The Experts below are selected from a list of 360 Experts worldwide ranked by ideXlab platform
Peter Imming - One of the best experts on this subject based on the ideXlab platform.
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Chamazulene carboxylic acid and Matricin: A natural profen and its natural prodrug, identified through similarity to synthetic drug substances
Journal of Natural Products, 2006Co-Authors: Mai Ramadan, Susanne Goeters, Bernhard Watzer, Eva Krause, Klaus Lohmann, Bernd Hempel, Rudolf Bauer, Peter ImmingAbstract:Chamazulene carboxylic acid (1) is a natural profen with anti-inflammatory activity and a degradation product of proazulenic sesquiterpene lactones, e.g., Matricin. Both 1 and proazulenes occur in chamomile (Matricaria recutita), yarrow (Achillea millefolium), and a few other Asteraceae species. It was isolated in improved yields, characterized physicochemically, and found to be an inhibitor of cyclooxygenase-2, but not of cyclooxygenase-1. It had anti-inflammatory activity in several animal models with local and systemic application. When human volunteers were given Matricin orally, plasma levels of 1 were found to be in the micromolar range. Matricin was converted to 1 in artificial gastric fluid, but not in artificial intestinal fluid. Matricin and the yarrow proazulenes are proposed to be anti-inflammatory through conversion to 1. Intriguingly, the biological activity of the natural compound 1 was found because of its similarity to fully synthetic drug substances. This is the reverse process of the common lead function of natural compounds in drug discovery.
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On the absolute configuration of Matricin.
Planta medica, 2001Co-Authors: Susanne Goeters, Peter Imming, Gregor Pawlitzki, Bernd HempelAbstract:The assignment of the absolute configuration of Matricin rests on indirect evidence. On the basis of synthetic, NMR and CD studies with its decomposition product, chamazulene carboxylic acid, we were able to firmly establish the accepted 3S,3aR,4S,9R,9aS,9bS configuration of Matricin.
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Absolute stereochemistry of guaianolides, of Matricin and its epimers, of yarrow proazulenes, and of chamazulene carboxylic acid
Chirality, 2001Co-Authors: Peter Imming, Susanne Goeters, Gregor Pawlitzki, Bernd HempelAbstract:Known determinations of the absolute configuration of guaianolides were collected and found to be few. The absolute configurations of guaianolides rest on the assumption that 7-H always has α-orientation. For Matricin, only the relative configuration was determined. On the basis of a detailed study of the NMR spectra of Matricin and its epimers, and of synthetic, NMR, and CD studies with its decomposition product, chamazulene carboxylic acid, we were able to reconfirm the accepted 3S,3aR,4S,9R,9aS,9bS configuration of Matricin. Chirality 13:337–341, 2001. © 2001 Wiley-Liss, Inc.
Bernd Hempel - One of the best experts on this subject based on the ideXlab platform.
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Chamazulene carboxylic acid and Matricin: A natural profen and its natural prodrug, identified through similarity to synthetic drug substances
Journal of Natural Products, 2006Co-Authors: Mai Ramadan, Susanne Goeters, Bernhard Watzer, Eva Krause, Klaus Lohmann, Bernd Hempel, Rudolf Bauer, Peter ImmingAbstract:Chamazulene carboxylic acid (1) is a natural profen with anti-inflammatory activity and a degradation product of proazulenic sesquiterpene lactones, e.g., Matricin. Both 1 and proazulenes occur in chamomile (Matricaria recutita), yarrow (Achillea millefolium), and a few other Asteraceae species. It was isolated in improved yields, characterized physicochemically, and found to be an inhibitor of cyclooxygenase-2, but not of cyclooxygenase-1. It had anti-inflammatory activity in several animal models with local and systemic application. When human volunteers were given Matricin orally, plasma levels of 1 were found to be in the micromolar range. Matricin was converted to 1 in artificial gastric fluid, but not in artificial intestinal fluid. Matricin and the yarrow proazulenes are proposed to be anti-inflammatory through conversion to 1. Intriguingly, the biological activity of the natural compound 1 was found because of its similarity to fully synthetic drug substances. This is the reverse process of the common lead function of natural compounds in drug discovery.
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On the absolute configuration of Matricin.
Planta medica, 2001Co-Authors: Susanne Goeters, Peter Imming, Gregor Pawlitzki, Bernd HempelAbstract:The assignment of the absolute configuration of Matricin rests on indirect evidence. On the basis of synthetic, NMR and CD studies with its decomposition product, chamazulene carboxylic acid, we were able to firmly establish the accepted 3S,3aR,4S,9R,9aS,9bS configuration of Matricin.
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Absolute stereochemistry of guaianolides, of Matricin and its epimers, of yarrow proazulenes, and of chamazulene carboxylic acid
Chirality, 2001Co-Authors: Peter Imming, Susanne Goeters, Gregor Pawlitzki, Bernd HempelAbstract:Known determinations of the absolute configuration of guaianolides were collected and found to be few. The absolute configurations of guaianolides rest on the assumption that 7-H always has α-orientation. For Matricin, only the relative configuration was determined. On the basis of a detailed study of the NMR spectra of Matricin and its epimers, and of synthetic, NMR, and CD studies with its decomposition product, chamazulene carboxylic acid, we were able to reconfirm the accepted 3S,3aR,4S,9R,9aS,9bS configuration of Matricin. Chirality 13:337–341, 2001. © 2001 Wiley-Liss, Inc.
Raimund Wagener - One of the best experts on this subject based on the ideXlab platform.
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Erratum The
2014Co-Authors: Dmitry Malin, Raimund Wagener, Attila Aszódi, Eva Sonnenberg-riethmacher, Daria Guseva, Andrey Irintchev, Dieter RiethmacherAbstract:extracellular-matrix protein matrilin 2 participates in peripheral nerve regeneratio
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Characterization of recombinantly expressed matrilin VWA domains.
Protein expression and purification, 2014Co-Authors: Ann-kathrin A. Becker, Mats Paulsson, Halina Mikolajek, Jörn M. Werner, Raimund WagenerAbstract:VWA domains are the predominant independent folding units within matrilins and mediate protein–protein interactions. Mutations in the matrilin-3 VWA domain cause various skeletal diseases. The analysis of the pathological mechanisms is hampered by the lack of detailed structural information on matrilin VWA domains. Attempts to resolve their structures were hindered by low solubility and a tendency to aggregation. We therefore took a comprehensive approach to improve the recombinant expression of functional matrilin VWA domains to enable X-ray crystallography and nuclear magnetic resonance (NMR) studies. The focus was on expression in Escherichia coli, as this allows incorporation of isotope-labeled amino acids, and on finding conditions that enhance solubility. Indeed, circular dichroism (CD) and NMR measurements indicated a proper folding of the bacterially expressed domains and, interestingly, expression of zebrafish matrilin VWA domains and addition of N-ethylmaleimide yielded the most stable proteins. However, such proteins did still not crystallize and allowed only partial peak assignment in NMR. Moreover, bacterially expressed matrilin VWA domains differ in their solubility and functional properties from the same domains expressed in eukaryotic cells. Structural studies of matrilin VWA domains will depend on the use of eukaryotic expression systems.
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The matrilin-3 VWA1 domain modulates interleukin-6 release from primary human chondrocytes.
Osteoarthritis and cartilage, 2013Co-Authors: Andreas R Klatt, Mats Paulsson, Brigitte Paul-klausch, Gabriele Klinger, U. Hillebrand, Gertrud Kühn, Birgit Kobbe, Joerg H. Renno, Wibke Johannis, Raimund WagenerAbstract:Summary Objective We previously demonstrated the ability of matrilin-3 to modulate the gene expression profile of primary human chondrocytes (PHCs) toward a state favoring cartilage catabolism. The structure within matrilin-3 responsible for the induction of these catabolic genes is unknown. Here, we investigated the potential of matrilin-3 (MATN3) and truncated matrilin-3 proteins, in both monomeric and oligomeric form, to stimulate interleukin (IL)-6 release in PHCs. Methods We expressed full-length matrilin-3 oligomers, matrilin-3 von Willebrand factor A (VWA) domain oligomers, matrilin-3 four epidermal growth factor (EGF) domain oligomers, matrilin-3 monomers without oligomerization domains, matrilin-3 VWA domain monomers, and matrilin-3 4EGF monomers. We then incubated PHCs in the absence or presence of full-length matrilin-3 or one of the truncated matrilin-3 proteins and finally determined the release of IL-6 in cell-culture supernatants. Results The addition of full-length matrilin-3 oligomers, matrilin-3 VWA domain oligomers, and, less pronounced, matrilin-3 monomers without oligomerization domains, and matrilin-3 4EGF-oligomers to the cell-culture medium led to a significant induction of IL-6 in PHCs. Discussion Based on recombinant expression of different matrilin-3 domains in both monomeric and oligomeric form, this work demonstrated that the VWA1 domain of matrilin-3 is primarily responsible for the induction of IL-6 release and that the oligomerization of the VWA1 domain markedly promotes its activity.
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a matrilin 3 mutation associated with osteoarthritis does not affect collagen affinity but promotes the formation of wider cartilage collagen fibrils
Human Mutation, 2010Co-Authors: Christiane Otten, Mats Paulsson, Raimund Wagener, Uwe Hansen, Anja Talke, Frank ZauckeAbstract:Mutations in matrilin-3 have been associated with common skeletal diseases like osteoarthritis as well as with the rare chondrodysplasias MED and SEMD. We have previously shown that the mutations p.R116W and p.C299S, associated with MED and SEMD, respectively, cause retention of matrilin-3 within the endoplasmic reticulum of primary chondrocytes, while the mutation associated with osteoarthritis, p.T298M, does not hinder secretion. The present study focused on the consequences of the p.T298M mutation on the structure of matrilin-3 and on the role of matrilin-3 in the formation of a functional extracellular matrix. Analysis of recombinant full-length matrilin-3 revealed that the p.T298M mutation does not influence oligomerization of matrilin-3 or its proteolytic processing by ADAMTS-4 and -5. Nevertheless, structural analyses indicate local conformational changes. These changes do not affect the affinity for collagens II, IX, XI, or COMP, but have a major impact on the in vitro fibrillogenesis of collagen II/IX/XI heterofibrils. Hum Mutat 31:254–263, 2010. © 2010 Wiley-Liss, Inc.
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matrilin 3 activates the expression of osteoarthritis associated genes in primary human chondrocytes
FEBS Letters, 2009Co-Authors: Andreas R Klatt, Mats Paulsson, Raimund Wagener, Gabriele Klinger, Gertrud Kühn, Joerg H. Renno, Joachim Schmidt, Gebhart Malchau, Brigitte Paulklausch, Klaus WielckensAbstract:Here, we tested the matrilin-3-dependent induction of osteoarthritis-associated genes in primary human chondrocytes. Matrilin stimulation leads to the induction of MMP1, MMP3, MMP13, COX-2, iNOS, IL-1β, TNFα, IL-6 and IL-8. Furthermore, we show the participation of ADAMTS4 and ADAMTS5 in the in vitro degradation of matrilin-3. We provide evidence for a matrilin-3-dependent feed-forward mechanism of matrix degradation, whereby proteolytically-released matrilin-3 induces pro-inflammatory cytokines as well as ADAMTS4 and -5 indirectly via IL-1β. ADAMTS4 and ADAMTS5, in turn, cleave matrilin-3 and may release more matrilin-3 from the matrix, which could lead to further release of pro-inflammatory cytokines and proteases in cartilage.
Mats Paulsson - One of the best experts on this subject based on the ideXlab platform.
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Characterization of recombinantly expressed matrilin VWA domains.
Protein expression and purification, 2014Co-Authors: Ann-kathrin A. Becker, Mats Paulsson, Halina Mikolajek, Jörn M. Werner, Raimund WagenerAbstract:VWA domains are the predominant independent folding units within matrilins and mediate protein–protein interactions. Mutations in the matrilin-3 VWA domain cause various skeletal diseases. The analysis of the pathological mechanisms is hampered by the lack of detailed structural information on matrilin VWA domains. Attempts to resolve their structures were hindered by low solubility and a tendency to aggregation. We therefore took a comprehensive approach to improve the recombinant expression of functional matrilin VWA domains to enable X-ray crystallography and nuclear magnetic resonance (NMR) studies. The focus was on expression in Escherichia coli, as this allows incorporation of isotope-labeled amino acids, and on finding conditions that enhance solubility. Indeed, circular dichroism (CD) and NMR measurements indicated a proper folding of the bacterially expressed domains and, interestingly, expression of zebrafish matrilin VWA domains and addition of N-ethylmaleimide yielded the most stable proteins. However, such proteins did still not crystallize and allowed only partial peak assignment in NMR. Moreover, bacterially expressed matrilin VWA domains differ in their solubility and functional properties from the same domains expressed in eukaryotic cells. Structural studies of matrilin VWA domains will depend on the use of eukaryotic expression systems.
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The matrilin-3 VWA1 domain modulates interleukin-6 release from primary human chondrocytes.
Osteoarthritis and cartilage, 2013Co-Authors: Andreas R Klatt, Mats Paulsson, Brigitte Paul-klausch, Gabriele Klinger, U. Hillebrand, Gertrud Kühn, Birgit Kobbe, Joerg H. Renno, Wibke Johannis, Raimund WagenerAbstract:Summary Objective We previously demonstrated the ability of matrilin-3 to modulate the gene expression profile of primary human chondrocytes (PHCs) toward a state favoring cartilage catabolism. The structure within matrilin-3 responsible for the induction of these catabolic genes is unknown. Here, we investigated the potential of matrilin-3 (MATN3) and truncated matrilin-3 proteins, in both monomeric and oligomeric form, to stimulate interleukin (IL)-6 release in PHCs. Methods We expressed full-length matrilin-3 oligomers, matrilin-3 von Willebrand factor A (VWA) domain oligomers, matrilin-3 four epidermal growth factor (EGF) domain oligomers, matrilin-3 monomers without oligomerization domains, matrilin-3 VWA domain monomers, and matrilin-3 4EGF monomers. We then incubated PHCs in the absence or presence of full-length matrilin-3 or one of the truncated matrilin-3 proteins and finally determined the release of IL-6 in cell-culture supernatants. Results The addition of full-length matrilin-3 oligomers, matrilin-3 VWA domain oligomers, and, less pronounced, matrilin-3 monomers without oligomerization domains, and matrilin-3 4EGF-oligomers to the cell-culture medium led to a significant induction of IL-6 in PHCs. Discussion Based on recombinant expression of different matrilin-3 domains in both monomeric and oligomeric form, this work demonstrated that the VWA1 domain of matrilin-3 is primarily responsible for the induction of IL-6 release and that the oligomerization of the VWA1 domain markedly promotes its activity.
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Abnormal bone quality in cartilage oligomeric matrix protein and matrilin 3 double-deficient mice caused by increased tissue inhibitor of metalloproteinases 3 deposition and delayed aggrecan degradation.
Arthritis and rheumatism, 2012Co-Authors: Gergely Groma, Mats Paulsson, Anja Niehoff, Wei Xin, Ivan Grskovic, Bent Brachvogel, Frank ZauckeAbstract:Objective Cartilage oligomeric matrix protein (COMP) and matrilin 3 are extracellular matrix proteins that are abundant in cartilage. As adaptor molecules, both proteins bridge and stabilize macromolecular networks consisting of fibrillar collagens and proteoglycans. Mutations in the genes coding for COMP and matrilin 3 have been linked to human chondrodysplasias, while in mice, deficiency in COMP or matrilin 3 does not cause any pronounced skeletal abnormalities. Given the similar functions of COMP and matrilin 3 in the assembly and stabilization of the extracellular matrix, our aim was to determine whether these proteins could functionally compensate for each other. Methods To assess this putative redundancy of COMP and matrilin 3, we generated COMP/matrilin 3 double-deficient mice and performed an in-depth analysis of their skeletal development. Results At the newborn stage, the overall skeletal morphology of the double mutants was normal, but at 1 month of age, the long bones were shortened and the total body length reduced. Peripheral quantitative computed tomography revealed increased metaphyseal trabecular bone mineral density in the femora. Moreover, the degradation of aggrecan in the cartilage remnants in the metaphyseal trabecular bone was delayed, paralleled by increased deposition of tissue inhibitor of metalloproteinases 3 (TIMP-3). The structure and morphology of the growth plate were grossly normal, but in the center, focal closures were observed, a phenotype very similar to that described in matrix metalloproteinase 13 (MMP-13)–deficient mice. Conclusion We propose that a lack of COMP and matrilin 3 leads to increased deposition of TIMP-3, which causes partial inactivation of MMPs, including MMP-13, a mechanism that would explain the similarities in phenotype between COMP/matrilin 3 double-deficient and MMP-13–deficient mice.
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a matrilin 3 mutation associated with osteoarthritis does not affect collagen affinity but promotes the formation of wider cartilage collagen fibrils
Human Mutation, 2010Co-Authors: Christiane Otten, Mats Paulsson, Raimund Wagener, Uwe Hansen, Anja Talke, Frank ZauckeAbstract:Mutations in matrilin-3 have been associated with common skeletal diseases like osteoarthritis as well as with the rare chondrodysplasias MED and SEMD. We have previously shown that the mutations p.R116W and p.C299S, associated with MED and SEMD, respectively, cause retention of matrilin-3 within the endoplasmic reticulum of primary chondrocytes, while the mutation associated with osteoarthritis, p.T298M, does not hinder secretion. The present study focused on the consequences of the p.T298M mutation on the structure of matrilin-3 and on the role of matrilin-3 in the formation of a functional extracellular matrix. Analysis of recombinant full-length matrilin-3 revealed that the p.T298M mutation does not influence oligomerization of matrilin-3 or its proteolytic processing by ADAMTS-4 and -5. Nevertheless, structural analyses indicate local conformational changes. These changes do not affect the affinity for collagens II, IX, XI, or COMP, but have a major impact on the in vitro fibrillogenesis of collagen II/IX/XI heterofibrils. Hum Mutat 31:254–263, 2010. © 2010 Wiley-Liss, Inc.
