Jitka Ulrichová - Academia.edu (original) (raw)
Papers by Jitka Ulrichová
Journal of Medicinal Chemistry, 2013
Quercetin and gallic acid are natural activators of the transcription factor Nrf2, which regulate... more Quercetin and gallic acid are natural activators of the transcription factor Nrf2, which regulates the expression of many cytoprotective enzymes including heme oxygenase-1 (HO-1). We developed procedures for the synthesis of monogalloyl esters of quercetin and taxifolin (dihydroquercetin), namely, 3-Ogalloylquercetin and 7-O-galloyltaxifolin, and examined their effect on the Nrf2 pathway in RAW264.7 cells. Unlike quercetin and free gallic acid, 3-O-galloylquercetin and natural quercetin derivatives isoquercitrin (quercetin-3-O-β-D-glucoside) and taxifolin had no effect on the expression of HO-1. In contrast, 7-O-galloyltaxifolin increased both mRNA and protein levels of HO-1 at concentrations of 25 μM and above. The induction of HO-1 by 7-O-galloyltaxifolin was primarily associated with the production of reactive oxygen species and phosphorylation of mitogen-activated protein kinases (MAPKs), including p38 MAPKs and ERKs, followed by nuclear accumulation of Nrf2 and downregulation of Keap1, a negative regulator of Nrf2. We conclude that 7-O-galloyltaxifolin upregulates HO-1 via activation of the MAPK/Nrf2 signaling pathway.
Journal of Separation Science, 2001
The octanol-water partition coefficients of 18 potential pharmaceuticals derived from 2-quinolone... more The octanol-water partition coefficients of 18 potential pharmaceuticals derived from 2-quinolone and 2-indolone were measured by means of MEKC. Their values range from 2.2 to 4.7 (expressed in logarithmic form). The critical micelle concentration (CMC) of SDS was determined conductometrically and the partial specific volumes of the micelles in the buffer (25 mM sodium borate, pH 9.5) were calculated from density data. The values were used for determination of the phase ratio and for estimation of the micelle-water (K mw ) and octanol-water (K ow ) partition coefficients. Direct calculation of K ow from the easily measurable capacity factors (k9) gives results comparable with those laboriously determined from K mw . Extrapolation of the micellar time from the set of migration times of alkylbenzene standards proved to be viable alternative to measurements using a marker.
Biochemical Pharmacology, 2008
SP600125, a specific inhibitor of c-Jun-N-Terminal kinase (JNK), was reported as a ligand and ant... more SP600125, a specific inhibitor of c-Jun-N-Terminal kinase (JNK), was reported as a ligand and antagonist of aryl hydrocarbon receptor (AhR) [Joiakim A, Mathieu PA, Palermo C, Gasiewicz TA, Reiners Jr JJ. The Jun N terminal kinase inhibitor SP600125 is a ligand and antagonist of the aryl hydrocarbon receptor. Drug Metab Dispos 2003;31(11):1279-82]. Here we show that SP600125 is not an antagonist but a partial agonist of human AhR. SP600125 significantly induced CYP1A1 and CYP1A2 mRNAs in primary human hepatocytes and CYP1A1 mRNA in human hepatoma cells HepG2. This effect was abolished by resveratrol, an antagonist of AhR. Consistent with the recent report, SP600125 dose-dependently inhibited CYP1A1 and CYP1A2 genes induction by a prototype AhR ligand 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in human hepatocytes. Moreover, SP600125 displayed typical behavior of a partial agonist in HepG2 cells transiently transfected with a reporter plasmid containing two inverted repeats of the dioxin responsive element or with a plasmid containing 5'-flanking region of human CYP1A1 gene. SP600125 transactivated the reporter plasmids with EC(50) of 0.005 and 1.89 microM, respectively. On the other hand, TCDD-dependent transactivation of the reporter plasmids was inhibited by SP600125 with IC(50) values of 1.54 and 2.63 microM, respectively. We also tested, whether the effects of SP600125 are due to metabolism. Using liquid chromatography/mass spectrometry approach, we observed formation of two minor monohydroxylated metabolites of SP600125 in human hepatocytes, human liver microsomes but not in HepG2 cells. These data imply that biotransformation is not responsible for the effects of SP600125 on AhR signaling. In conclusion, we demonstrate that SP600125 is a partial agonist of human AhR, which induces CYP1A genes.
![Research paper thumbnail of Cytotoxicity of Benzo[c]phenanthridinium Alkaloids in Isolated Rat Hepatocytes](https://attachments.academia-assets.com/39890232/thumbnails/1.jpg)
](Phytotherapy Research, 1996
Sanguinarine, chelerythrine and fagaronine were examined for hepatotoxic effect. Administration o... more Sanguinarine, chelerythrine and fagaronine were examined for hepatotoxic effect. Administration of sanguinarine and chelerythrine (10mglkglday; i.p.) produced marked parenchymal injury not found in the livers of fagaronine treated rats. In chronic administration of sanguinarine (0.2 mgFgl56 days; i.p.) degeneration and necrosis were not observed in the liver. The effect of the alkaloids was tested by enzyme leakage (LDH and ASAT) and changes in glutathione levels in isolated rat hepatocytes. Sanguinarine produced the greatest toxicity followed by lesser toxicity in the case of chelerythrine while no toxicity was displayed with fagaronine. These effects correlate with pK,. values for pseudobase formation. Finally, no increased lipid peroxidation or mitochondria1 membrane damage were found.
Hepatology, 2000
... 12. Sonnenbichler J, Scalera F, Sonnenbichler I, Weyhenmeyer R. Stimula-tory effect of silibi... more ... 12. Sonnenbichler J, Scalera F, Sonnenbichler I, Weyhenmeyer R. Stimula-tory effect of silibinin and silicristin from the milk thistle Silybum mari-anum on kidney cells. ... 4. Keeffe EB, Iwarson S, McMahon BJ, Lindsay K, Koff RS, Manns M, Baum-garten R, et al. ...
Lonicera caerulea L. (Blue honeysuckle, Caprifoliaceae) is a native northern hemisphere shrub wit... more Lonicera caerulea L. (Blue honeysuckle, Caprifoliaceae) is a native northern hemisphere shrub with typical dark blue berries whose chemical composition is similar to Vaccinium myrtillus (Bilberry, Ericaceae), due to the high anthocyanin content. Our research was inspired by the traditional use of these fruits in the treatment of hypertension, gastrointestinal disorders and bacterial infection among others. The berry contains mainly ascorbic acid, magnesium and potassium, phenolic acids and colour pigments. This paper aims to (i) identify polyphenolic compounds in the fruits and (ii) study the fruit/extract in vitro and in vivo biological activities. The results showed that the fruits contained 0.03 % phenolic acids and 0.3 % anthocyanins. Cyanidin-3-glucoside predominated1. Fruit extract (FE) had 0.8 % phenolic acids and 80.0 % anthocyanins. In vitro FE displayed reducing capacity, inhibited rat liver microsomes and human low density lipoprotein peroxidation. The polyphenolic level ...
Angiogenesis is a normal and vital process in growth and development, as well as in wound healing... more Angiogenesis is a normal and vital process in growth and development, as well as in wound healing and in tissue granulation. However, it is also a fundamental step in the growth of solid tumors and their transformation from a dormant state to a malignant one, leading to the research of angiogenesis inhibitors. Photosynthesizing organisms are a rich source of biologically active natural products and up to date, many phytochemicals have been tested for antiangiogenic properties [1]. One interesting polyphenolic compound has been recently identified in cyanobacteria as 2,2’-bis[4,5-bis(4-hydroxybenzyl)-2-(4-hydroxyphenyl)-cyclopent-4-ene-1,3-dione] nostotrebin 6 (NOS-6). NOS-6 is an effective acetylcholinesterase and butyrylcholinesterase inhibitor and its cytotoxicity and pro-apoptotic activity has recently been evaluated in mouse fibroblasts BALB/c by our group [2]. In the present study, NOS-6 and a synthetic cyclopentenedione derivative TX-1123 [3] were tested for antiangiogenic act...
Silybin is a popular flavonolignan isolated from milk thistle (Silybum marianum), possessing mult... more Silybin is a popular flavonolignan isolated from milk thistle (Silybum marianum), possessing multiple biological activities operating at various cell levels including anticancer and antiangiogenic properties. As the ability of silybin against angiogenesis is quite poor, we tried to improve it by its gallolyation. In the present study, a series of silybin gallates were tested for antiangiogenic activity in a variety of in vitro tests with human umbilical vein endothelial cells (HUVEC). Primary screening was performed using MTT cytotoxicity and wound healing migration tests. Subsequently, capillary-like tube formation of HUVEC on Matrigel and cell proliferation were evaluated for the most potent angiogenesis inhibitors. Silybin itself exhibited quite poor activities, inhibition of cell migration was observed in concentrations higher than 50 µM. Mono-galloylation of silybin 7-hydroxyl group decreased the minimal inhibitory concentration (MIC) to 10-20 µM. MICs for isomeric 3-O-galloyls...
Food supplements are intended to supplement the diet and provide nutrients, such as vitamins, min... more Food supplements are intended to supplement the diet and provide nutrients, such as vitamins, minerals, fatty acids, or amino acids. In addition, they often contain numerous natural plant constituents and herbal extracts with proposed beneficial effects for individual’s health. Herbal supplements are often considered harmless as they are based on “natural plant” extracts and compounds. However, many problems may be associated with food supplement use, including potential adverse effects and food supplement-drug interactions. The aim of this preliminary study was to investigate the biotransformation of the active component of a food supplement based on cranberries (Vaccinium macrocarpon Ait., Ericaceae), recommended to prevent urinary tract infections. A commercial cranberry product HI-PAC 4.0 (spray-dried fruit juice) was incubated with i) liver microsomes from rats treated with phenobarbital or β-naphtoflavone and from control rats and ii) with rat hepatocytes in suspension. The sa...
Angiogenesis is a complex physiological process through which formation of new blood vessels occu... more Angiogenesis is a complex physiological process through which formation of new blood vessels occurs from pre-existing ones. Its role is essential in ovulation, embryonic growth, placenta development, wound and injury healing and especially in growth and metastases of most solid malignancies. Excessive or insufficient angiogenesis is connected with many different human diseases (e.g. macular degeneration, rheumatoid arthritis, psoriasis, cancer, infertility, ulcers, heart diseases, obesity, teratogenesis). Plant kingdom is a rich source of biologically active natural compounds and up to date, many phytochemicals have been tested for antiangiogenic properties. Flavonolignan silybin, isolated from milk thistle (Silybum marianum), is a popular flavonoid possessing multiple biological activities operating at various cell levels including anticancer and antiangiogenic properties. We have recently demonstrated an influence of galloyl moiety in position 7 of silybin resulting in increase of...
The formation of new capillaries through angiogenesis is an important phenomenon involved in norm... more The formation of new capillaries through angiogenesis is an important phenomenon involved in normal growth and healing processes, but also in pathological conditions such as solid tumor progression, metastasis, diabetic retinopathy, hemangiomas, arthritis, psoriasis and atherosclerosis. Flavonolignan silybin, isolated from milk thistle (Silybum marianum), is a popular flavonoid possessing multiple biological activities operating at various cell levels including anticancer and antiangiogenic properties. In the present study, several natural and synthetic derivatives of silybin and 2,3-dehydrosilybin were tested for antiangiogenic activity in a variety of in vitro tests with human umbilical vein endothelial cells (HUVEC). Primary screening was performed using MTT cytotoxicity and wound healing migration tests. Subsequently, capillary-like tube formation of HUVEC on Matrigel and cell proliferation was evaluated for the most potent angiogenesis inhibitors. Silybin itself, as well as iso...
Toxicology in Vitro
A quaternary benzo[c]phenanthridine alkaloid chelerythrine displays a wide range of biological ac... more A quaternary benzo[c]phenanthridine alkaloid chelerythrine displays a wide range of biological activities including cytotoxicity to normal and cancer cells. In contrast, less is known about the biological activity of dihydrochelerythrine, a product of chelerythrine reduction. We examined the cytotoxicity of chelerythrine and dihydrochelerythrine in human promyelocytic leukemia HL-60 cells. After 4h of treatment, chelerythrine induced a dose-dependent decrease in the cell viability with IC50 of 2.6 microM as shown by MTT reduction assay. Dihydrochelerythrine appeared to be less cytotoxic since the viability of cells exposed to 20 microM dihydrochelerythrine for 24h was reduced only to 53%. Decrease in the viability induced by both alkaloids was accompanied by apoptotic events including the dissipation of mitochondrial membrane potential, activation of caspase-9 and -3, and appearance of cells with sub-G1 DNA. Moreover, chelerythrine, but not dihydrochelerythrine, elevated the activit...
Toxicology in Vitro
The benzo[c]phenanthridine alkaloid sanguinarine has been studied for its antiproliferative activ... more The benzo[c]phenanthridine alkaloid sanguinarine has been studied for its antiproliferative activity in many cell types. Almost nothing however, is known about the cytotoxic effects of dihydrosanguinarine, a metabolite of sanguinarine. We compared the cytotoxicity of sanguinarine and dihydrosanguinarine in human leukemia HL-60 cells. Sanguinarine produced a dose-dependent decline in cell viability with IC(50) (inhibitor concentration required for 50% inhibition of cell viability) of 0.9 microM as determined by MTT assay after 4h exposure. Dihydrosanguinarine showed much less cytotoxicity than sanguinarine: at the highest concentration tested (20 microM) and 24h exposure, dihydrosanguinarine decreased viability only to 52%. Cytotoxic effects of both alkaloids were accompanied by activation of the intrinsic apoptotic pathway since we observed the dissipation of mitochondrial membrane potential, induction of caspase-9 and -3 activities, the appearance of sub-G(1) DNA and loss of plasma...
![Research paper thumbnail of Quaternary Benzo[c]phenanthridine Alkaloids: Biological Activities](https://attachments.academia-assets.com/42061290/thumbnails/1.jpg)
](Cheminform, 2005
Quarternary benzo[c]phenanthridine alkaloids (QBA) are a small class of compounds commonly isolat... more Quarternary benzo[c]phenanthridine alkaloids (QBA) are a small class of compounds commonly isolated from Caprifoliaceae, Fumariaceae, Meliacea, Papaveraceae and Rutaceae plants. QBA belong to the elicitor-inducible secondary metabolites and are considered phytoalexines because of their antifungal and nematocidal activities.
![Research paper thumbnail of Quaternary Benzo[C]Phenanthridine Alkaloids — Biological Activities](https://attachments.academia-assets.com/39890238/thumbnails/1.jpg)
](NATO Science Series II: Mathematics, Physics and Chemistry, 2003
Quarternary benzo[c]phenanthridine alkaloids (QBA) are a small class of compounds commonly isolat... more Quarternary benzo[c]phenanthridine alkaloids (QBA) are a small class of compounds commonly isolated from Caprifoliaceae, Fumariaceae, Meliacea, Papaveraceae and Rutaceae plants. QBA belong to the elicitor-inducible secondary metabolites and are considered phytoalexines because of their antifungal and nematocidal activities.
In the present work, the effects of colchicine (COL) and/or all- trans retinoic acid (ATRA) on ex... more In the present work, the effects of colchicine (COL) and/or all- trans retinoic acid (ATRA) on expression of rexinoid receptors (RXRs) (α, β, γ), thyroid hormone receptor α and coregulators N-CoR, SMRT and SRC-1 mRNA in primary rat hepatocytes as a model of no-proliferating cells were investigated. Treatment with these components, either alone or in combination, induced differences of the
Life Sciences, 2015
Cytochromes P450 (CYPs) are enzymes present from bacteria to man involved in metabolism of endoge... more Cytochromes P450 (CYPs) are enzymes present from bacteria to man involved in metabolism of endogenous and exogenous compounds incl. drugs. Our objective was to assess whether obesity leads to changes in activities and expression of CYPs in the mouse liver, small intestine and colon. An obese mouse model with repeated injection of monosodium glutamate (MSG) to newborns was used. Controls were treated with saline. All mice were sacrificed at 8months. In the liver and intestines, levels of CYP mRNA and proteins were analyzed using RT-PCR and Western blotting. Activities of CYP enzymes were measured with specific substrates of human orthologous forms. At the end of the experiment, body weight, plasma insulin and leptin levels as well as the specific content of hepatic CYP enzymes were increased in obese mice. Among CYP enzymes, hepatic CYP2A5 activity, protein and mRNA expression increased most significantly in obese animals. Higher activities and protein levels of hepatic CYP2E1 and 3A in the obese mice were also found. No or a weak effect on CYPs 2C and 2D was observed. In the small intestine and colon, no changes of CYP enzymes were detected except for increased expression of CYP2E1 and decreased expression of CYP3A mRNAs in the colon of the obese mice. Results of our study suggest that the specific content and activities of some liver CYP enzymes (especially CYP2A5) can be increased in obese mice. Higher activity of CYP2A5 (CYP2A6 human ortholog) could lead to altered metabolism of drug substrates of this enzyme (valproic acid, nicotine, methoxyflurane).
Journal of Medicinal Chemistry, 2013
Quercetin and gallic acid are natural activators of the transcription factor Nrf2, which regulate... more Quercetin and gallic acid are natural activators of the transcription factor Nrf2, which regulates the expression of many cytoprotective enzymes including heme oxygenase-1 (HO-1). We developed procedures for the synthesis of monogalloyl esters of quercetin and taxifolin (dihydroquercetin), namely, 3-Ogalloylquercetin and 7-O-galloyltaxifolin, and examined their effect on the Nrf2 pathway in RAW264.7 cells. Unlike quercetin and free gallic acid, 3-O-galloylquercetin and natural quercetin derivatives isoquercitrin (quercetin-3-O-β-D-glucoside) and taxifolin had no effect on the expression of HO-1. In contrast, 7-O-galloyltaxifolin increased both mRNA and protein levels of HO-1 at concentrations of 25 μM and above. The induction of HO-1 by 7-O-galloyltaxifolin was primarily associated with the production of reactive oxygen species and phosphorylation of mitogen-activated protein kinases (MAPKs), including p38 MAPKs and ERKs, followed by nuclear accumulation of Nrf2 and downregulation of Keap1, a negative regulator of Nrf2. We conclude that 7-O-galloyltaxifolin upregulates HO-1 via activation of the MAPK/Nrf2 signaling pathway.
Journal of Separation Science, 2001
The octanol-water partition coefficients of 18 potential pharmaceuticals derived from 2-quinolone... more The octanol-water partition coefficients of 18 potential pharmaceuticals derived from 2-quinolone and 2-indolone were measured by means of MEKC. Their values range from 2.2 to 4.7 (expressed in logarithmic form). The critical micelle concentration (CMC) of SDS was determined conductometrically and the partial specific volumes of the micelles in the buffer (25 mM sodium borate, pH 9.5) were calculated from density data. The values were used for determination of the phase ratio and for estimation of the micelle-water (K mw ) and octanol-water (K ow ) partition coefficients. Direct calculation of K ow from the easily measurable capacity factors (k9) gives results comparable with those laboriously determined from K mw . Extrapolation of the micellar time from the set of migration times of alkylbenzene standards proved to be viable alternative to measurements using a marker.
Biochemical Pharmacology, 2008
SP600125, a specific inhibitor of c-Jun-N-Terminal kinase (JNK), was reported as a ligand and ant... more SP600125, a specific inhibitor of c-Jun-N-Terminal kinase (JNK), was reported as a ligand and antagonist of aryl hydrocarbon receptor (AhR) [Joiakim A, Mathieu PA, Palermo C, Gasiewicz TA, Reiners Jr JJ. The Jun N terminal kinase inhibitor SP600125 is a ligand and antagonist of the aryl hydrocarbon receptor. Drug Metab Dispos 2003;31(11):1279-82]. Here we show that SP600125 is not an antagonist but a partial agonist of human AhR. SP600125 significantly induced CYP1A1 and CYP1A2 mRNAs in primary human hepatocytes and CYP1A1 mRNA in human hepatoma cells HepG2. This effect was abolished by resveratrol, an antagonist of AhR. Consistent with the recent report, SP600125 dose-dependently inhibited CYP1A1 and CYP1A2 genes induction by a prototype AhR ligand 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in human hepatocytes. Moreover, SP600125 displayed typical behavior of a partial agonist in HepG2 cells transiently transfected with a reporter plasmid containing two inverted repeats of the dioxin responsive element or with a plasmid containing 5'-flanking region of human CYP1A1 gene. SP600125 transactivated the reporter plasmids with EC(50) of 0.005 and 1.89 microM, respectively. On the other hand, TCDD-dependent transactivation of the reporter plasmids was inhibited by SP600125 with IC(50) values of 1.54 and 2.63 microM, respectively. We also tested, whether the effects of SP600125 are due to metabolism. Using liquid chromatography/mass spectrometry approach, we observed formation of two minor monohydroxylated metabolites of SP600125 in human hepatocytes, human liver microsomes but not in HepG2 cells. These data imply that biotransformation is not responsible for the effects of SP600125 on AhR signaling. In conclusion, we demonstrate that SP600125 is a partial agonist of human AhR, which induces CYP1A genes.
Phytotherapy Research, 1996
Sanguinarine, chelerythrine and fagaronine were examined for hepatotoxic effect. Administration o... more Sanguinarine, chelerythrine and fagaronine were examined for hepatotoxic effect. Administration of sanguinarine and chelerythrine (10mglkglday; i.p.) produced marked parenchymal injury not found in the livers of fagaronine treated rats. In chronic administration of sanguinarine (0.2 mgFgl56 days; i.p.) degeneration and necrosis were not observed in the liver. The effect of the alkaloids was tested by enzyme leakage (LDH and ASAT) and changes in glutathione levels in isolated rat hepatocytes. Sanguinarine produced the greatest toxicity followed by lesser toxicity in the case of chelerythrine while no toxicity was displayed with fagaronine. These effects correlate with pK,. values for pseudobase formation. Finally, no increased lipid peroxidation or mitochondria1 membrane damage were found.
Hepatology, 2000
... 12. Sonnenbichler J, Scalera F, Sonnenbichler I, Weyhenmeyer R. Stimula-tory effect of silibi... more ... 12. Sonnenbichler J, Scalera F, Sonnenbichler I, Weyhenmeyer R. Stimula-tory effect of silibinin and silicristin from the milk thistle Silybum mari-anum on kidney cells. ... 4. Keeffe EB, Iwarson S, McMahon BJ, Lindsay K, Koff RS, Manns M, Baum-garten R, et al. ...
Lonicera caerulea L. (Blue honeysuckle, Caprifoliaceae) is a native northern hemisphere shrub wit... more Lonicera caerulea L. (Blue honeysuckle, Caprifoliaceae) is a native northern hemisphere shrub with typical dark blue berries whose chemical composition is similar to Vaccinium myrtillus (Bilberry, Ericaceae), due to the high anthocyanin content. Our research was inspired by the traditional use of these fruits in the treatment of hypertension, gastrointestinal disorders and bacterial infection among others. The berry contains mainly ascorbic acid, magnesium and potassium, phenolic acids and colour pigments. This paper aims to (i) identify polyphenolic compounds in the fruits and (ii) study the fruit/extract in vitro and in vivo biological activities. The results showed that the fruits contained 0.03 % phenolic acids and 0.3 % anthocyanins. Cyanidin-3-glucoside predominated1. Fruit extract (FE) had 0.8 % phenolic acids and 80.0 % anthocyanins. In vitro FE displayed reducing capacity, inhibited rat liver microsomes and human low density lipoprotein peroxidation. The polyphenolic level ...
Angiogenesis is a normal and vital process in growth and development, as well as in wound healing... more Angiogenesis is a normal and vital process in growth and development, as well as in wound healing and in tissue granulation. However, it is also a fundamental step in the growth of solid tumors and their transformation from a dormant state to a malignant one, leading to the research of angiogenesis inhibitors. Photosynthesizing organisms are a rich source of biologically active natural products and up to date, many phytochemicals have been tested for antiangiogenic properties [1]. One interesting polyphenolic compound has been recently identified in cyanobacteria as 2,2’-bis[4,5-bis(4-hydroxybenzyl)-2-(4-hydroxyphenyl)-cyclopent-4-ene-1,3-dione] nostotrebin 6 (NOS-6). NOS-6 is an effective acetylcholinesterase and butyrylcholinesterase inhibitor and its cytotoxicity and pro-apoptotic activity has recently been evaluated in mouse fibroblasts BALB/c by our group [2]. In the present study, NOS-6 and a synthetic cyclopentenedione derivative TX-1123 [3] were tested for antiangiogenic act...
Silybin is a popular flavonolignan isolated from milk thistle (Silybum marianum), possessing mult... more Silybin is a popular flavonolignan isolated from milk thistle (Silybum marianum), possessing multiple biological activities operating at various cell levels including anticancer and antiangiogenic properties. As the ability of silybin against angiogenesis is quite poor, we tried to improve it by its gallolyation. In the present study, a series of silybin gallates were tested for antiangiogenic activity in a variety of in vitro tests with human umbilical vein endothelial cells (HUVEC). Primary screening was performed using MTT cytotoxicity and wound healing migration tests. Subsequently, capillary-like tube formation of HUVEC on Matrigel and cell proliferation were evaluated for the most potent angiogenesis inhibitors. Silybin itself exhibited quite poor activities, inhibition of cell migration was observed in concentrations higher than 50 µM. Mono-galloylation of silybin 7-hydroxyl group decreased the minimal inhibitory concentration (MIC) to 10-20 µM. MICs for isomeric 3-O-galloyls...
Food supplements are intended to supplement the diet and provide nutrients, such as vitamins, min... more Food supplements are intended to supplement the diet and provide nutrients, such as vitamins, minerals, fatty acids, or amino acids. In addition, they often contain numerous natural plant constituents and herbal extracts with proposed beneficial effects for individual’s health. Herbal supplements are often considered harmless as they are based on “natural plant” extracts and compounds. However, many problems may be associated with food supplement use, including potential adverse effects and food supplement-drug interactions. The aim of this preliminary study was to investigate the biotransformation of the active component of a food supplement based on cranberries (Vaccinium macrocarpon Ait., Ericaceae), recommended to prevent urinary tract infections. A commercial cranberry product HI-PAC 4.0 (spray-dried fruit juice) was incubated with i) liver microsomes from rats treated with phenobarbital or β-naphtoflavone and from control rats and ii) with rat hepatocytes in suspension. The sa...
Angiogenesis is a complex physiological process through which formation of new blood vessels occu... more Angiogenesis is a complex physiological process through which formation of new blood vessels occurs from pre-existing ones. Its role is essential in ovulation, embryonic growth, placenta development, wound and injury healing and especially in growth and metastases of most solid malignancies. Excessive or insufficient angiogenesis is connected with many different human diseases (e.g. macular degeneration, rheumatoid arthritis, psoriasis, cancer, infertility, ulcers, heart diseases, obesity, teratogenesis). Plant kingdom is a rich source of biologically active natural compounds and up to date, many phytochemicals have been tested for antiangiogenic properties. Flavonolignan silybin, isolated from milk thistle (Silybum marianum), is a popular flavonoid possessing multiple biological activities operating at various cell levels including anticancer and antiangiogenic properties. We have recently demonstrated an influence of galloyl moiety in position 7 of silybin resulting in increase of...
The formation of new capillaries through angiogenesis is an important phenomenon involved in norm... more The formation of new capillaries through angiogenesis is an important phenomenon involved in normal growth and healing processes, but also in pathological conditions such as solid tumor progression, metastasis, diabetic retinopathy, hemangiomas, arthritis, psoriasis and atherosclerosis. Flavonolignan silybin, isolated from milk thistle (Silybum marianum), is a popular flavonoid possessing multiple biological activities operating at various cell levels including anticancer and antiangiogenic properties. In the present study, several natural and synthetic derivatives of silybin and 2,3-dehydrosilybin were tested for antiangiogenic activity in a variety of in vitro tests with human umbilical vein endothelial cells (HUVEC). Primary screening was performed using MTT cytotoxicity and wound healing migration tests. Subsequently, capillary-like tube formation of HUVEC on Matrigel and cell proliferation was evaluated for the most potent angiogenesis inhibitors. Silybin itself, as well as iso...
Toxicology in Vitro
A quaternary benzo[c]phenanthridine alkaloid chelerythrine displays a wide range of biological ac... more A quaternary benzo[c]phenanthridine alkaloid chelerythrine displays a wide range of biological activities including cytotoxicity to normal and cancer cells. In contrast, less is known about the biological activity of dihydrochelerythrine, a product of chelerythrine reduction. We examined the cytotoxicity of chelerythrine and dihydrochelerythrine in human promyelocytic leukemia HL-60 cells. After 4h of treatment, chelerythrine induced a dose-dependent decrease in the cell viability with IC50 of 2.6 microM as shown by MTT reduction assay. Dihydrochelerythrine appeared to be less cytotoxic since the viability of cells exposed to 20 microM dihydrochelerythrine for 24h was reduced only to 53%. Decrease in the viability induced by both alkaloids was accompanied by apoptotic events including the dissipation of mitochondrial membrane potential, activation of caspase-9 and -3, and appearance of cells with sub-G1 DNA. Moreover, chelerythrine, but not dihydrochelerythrine, elevated the activit...
