharmacological targeting of Rho/ROCK signaling in tumor cells, and the growing evidence supporting the hypothesis that Rho/ROCK dependent amoeboid mode of invasion could play a substantial role in metastatic potential of cells of malignant tumors, particularly of sarcomas. We attempt to cover pharmacological, biological and pathological aspects of the problematic in a multidisciplinary manner, from the views of molecular biology to medical practice. We are presenting evidence that blockade of Rho/ROCK pathway decreases amoeboid tumor cell invasion in vitro and substantially attenuates tumor growth and metastasis in vivo. While ROCK inhibitors have been used for a long time in treatment of cardiovascular diseases, the potential use of ROCK inhibitors to treat cancer metastasis has been considered only very recently. We propose that determination of the invasion mode that prevails in a particular sarcoma tumor, together with appropriate use of Rho/ROCK inhibitors could significantly improve the effectiveness of sarcoma tumor treatment in the future.

• MeSH
• buněčná adheze účinky léků   MeSH
• inhibitory proteas terapeutické užití   MeSH
• inhibitory proteinkinas terapeutické užití   MeSH
• kinázy asociované s rho antagonisté a inhibitory   metabolismus   MeSH
• lidé MeSH
• pohyb buněk účinky léků   MeSH
• sarkom farmakoterapie   MeSH
• signální transdukce účinky léků   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

• Publikační typ
• abstrakty MeSH

BACKGROUND AND AIM: The present study was aimed to evaluate the hepatic zonation of multidrug resistance-associated protein 2 (mrp2), an important drug transporter, and its potential changes during the induction of its expression by known inducer, dexamethasone (DEX). METHODS: The hepatic expression of mrp2 was studied by immunohistochemistry with consequent quantification by measurement of integral optical densities of mrp2 staining in the periportal and perivenous areas of the liver acinus in control and DEX-pretreated rats (1 mg/kg daily per os for 4 days). Overall changes in mrp2 expression and function produced by DEX were monitored using Western blotting and an in vivo clearance study of endogenous-conjugated bilirubin, a mrp2 substrate. RESULTS: In the control animals, a quantitative image analysis revealed the primary periportal localization of mrp2 within the liver acinus with the expression of mrp2 being 16.7-fold of that in the perivenous area. After DEX pretreatment, the expression of mrp2 increased, especially in the perivenous hepatocytes. The overall expression of mrp2 increased 3.2-fold in comparison with the control group. This observation was confirmed by Western blotting, which showed a 1.3-fold increase in the mrp2 protein after DEX pretreatment. The functional consequences of the induced mrp2 protein in the livers of the DEX-pretreated rats were demonstrated by the increased biliary excretion of conjugated bilirubin. CONCLUSION: In conclusion, these results indicate the zonation of mrp2 protein expression primarily to periportal hepatocytes. The induction by DEX produced spatially disproportional changes with an increase in the mrp2 protein being most prominent in the perivenous hepatocytes.

• MeSH
• ABC transportéry metabolismus   MeSH
• aplikace orální MeSH
• bilirubin metabolismus   MeSH
• dexamethason aplikace a dávkování   farmakologie   MeSH
• financování organizované MeSH
• gastrointestinální intubace MeSH
• hepatocyty metabolismus   účinky léků   MeSH
• imunohistochemie MeSH
• játra enzymologie   metabolismus   účinky léků   MeSH
• krysa rodu rattus MeSH
• potkani Wistar MeSH
• upregulace MeSH
• western blotting MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH

OBJECTIVES: The present study was aimed at evaluation of in vivo biliary and renal excretion of rhodamine 123 (Rho123), a P-glycoprotein (P-gp) substrate, in rats during either acute or chronic cholestasis induced by bile duct obstruction (BDO). METHODS: The Rho123 clearance study was performed either one (BDO1) or seven (BDO7) days after BDO. Bile flow was reconstituted, and bile and urine were collected after steady-state plasma concentration of Rho123 was attained. Tissue expression of P-gp was evaluated by quantitative immunohistochemistry, and immunoblotting. RESULTS: Significant up-regulation of the liver P-gp protein was observed in acute and chronic cholestasis. Primary periportal location of P-gp was enlarged also to pericentral areas. In the kidneys, immunohistochemistry showed pancellular increase in P-gp after 1 day of BDO, which subsided after 7 days of BDO. Nevertheless, biliary and renal clearances (CL(Bile) and CL(R)) of Rho123 did not reflect the induction of P-gp expression. While CL(Bile) was reduced one day after cholestasis and restored on the seventh day, the CL(R) was preserved in BDO1 group and reduced in BDO7 group without change in glomerular filtration rate. In parallel, biliary and renal clearances of conjugated bilirubin were significantly reduced in both cholestatic groups compared with controls. CONCLUSION: These findings suggest that extrahepatic cholestasis causes time-dependent changes in elimination of Rho123 which do not exactly reflect alteration of P-gp expression in the rat liver and kidney. These data may help to explain impaired elimination of P-gp substrates after short-term cholestasis that may commonly occur in clinical practice.

• MeSH
• akutní nemoc MeSH
• bilirubin metabolismus   MeSH
• chronická nemoc MeSH
• extrahepatální cholestáza etiologie   metabolismus   MeSH
• financování organizované MeSH
• fluorescenční barviva diagnostické užití   MeSH
• krysa rodu rattus MeSH
• ledviny metabolismus   MeSH
• modely nemocí na zvířatech MeSH
• P-glykoproteiny fyziologie   metabolismus   MeSH
• potkani Wistar MeSH
• rhodamin 123 diagnostické užití   MeSH
• western blotting MeSH
• žluč metabolismus   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH