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Irmgard Merfort - One of the best experts on this subject based on the ideXlab platform.
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Sesquiterpene Lactones inhibit yersinia invasin protein induced il 8 and mcp 1 production in epithelial cells
International Journal of Medical Microbiology, 2005Co-Authors: Guntram A Grassl, Irmgard Merfort, Sabine Fessele, Maja T Lindenmeyer, Victor Castro, Renato Murillo, Peter J Nelson, Ingo B AutenriethAbstract:Abstract Enteric Yersinia bacteria trigger transcription and secretion of the proinflammatory chemokines interleukin-8 (IL-8) and monocyte chemoattractant protein-1 (MCP-1) in epithelial cells. Both chemokines are controlled by NF-κB. The NF-κB-binding site in the IL-8 promoter preferentially binds Rel p65/p65 homodimers and p50/p65 heterodimers while the NF-κB-binding motifs of the MCP-1 promoter preferably bind p50/p65 heterodimers and p50/p50 homodimers. Sesquiterpene Lactones inhibit the transcription factor NF-κB by alkylating the p65 subunit. In this study we investigated the inhibitory effects of Sesquiterpene Lactones and the NF-κB inhibitor SN50 on NF-κB p50 and p65 subunits in Yersinia-triggered IL-8 and MCP-1 production. The Sesquiterpene Lactones blocked Yersinia-triggered IL-8 and MCP-1 production in a dose-dependent manner. In contrast, SN50 inhibited IL-8 production at high concentrations whereas it diminished the amount of secreted MCP-1 significantly already at low concentrations. By means of electrophoretic mobility shift assays we demonstrate that Sesquiterpene Lactones inhibit Yersinia-triggered activation of NF-κB by inhibiting Rel p65, but not Rel p50. Our results also demonstrate that SN50 is useful for inhibition of nuclear translocation of the NF-κB p50 subunit but cannot be considered a general NF-κB inhibitor.
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quantitative structure activity relationship of Sesquiterpene Lactones as inhibitors of the transcription factor nf kappab
Journal of Medicinal Chemistry, 2004Co-Authors: Bettina Siedle, Wanda Kisiel, Victor Castro, Renato Murillo, Alfonso J Garciapineres, Jurgen Schultemonting, Peter Rungeler, Christoph A Klaas, Fernando B Da Costa, Irmgard MerfortAbstract:Sesquiterpene Lactones (SLs) are the active compounds of a variety of traditionally used medicinal plants from the Asteraceae family. They are known to possess a considerable antiinflammatory activity in different inflammation models. They inhibit the transcription factor NF-kappaB probably by alkylating cysteine38 in the DNA binding domain of the p65 subunit. Here we investigate a set of 103 different Sesquiterpene Lactones representing 6 structural groups (44 germacranolides, 16 heliangolides, 22 guaianolides, 9 pseudoguaianolides, 2 hypocretenolides, 10 eudesmanolides) for their NF-kappaB inhibiting properties and the resulting IC(100)-values were submitted to a QSAR study. Properties important for the inhibition potency are discussed for the whole data set and for subsets of the different structural classes.
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inhibition of transcription factor nf κb by Sesquiterpene Lactones a proposed molecular mechanism of action
Bioorganic & Medicinal Chemistry, 1999Co-Authors: Peter Rungeler, Irmgard Merfort, Victor Castro, Gerardo A Mora, Nezhun Goren, Walter Vichnewski, Heike L Pahl, Thomas J. SchmidtAbstract:Many Sesquiterpene Lactones (SLs) possess considerable anti-inflammatory activity. They inhibit the transcription factor NF-kappaB by selectively alkylating its p65 subunit probably by reacting with cysteine residues. Here we assayed 28 Sesquiterpene Lactones for their ability to inhibit NF-kappaB. The majority of the potent NF-kappaB inhibitors possess two reactive centers in form of an alpha-methylene-gamma-lactone group and an alpha,beta- or alpha,beta,gamma,delta-unsaturated carbonyl group. Based on computer molecular modelling we propose a molecular mechanism of action, which is able to explain the p65 selectivity of the SLs and the observed correlation of high activity with alkylant bifunctionality. A single bifunctional SL molecule can alkylate the cysteine residue (Cys 38) in the DNA binding loop 1 (L1) and a further cysteine (Cys 120) in the nearby E' region. This cross link alters the position of tyrosine 36 and additional amino acids in such a way that their specific interactions with the DNA become impossible. We also created a model for monofunctional SLs.
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cytotoxicity of flavonoids and Sesquiterpene Lactones from arnica species against the glc4 and the colo 320 cell lines
Planta Medica, 1994Co-Authors: Herman J Woerdenbag, Irmgard Merfort, Cm Passreiter, Tj Schmidt, Gunter Willuhn, W Van Uden, Niesko Pras, Harm H Kampinga, Awt KoningsAbstract:The cytotoxicity of 21 flavonoids and 5 Sesquiterpene Lactones, as present in Arnica species, was studied in GLC4, a human small cell lung carcinoma cell line, and in COLO 320, a human colorectal cancer cell line, using the microculture tetrazolium (MTT) assay. Following continuous incubation, most flavonoids showed moderate to low cytotoxicity, as compared with the reference compound cisplatin (IC50 = 1.1 microM against GLC4 and 2.9 microM against COLO 320). Their IC50 values varied from 17 to > 200 microM. The most toxic compound was the flavone jaceosidin. Of the Sesquiterpene Lactones tested, helenalin, possessing both the reactive alpha-methylene-gamma-lactone moiety and a reactive alpha,beta-unsubstituted cyclopentenone ring, displayed the strongest cytotoxicity. For 2 h exposure, its IC50 value was 0.44 microM against GLC4 and 1.0 microM against COLO 320. COLO 320 was more sensitive than GLC4 for many flavonoids (especially for flavones), but more resistant to the cytotoxic effect of the Sesquiterpene Lactones bearing an exocylic methylene group fused to the lactone function.
Wanda Kisiel - One of the best experts on this subject based on the ideXlab platform.
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variation of Sesquiterpene Lactones in lactuca aculeata natural populations from israel jordan and turkey
Biochemical Systematics and Ecology, 2010Co-Authors: Alex Beharav, J. Malarz, Anna Stojakowska, Klaudia Michalska, Roi Bendavid, Ivana Doležalova, A Lebeda, Wanda KisielAbstract:A comparative phytochemical study of seven Sesquiterpene Lactones in natural populations of the wild lettuce Lactuca aculeata Boiss. (Asteraceae) was performed, based on 23 accessions derived from eight, two, and single localities from Israel, Jordan, and Turkey, respectively. The compounds were profiled and quantified in leaves and roots of the plants, grown from achenes (cypselas) in a greenhouse under controlled conditions, using reverse phase HPLC with on-line photodiode array detector. In the present study, L. aculeata was confirmed as a taxon strongly characterized by four dominant Sesquiterpene Lactones: 8-deoxylactucin, jacquinelin, crepidiaside B and lactuside A. An analysis of quantitative results of these four constituents led to the following conclusions: (i) the Sesquiterpene lactone contents varied significantly, mainly within the populations; however, for two variables (crepidiaside B and lactuside A in root samples) the contents varied mostly between populations, (ii) these differences are likely to be genetically controlled since all accessions were grown under standardized glasshouse conditions. Accessions containing high levels of some Sesquiterpene Lactones were found in several populations. These traits should be conserved in situ and ex situ and utilized in further research and lettuce improvement.
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antifeedant properties and chemotaxonomic implications of Sesquiterpene Lactones and syringin from rhaponticum pulchrum
Biochemical Systematics and Ecology, 2006Co-Authors: Gerard Nowak, Wanda KisielAbstract:From aerial parts of Rhaponticum pulchrum the guaiane-type Sesquiterpene Lactones aguerin B, janerin, 19-deoxyjanerin, chlorojanerin, 15-dechloro-15-hydroxychlorojanerin, cynaropicrin, cebellin G, repdiolide and repensolide were isolated, together with the phenylpropanoid glucoside syringin. In no-choice and two-choice feeding experiments aguerin B, chlorojanerin and syringin were shown to be good antifeedants against the three species of the stored product insect pests Sitophilus granarius, Trogoderma granarium and Tribolium confusum, while janerin and cynaropicrin inhibited feeding of the latter species. However, the highest antifeedant activity was recorded for the extract of the plant enriched in Sesquiterpene Lactones. The unexpected finding was that syringin inhibited feeding of the insects.
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quantitative structure activity relationship of Sesquiterpene Lactones as inhibitors of the transcription factor nf kappab
Journal of Medicinal Chemistry, 2004Co-Authors: Bettina Siedle, Wanda Kisiel, Victor Castro, Renato Murillo, Alfonso J Garciapineres, Jurgen Schultemonting, Peter Rungeler, Christoph A Klaas, Fernando B Da Costa, Irmgard MerfortAbstract:Sesquiterpene Lactones (SLs) are the active compounds of a variety of traditionally used medicinal plants from the Asteraceae family. They are known to possess a considerable antiinflammatory activity in different inflammation models. They inhibit the transcription factor NF-kappaB probably by alkylating cysteine38 in the DNA binding domain of the p65 subunit. Here we investigate a set of 103 different Sesquiterpene Lactones representing 6 structural groups (44 germacranolides, 16 heliangolides, 22 guaianolides, 9 pseudoguaianolides, 2 hypocretenolides, 10 eudesmanolides) for their NF-kappaB inhibiting properties and the resulting IC(100)-values were submitted to a QSAR study. Properties important for the inhibition potency are discussed for the whole data set and for subsets of the different structural classes.
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Sesquiterpene Lactones from taraxacum obovatum
Planta Medica, 2003Co-Authors: Klaudia Michalska, Wanda KisielAbstract:Two new guaianolide glucosides, deacetylmatricarin 8-O-beta-glucopyranoside and 11beta-hydroxyleukodin 11-O-beta-glucopyranoside, were isolated from roots of Taraxacum obovatum, along with four known Sesquiterpene Lactones, deacetylmatricarin, sonchuside A, taraxinic acid beta-glucopyranosyl ester and its 11beta,13-dihydro derivative. Their structures were established by spectral methods.
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Sesquiterpene Lactones in a Hairy Root Culture of Cichorium intybus
Zeitschrift fur Naturforschung. C Journal of biosciences, 2002Co-Authors: J. Malarz, Anna Stojakowska, Wanda KisielAbstract:A transformed root culture of Cichorium intybus L. (Asteraceae) was found to produce Sesquiterpene Lactones of guaiane and germacrane type. Lactucopicrin, 8-desoxylactucin and three Sesquiterpene lactone glycosides: crepidiaside B, sonchuside A and ixerisoside D were isolated from the roots. The yield of 8-desoxylactucin reached 0.03 g l(-1) at the early stationary phase of the culture.
Thomas J. Schmidt - One of the best experts on this subject based on the ideXlab platform.
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anti trypanosomatid elemanolide Sesquiterpene Lactones from vernonia lasiopus o hoffm
Molecules, 2017Co-Authors: Njogu M Kimani, Marcel Kaiser, Reto Brun, Josphat C Matasyoh, Thomas J. SchmidtAbstract:Sleeping sickness or human African trypanosomiasis (HAT) is a neglected tropical disease (NTD) threatening millions of peoples’ lives with thousands infected. The disease is endemic in poorly developed regions of sub-Saharan Africa and is caused by the kinetoplastid “protozoan” parasite Trypanosoma brucei. The parasites are transmitted to humans through bites of infected tsetse flies of the genus Glossina. The few available drugs for treatment of this disease are highly toxic, difficult to administer, costly and unavailable to poor rural communities bearing the major burden of this infection. Therefore, the search for new efficacious, safe and affordable drugs is of high importance. Vernonia lasiopus O. Hoffm., an indigenous African plant of the Asteraceae family, has been extensively reported to be used ethno-medicinally as a treatment for malaria. Its crude extracts obtained with solvents of different polarity were screened in vitro for anti-protozoal activity and the dichloromethane extract was found to be particularly active against Trypanosoma brucei rhodesiense (IC50 = 0.17 µg/mL). Bioassay-guided chromatographic fractionation of the dichloromethane extract led to the isolation and identification of six elemanolide type Sesquiterpene Lactones: 8-desacylvernolide, vernolepin, vernomenin, vernodalol, vernodalin and 11,13-dihydrovernodalin. All these elemanolide Sesquiterpene Lactones showed in vitro anti-trypanosomal activity. They were also tested for cytotoxicity against mammalian cells (L6 cell line). Vernolepin, the main component in the extract, was also the most potent with an IC50 value of 0.05 µg/mL against T.b. rhodesiense trypomastigotes. This compound showed a selectivity index of 14.5, which makes it an interesting candidate for in vivo tests and determination of its mechanism of action.
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anti trypanosomal activity of helenalin and some structurally related Sesquiterpene Lactones
Planta Medica, 2002Co-Authors: Thomas J. Schmidt, Reto Brun, Ga Nter Willuhn, Sami A KhalidAbstract:The anti-trypanosomal activity of six Sesquiterpene Lactones (helenalin, mexicanin I, 11alpha,13-dihydrohelenalin acetate, chamissonolide, ivalin and isoalantolactone) against the African Trypanosoma brucei rhodesiense and American T. cruzi was investigated. All tested compounds were found active towards both parasites, the former being generally more sensitive. Helenalin was the most active compound in the series with IC50 values of 0.051 and 0.695 microM against T. brucei rhodesiense and T. cruzi, respectively. The low IC50 value for T. b. rhodesiense indicates that helenalin type compounds may be interesting candidates for further evaluation.
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inhibition of transcription factor nf κb by Sesquiterpene Lactones a proposed molecular mechanism of action
Bioorganic & Medicinal Chemistry, 1999Co-Authors: Peter Rungeler, Irmgard Merfort, Victor Castro, Gerardo A Mora, Nezhun Goren, Walter Vichnewski, Heike L Pahl, Thomas J. SchmidtAbstract:Many Sesquiterpene Lactones (SLs) possess considerable anti-inflammatory activity. They inhibit the transcription factor NF-kappaB by selectively alkylating its p65 subunit probably by reacting with cysteine residues. Here we assayed 28 Sesquiterpene Lactones for their ability to inhibit NF-kappaB. The majority of the potent NF-kappaB inhibitors possess two reactive centers in form of an alpha-methylene-gamma-lactone group and an alpha,beta- or alpha,beta,gamma,delta-unsaturated carbonyl group. Based on computer molecular modelling we propose a molecular mechanism of action, which is able to explain the p65 selectivity of the SLs and the observed correlation of high activity with alkylant bifunctionality. A single bifunctional SL molecule can alkylate the cysteine residue (Cys 38) in the DNA binding loop 1 (L1) and a further cysteine (Cys 120) in the nearby E' region. This cross link alters the position of tyrosine 36 and additional amino acids in such a way that their specific interactions with the DNA become impossible. We also created a model for monofunctional SLs.
Hongfeng Zhang - One of the best experts on this subject based on the ideXlab platform.
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antiproliferative and apoptotic Sesquiterpene Lactones from carpesium faberi
ChemInform, 2011Co-Authors: Liang Weng, Xue Gao, Yun Zhao, Fei Pang, Jianhui Liu, Hongfeng ZhangAbstract:Four new (I)—(IV) and 13 known Sesquiterpene Lactones along with two known diterpenes are isolated from the whole plant mentioned in title.
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antiproliferative and apoptotic Sesquiterpene Lactones from carpesium faberi
Bioorganic & Medicinal Chemistry Letters, 2011Co-Authors: Liang Weng, Xue Gao, Yun Zhao, Fei Pang, Jianhui Liu, Hongfeng ZhangAbstract:Four new (1-4) and 13 known (5-17) Sesquiterpene Lactones along with two known diterpenes (18, 19) were isolated from the whole plant of Carpesium faberi. The new structures were elucidated by means of spectroscopic techniques and some chemical transformations to be pseudoguaian-1α(H)-8α,12-olide-4β-O-β-d-glucopyranoside (1), 4β,10α-dihydroxy-5α(H)-1,11(13)-guaidien-8α,12-olide (2), 4β,10β-dihydroxy-5α(H)-1, 11(13)-guaidien-8β,12-olide (3), and (4S)-acetyloxyl-11(13)-carabren-8β,12-olide (4). All isolates were tested against MCF-7 human breast cancer cells using the MTT assay. Among them, the Sesquiterpene Lactones (except tomentosin 17) possessing an α-methylene-γ-lactone moiety were found to have in vitro antiproliferative activities, with IC(50) values of 3.0-38.8μg/mL. The effects of four selected Sesquiterpene Lactones (guaianolide 2, carabranolide 4, pseudoguaianolide 9, eudesmanolide 13) on the cell cycle were examined using flow cytometry (FCM).
Victor Castro - One of the best experts on this subject based on the ideXlab platform.