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matrilin 3 activates the expression of osteoarthritis associated genes in primary human chondrocytes
FEBS Letters, 2009Co-Authors: Andreas R Klatt, Mats Paulsson, Raimund Wagener, Gabriele Klinger, Gertrud Kühn, Joerg H. Renno, Joachim Schmidt, Gebhart Malchau, Brigitte Paulklausch, Klaus WielckensAbstract:Here, we tested the matrilin-3-dependent induction of osteoarthritis-associated genes in primary human chondrocytes. Matrilin stimulation leads to the induction of MMP1, MMP3, MMP13, COX-2, iNOS, IL-1β, TNFα, IL-6 and IL-8. Furthermore, we show the participation of ADAMTS4 and ADAMTS5 in the in vitro degradation of matrilin-3. We provide evidence for a matrilin-3-dependent feed-forward mechanism of matrix degradation, whereby proteolytically-released matrilin-3 induces pro-inflammatory cytokines as well as ADAMTS4 and -5 indirectly via IL-1β. ADAMTS4 and ADAMTS5, in turn, cleave matrilin-3 and may release more matrilin-3 from the matrix, which could lead to further release of pro-inflammatory cytokines and proteases in cartilage.
Susanne Goeters - One of the best experts on this subject based on the ideXlab platform.
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Chamazulene carboxylic acid and Matricin: A natural profen and its natural prodrug, identified through similarity to synthetic drug substances
Journal of Natural Products, 2006Co-Authors: Mai Ramadan, Susanne Goeters, Bernhard Watzer, Eva Krause, Klaus Lohmann, Bernd Hempel, Rudolf Bauer, Peter ImmingAbstract:Chamazulene carboxylic acid (1) is a natural profen with anti-inflammatory activity and a degradation product of proazulenic sesquiterpene lactones, e.g., Matricin. Both 1 and proazulenes occur in chamomile (Matricaria recutita), yarrow (Achillea millefolium), and a few other Asteraceae species. It was isolated in improved yields, characterized physicochemically, and found to be an inhibitor of cyclooxygenase-2, but not of cyclooxygenase-1. It had anti-inflammatory activity in several animal models with local and systemic application. When human volunteers were given Matricin orally, plasma levels of 1 were found to be in the micromolar range. Matricin was converted to 1 in artificial gastric fluid, but not in artificial intestinal fluid. Matricin and the yarrow proazulenes are proposed to be anti-inflammatory through conversion to 1. Intriguingly, the biological activity of the natural compound 1 was found because of its similarity to fully synthetic drug substances. This is the reverse process of the common lead function of natural compounds in drug discovery.
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On the absolute configuration of Matricin.
Planta medica, 2001Co-Authors: Susanne Goeters, Peter Imming, Gregor Pawlitzki, Bernd HempelAbstract:The assignment of the absolute configuration of Matricin rests on indirect evidence. On the basis of synthetic, NMR and CD studies with its decomposition product, chamazulene carboxylic acid, we were able to firmly establish the accepted 3S,3aR,4S,9R,9aS,9bS configuration of Matricin.
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Absolute stereochemistry of guaianolides, of Matricin and its epimers, of yarrow proazulenes, and of chamazulene carboxylic acid
Chirality, 2001Co-Authors: Peter Imming, Susanne Goeters, Gregor Pawlitzki, Bernd HempelAbstract:Known determinations of the absolute configuration of guaianolides were collected and found to be few. The absolute configurations of guaianolides rest on the assumption that 7-H always has α-orientation. For Matricin, only the relative configuration was determined. On the basis of a detailed study of the NMR spectra of Matricin and its epimers, and of synthetic, NMR, and CD studies with its decomposition product, chamazulene carboxylic acid, we were able to reconfirm the accepted 3S,3aR,4S,9R,9aS,9bS configuration of Matricin. Chirality 13:337–341, 2001. © 2001 Wiley-Liss, Inc.