Toxicology in Vitro
The benzo[c]phenanthridine alkaloid sanguinarine has been studied for its antiproliferative activ... more The benzo[c]phenanthridine alkaloid sanguinarine has been studied for its antiproliferative activity in many cell types. Almost nothing however, is known about the cytotoxic effects of dihydrosanguinarine, a metabolite of sanguinarine. We compared the cytotoxicity of sanguinarine and dihydrosanguinarine in human leukemia HL-60 cells. Sanguinarine produced a dose-dependent decline in cell viability with IC(50) (inhibitor concentration required for 50% inhibition of cell viability) of 0.9 microM as determined by MTT assay after 4h exposure. Dihydrosanguinarine showed much less cytotoxicity than sanguinarine: at the highest concentration tested (20 microM) and 24h exposure, dihydrosanguinarine decreased viability only to 52%. Cytotoxic effects of both alkaloids were accompanied by activation of the intrinsic apoptotic pathway since we observed the dissipation of mitochondrial membrane potential, induction of caspase-9 and -3 activities, the appearance of sub-G(1) DNA and loss of plasma...
Cheminform, 2005
Quarternary benzo[c]phenanthridine alkaloids (QBA) are a small class of compounds commonly isolat... more Quarternary benzo[c]phenanthridine alkaloids (QBA) are a small class of compounds commonly isolated from Caprifoliaceae, Fumariaceae, Meliacea, Papaveraceae and Rutaceae plants. QBA belong to the elicitor-inducible secondary metabolites and are considered phytoalexines because of their antifungal and nematocidal activities.
NATO Science Series II: Mathematics, Physics and Chemistry, 2003
Quarternary benzo[c]phenanthridine alkaloids (QBA) are a small class of compounds commonly isolat... more Quarternary benzo[c]phenanthridine alkaloids (QBA) are a small class of compounds commonly isolated from Caprifoliaceae, Fumariaceae, Meliacea, Papaveraceae and Rutaceae plants. QBA belong to the elicitor-inducible secondary metabolites and are considered phytoalexines because of their antifungal and nematocidal activities.
In the present work, the effects of colchicine (COL) and/or all- trans retinoic acid (ATRA) on ex... more In the present work, the effects of colchicine (COL) and/or all- trans retinoic acid (ATRA) on expression of rexinoid receptors (RXRs) (α, β, γ), thyroid hormone receptor α and coregulators N-CoR, SMRT and SRC-1 mRNA in primary rat hepatocytes as a model of no-proliferating cells were investigated. Treatment with these components, either alone or in combination, induced differences of the
Life Sciences, 2015
Cytochromes P450 (CYPs) are enzymes present from bacteria to man involved in metabolism of endoge... more Cytochromes P450 (CYPs) are enzymes present from bacteria to man involved in metabolism of endogenous and exogenous compounds incl. drugs. Our objective was to assess whether obesity leads to changes in activities and expression of CYPs in the mouse liver, small intestine and colon. An obese mouse model with repeated injection of monosodium glutamate (MSG) to newborns was used. Controls were treated with saline. All mice were sacrificed at 8months. In the liver and intestines, levels of CYP mRNA and proteins were analyzed using RT-PCR and Western blotting. Activities of CYP enzymes were measured with specific substrates of human orthologous forms. At the end of the experiment, body weight, plasma insulin and leptin levels as well as the specific content of hepatic CYP enzymes were increased in obese mice. Among CYP enzymes, hepatic CYP2A5 activity, protein and mRNA expression increased most significantly in obese animals. Higher activities and protein levels of hepatic CYP2E1 and 3A in the obese mice were also found. No or a weak effect on CYPs 2C and 2D was observed. In the small intestine and colon, no changes of CYP enzymes were detected except for increased expression of CYP2E1 and decreased expression of CYP3A mRNAs in the colon of the obese mice. Results of our study suggest that the specific content and activities of some liver CYP enzymes (especially CYP2A5) can be increased in obese mice. Higher activity of CYP2A5 (CYP2A6 human ortholog) could lead to altered metabolism of drug substrates of this enzyme (valproic acid, nicotine, methoxyflurane).