The Experts below are selected from a list of 522 Experts worldwide ranked by ideXlab platform
Michael J Adam - One of the best experts on this subject based on the ideXlab platform.
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towards kit like 18f labeling of Marimastat a noncovalent inhibitor drug for in vivo pet imaging cancer associated matrix metalloproteases
MedChemComm, 2011Co-Authors: Ying Li, Ulrich Auf Dem Keller, Caroline L Bellac, Philipp F Lange, Richard Ting, Curtis Harwig, Michael J Adam, James A H Inkster, Paul SchafferAbstract:Marimastat, a clinically trialed drug developed to treat breast cancer by inhibiting cancer-associated matrix metalloproteases (MMPs), was linked to an aryl boronic ester for single-step [18F]-aqueous fluoride capture and the labeled product revealed tumor associated MMP activity in vivo. Herein, we report important radiosynthetic attributes for labeling Marimastat that enabled the first PET images of breast cancer-associated matrix metalloproteases in a syngenic murine model. The advantages of this method include one-step post synthetic labeling in less than one hour at ambient temperature, the ability to work in aqueous media without drying the 18F-fluoride, observation of high radiochemical purity, and the potential for tripling the specific activity of the fluoride used in labeling. Using low levels of activity e.g. 60 mCi in low volumes this method affords reasonable yields of labeled Marimastat with decay-corrected specific activities of 0.39 and 0.75 Ci/μmol, and real specific activities of 0.16 and 0.39 Ci/μmol. Current limitations of this method along with anticipated improvements are discussed.
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towards kit like 18f labeling of Marimastat a noncovalent inhibitor drug for in vivo pet imaging cancer associated matrix metalloproteases
MedChemComm, 2011Co-Authors: Richard Ting, Ulrich Auf Dem Keller, Caroline L Bellac, Philipp F Lange, Curtis Harwig, Michael J Adam, James A H Inkster, Paul Schaffer, Thomas J RuthAbstract:Marimastat, a clinically trialed drug developed to treat breast cancer by inhibiting cancer-associated matrix metalloproteases (MMPs), was linked to an aryl boronic ester for single-step [18F]-aqueous fluoride capture and the labeled product revealed tumor associated MMP activity in vivo. Herein, we report important radiosynthetic attributes for labeling Marimastat that enabled the first PET images of breast cancer-associated matrix metalloproteases in a syngenic murine model. The advantages of this method include one-step post synthetic labeling in less than one hour at ambient temperature, the ability to work in aqueous media without drying the 18F-fluoride, observation of high radiochemical purity, and the potential for tripling the specific activity of the fluoride used in labeling. Using low levels of activity e.g. 60 mCi in low volumes this method affords reasonable yields of labeled Marimastat with decay-corrected specific activities of 0.39 and 0.75 Ci/μmol, and real specific activities of 0.16 and 0.39 Ci/μmol. Current limitations of this method along with anticipated improvements are discussed.
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novel matrix metalloproteinase inhibitor 18f Marimastat aryltrifluoroborate as a probe for in vivo positron emission tomography imaging in cancer
Cancer Research, 2010Co-Authors: Ulrich Auf Dem Keller, Caroline L Bellac, Yuanmei Lou, Philipp F Lange, Richard Ting, Curtis Harwig, Reinhild Kappelhoff, Shoukat Dedhar, Michael J Adam, Thomas J RuthAbstract:Matrix metalloproteinases (MMP), strongly associated pathogenic markers of cancer, have undergone extensive drug development programs. Marimastat, a noncovalent MMP inhibitor, was conjugated with FITC to label cellular metalloproteinase cancer targets in MDA-MB-231 cells in vitro. Punctate localization of active transmembrane MMP14 was observed. For molecular-targeted positron emission tomography imaging of syngeneic 67NR murine mammary carcinoma in vivo, Marimastat was (18)F-labeled using a shelf-stable arylboronic ester conjugate as a captor for aqueous [(18)F]fluoride in a novel, rapid one-step reaction at ambient temperature. [(18)F]Marimastat-aryltrifluoroborate localized to the tumors, with labeling being blocked in control animals first loaded with >10-fold excess unlabeled Marimastat. The labeled drug cleared primarily via the hepatobiliary and gastrointestinal tract, with multiple animals imaged in independent experiments, confirming the ease of this new labeling strategy.
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novel matrix metalloproteinase inhibitor 18f Marimastat aryltrifluoroborate as a probe for in vivo positron emission tomography imaging in cancer
Cancer Research, 2010Co-Authors: Ulrich Auf Dem Keller, Caroline L Bellac, Yuanmei Lou, Philipp F Lange, Richard Ting, Curtis Harwig, Reinhild Kappelhoff, Shoukat Dedhar, Michael J Adam, Thomas J RuthAbstract:Matrix metalloproteinases (MMP), strongly associated pathogenic markers of cancer, have undergone extensive drug development programs. Marimastat, a noncovalent MMP inhibitor, was conjugated with FITC to label cellular metalloproteinase cancer targets in MDA-MB-231 cells in vitro . Punctate localization of active transmembrane MMP14 was observed. For molecular-targeted positron emission tomography imaging of syngeneic 67NR murine mammary carcinoma in vivo , Marimastat was 18 F-labeled using a shelf-stable arylboronic ester conjugate as a captor for aqueous [ 18 F]fluoride in a novel, rapid one-step reaction at ambient temperature. [ 18 F]Marimastat-aryltrifluoroborate localized to the tumors, with labeling being blocked in control animals first loaded with >10-fold excess unlabeled Marimastat. The labeled drug cleared primarily via the hepatobiliary and gastrointestinal tract, with multiple animals imaged in independent experiments, confirming the ease of this new labeling strategy. Cancer Res; 70(19); 7562–9. ©2010 AACR.