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Sesquiterpene Lactones inhibit yersinia invasin protein induced il 8 and mcp 1 production in epithelial cells
International Journal of Medical Microbiology, 2005Co-Authors: Guntram A Grassl, Irmgard Merfort, Sabine Fessele, Maja T Lindenmeyer, Victor Castro, Renato Murillo, Peter J Nelson, Ingo B AutenriethAbstract:Abstract Enteric Yersinia bacteria trigger transcription and secretion of the proinflammatory chemokines interleukin-8 (IL-8) and monocyte chemoattractant protein-1 (MCP-1) in epithelial cells. Both chemokines are controlled by NF-κB. The NF-κB-binding site in the IL-8 promoter preferentially binds Rel p65/p65 homodimers and p50/p65 heterodimers while the NF-κB-binding motifs of the MCP-1 promoter preferably bind p50/p65 heterodimers and p50/p50 homodimers. Sesquiterpene Lactones inhibit the transcription factor NF-κB by alkylating the p65 subunit. In this study we investigated the inhibitory effects of Sesquiterpene Lactones and the NF-κB inhibitor SN50 on NF-κB p50 and p65 subunits in Yersinia-triggered IL-8 and MCP-1 production. The Sesquiterpene Lactones blocked Yersinia-triggered IL-8 and MCP-1 production in a dose-dependent manner. In contrast, SN50 inhibited IL-8 production at high concentrations whereas it diminished the amount of secreted MCP-1 significantly already at low concentrations. By means of electrophoretic mobility shift assays we demonstrate that Sesquiterpene Lactones inhibit Yersinia-triggered activation of NF-κB by inhibiting Rel p65, but not Rel p50. Our results also demonstrate that SN50 is useful for inhibition of nuclear translocation of the NF-κB p50 subunit but cannot be considered a general NF-κB inhibitor.
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quantitative structure activity relationship of Sesquiterpene Lactones as inhibitors of the transcription factor nf kappab
Journal of Medicinal Chemistry, 2004Co-Authors: Bettina Siedle, Wanda Kisiel, Victor Castro, Renato Murillo, Alfonso J Garciapineres, Jurgen Schultemonting, Peter Rungeler, Christoph A Klaas, Fernando B Da Costa, Irmgard MerfortAbstract:Sesquiterpene Lactones (SLs) are the active compounds of a variety of traditionally used medicinal plants from the Asteraceae family. They are known to possess a considerable antiinflammatory activity in different inflammation models. They inhibit the transcription factor NF-kappaB probably by alkylating cysteine38 in the DNA binding domain of the p65 subunit. Here we investigate a set of 103 different Sesquiterpene Lactones representing 6 structural groups (44 germacranolides, 16 heliangolides, 22 guaianolides, 9 pseudoguaianolides, 2 hypocretenolides, 10 eudesmanolides) for their NF-kappaB inhibiting properties and the resulting IC(100)-values were submitted to a QSAR study. Properties important for the inhibition potency are discussed for the whole data set and for subsets of the different structural classes.
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inhibition of transcription factor nf κb by Sesquiterpene Lactones a proposed molecular mechanism of action
Bioorganic & Medicinal Chemistry, 1999Co-Authors: Peter Rungeler, Irmgard Merfort, Victor Castro, Gerardo A Mora, Nezhun Goren, Walter Vichnewski, Heike L Pahl, Thomas J. SchmidtAbstract:Many Sesquiterpene Lactones (SLs) possess considerable anti-inflammatory activity. They inhibit the transcription factor NF-kappaB by selectively alkylating its p65 subunit probably by reacting with cysteine residues. Here we assayed 28 Sesquiterpene Lactones for their ability to inhibit NF-kappaB. The majority of the potent NF-kappaB inhibitors possess two reactive centers in form of an alpha-methylene-gamma-lactone group and an alpha,beta- or alpha,beta,gamma,delta-unsaturated carbonyl group. Based on computer molecular modelling we propose a molecular mechanism of action, which is able to explain the p65 selectivity of the SLs and the observed correlation of high activity with alkylant bifunctionality. A single bifunctional SL molecule can alkylate the cysteine residue (Cys 38) in the DNA binding loop 1 (L1) and a further cysteine (Cys 120) in the nearby E' region. This cross link alters the position of tyrosine 36 and additional amino acids in such a way that their specific interactions with the DNA become impossible. We also created a model for monofunctional SLs.