Thomas J Ruth - One of the best experts on this subject based on the ideXlab platform.
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towards kit like 18f labeling of Marimastat a noncovalent inhibitor drug for in vivo pet imaging cancer associated matrix metalloproteases
MedChemComm, 2011Co-Authors: Richard Ting, Ulrich Auf Dem Keller, Caroline L Bellac, Philipp F Lange, Curtis Harwig, Michael J Adam, James A H Inkster, Paul Schaffer, Thomas J RuthAbstract:Marimastat, a clinically trialed drug developed to treat breast cancer by inhibiting cancer-associated matrix metalloproteases (MMPs), was linked to an aryl boronic ester for single-step [18F]-aqueous fluoride capture and the labeled product revealed tumor associated MMP activity in vivo. Herein, we report important radiosynthetic attributes for labeling Marimastat that enabled the first PET images of breast cancer-associated matrix metalloproteases in a syngenic murine model. The advantages of this method include one-step post synthetic labeling in less than one hour at ambient temperature, the ability to work in aqueous media without drying the 18F-fluoride, observation of high radiochemical purity, and the potential for tripling the specific activity of the fluoride used in labeling. Using low levels of activity e.g. 60 mCi in low volumes this method affords reasonable yields of labeled Marimastat with decay-corrected specific activities of 0.39 and 0.75 Ci/μmol, and real specific activities of 0.16 and 0.39 Ci/μmol. Current limitations of this method along with anticipated improvements are discussed.
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novel matrix metalloproteinase inhibitor 18f Marimastat aryltrifluoroborate as a probe for in vivo positron emission tomography imaging in cancer
Cancer Research, 2010Co-Authors: Ulrich Auf Dem Keller, Caroline L Bellac, Yuanmei Lou, Philipp F Lange, Richard Ting, Curtis Harwig, Reinhild Kappelhoff, Shoukat Dedhar, Michael J Adam, Thomas J RuthAbstract:Matrix metalloproteinases (MMP), strongly associated pathogenic markers of cancer, have undergone extensive drug development programs. Marimastat, a noncovalent MMP inhibitor, was conjugated with FITC to label cellular metalloproteinase cancer targets in MDA-MB-231 cells in vitro. Punctate localization of active transmembrane MMP14 was observed. For molecular-targeted positron emission tomography imaging of syngeneic 67NR murine mammary carcinoma in vivo, Marimastat was (18)F-labeled using a shelf-stable arylboronic ester conjugate as a captor for aqueous [(18)F]fluoride in a novel, rapid one-step reaction at ambient temperature. [(18)F]Marimastat-aryltrifluoroborate localized to the tumors, with labeling being blocked in control animals first loaded with >10-fold excess unlabeled Marimastat. The labeled drug cleared primarily via the hepatobiliary and gastrointestinal tract, with multiple animals imaged in independent experiments, confirming the ease of this new labeling strategy.
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novel matrix metalloproteinase inhibitor 18f Marimastat aryltrifluoroborate as a probe for in vivo positron emission tomography imaging in cancer
Cancer Research, 2010Co-Authors: Ulrich Auf Dem Keller, Caroline L Bellac, Yuanmei Lou, Philipp F Lange, Richard Ting, Curtis Harwig, Reinhild Kappelhoff, Shoukat Dedhar, Michael J Adam, Thomas J RuthAbstract:Matrix metalloproteinases (MMP), strongly associated pathogenic markers of cancer, have undergone extensive drug development programs. Marimastat, a noncovalent MMP inhibitor, was conjugated with FITC to label cellular metalloproteinase cancer targets in MDA-MB-231 cells in vitro . Punctate localization of active transmembrane MMP14 was observed. For molecular-targeted positron emission tomography imaging of syngeneic 67NR murine mammary carcinoma in vivo , Marimastat was 18 F-labeled using a shelf-stable arylboronic ester conjugate as a captor for aqueous [ 18 F]fluoride in a novel, rapid one-step reaction at ambient temperature. [ 18 F]Marimastat-aryltrifluoroborate localized to the tumors, with labeling being blocked in control animals first loaded with >10-fold excess unlabeled Marimastat. The labeled drug cleared primarily via the hepatobiliary and gastrointestinal tract, with multiple animals imaged in independent experiments, confirming the ease of this new labeling strategy. Cancer Res; 70(19); 7562–9. ©2010 AACR.
Ulrich Auf Dem Keller - One of the best experts on this subject based on the ideXlab platform.
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towards kit like 18f labeling of Marimastat a noncovalent inhibitor drug for in vivo pet imaging cancer associated matrix metalloproteases
MedChemComm, 2011Co-Authors: Ying Li, Ulrich Auf Dem Keller, Caroline L Bellac, Philipp F Lange, Richard Ting, Curtis Harwig, Michael J Adam, James A H Inkster, Paul SchafferAbstract:Marimastat, a clinically trialed drug developed to treat breast cancer by inhibiting cancer-associated matrix metalloproteases (MMPs), was linked to an aryl boronic ester for single-step [18F]-aqueous fluoride capture and the labeled product revealed tumor associated MMP activity in vivo. Herein, we report important radiosynthetic attributes for labeling Marimastat that enabled the first PET images of breast cancer-associated matrix metalloproteases in a syngenic murine model. The advantages of this method include one-step post synthetic labeling in less than one hour at ambient temperature, the ability to work in aqueous media without drying the 18F-fluoride, observation of high radiochemical purity, and the potential for tripling the specific activity of the fluoride used in labeling. Using low levels of activity e.g. 60 mCi in low volumes this method affords reasonable yields of labeled Marimastat with decay-corrected specific activities of 0.39 and 0.75 Ci/μmol, and real specific activities of 0.16 and 0.39 Ci/μmol. Current limitations of this method along with anticipated improvements are discussed.
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towards kit like 18f labeling of Marimastat a noncovalent inhibitor drug for in vivo pet imaging cancer associated matrix metalloproteases
MedChemComm, 2011Co-Authors: Richard Ting, Ulrich Auf Dem Keller, Caroline L Bellac, Philipp F Lange, Curtis Harwig, Michael J Adam, James A H Inkster, Paul Schaffer, Thomas J RuthAbstract:Marimastat, a clinically trialed drug developed to treat breast cancer by inhibiting cancer-associated matrix metalloproteases (MMPs), was linked to an aryl boronic ester for single-step [18F]-aqueous fluoride capture and the labeled product revealed tumor associated MMP activity in vivo. Herein, we report important radiosynthetic attributes for labeling Marimastat that enabled the first PET images of breast cancer-associated matrix metalloproteases in a syngenic murine model. The advantages of this method include one-step post synthetic labeling in less than one hour at ambient temperature, the ability to work in aqueous media without drying the 18F-fluoride, observation of high radiochemical purity, and the potential for tripling the specific activity of the fluoride used in labeling. Using low levels of activity e.g. 60 mCi in low volumes this method affords reasonable yields of labeled Marimastat with decay-corrected specific activities of 0.39 and 0.75 Ci/μmol, and real specific activities of 0.16 and 0.39 Ci/μmol. Current limitations of this method along with anticipated improvements are discussed.
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novel matrix metalloproteinase inhibitor 18f Marimastat aryltrifluoroborate as a probe for in vivo positron emission tomography imaging in cancer
Cancer Research, 2010Co-Authors: Ulrich Auf Dem Keller, Caroline L Bellac, Yuanmei Lou, Philipp F Lange, Richard Ting, Curtis Harwig, Reinhild Kappelhoff, Shoukat Dedhar, Michael J Adam, Thomas J RuthAbstract:Matrix metalloproteinases (MMP), strongly associated pathogenic markers of cancer, have undergone extensive drug development programs. Marimastat, a noncovalent MMP inhibitor, was conjugated with FITC to label cellular metalloproteinase cancer targets in MDA-MB-231 cells in vitro. Punctate localization of active transmembrane MMP14 was observed. For molecular-targeted positron emission tomography imaging of syngeneic 67NR murine mammary carcinoma in vivo, Marimastat was (18)F-labeled using a shelf-stable arylboronic ester conjugate as a captor for aqueous [(18)F]fluoride in a novel, rapid one-step reaction at ambient temperature. [(18)F]Marimastat-aryltrifluoroborate localized to the tumors, with labeling being blocked in control animals first loaded with >10-fold excess unlabeled Marimastat. The labeled drug cleared primarily via the hepatobiliary and gastrointestinal tract, with multiple animals imaged in independent experiments, confirming the ease of this new labeling strategy.
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novel matrix metalloproteinase inhibitor 18f Marimastat aryltrifluoroborate as a probe for in vivo positron emission tomography imaging in cancer
Cancer Research, 2010Co-Authors: Ulrich Auf Dem Keller, Caroline L Bellac, Yuanmei Lou, Philipp F Lange, Richard Ting, Curtis Harwig, Reinhild Kappelhoff, Shoukat Dedhar, Michael J Adam, Thomas J RuthAbstract:Matrix metalloproteinases (MMP), strongly associated pathogenic markers of cancer, have undergone extensive drug development programs. Marimastat, a noncovalent MMP inhibitor, was conjugated with FITC to label cellular metalloproteinase cancer targets in MDA-MB-231 cells in vitro . Punctate localization of active transmembrane MMP14 was observed. For molecular-targeted positron emission tomography imaging of syngeneic 67NR murine mammary carcinoma in vivo , Marimastat was 18 F-labeled using a shelf-stable arylboronic ester conjugate as a captor for aqueous [ 18 F]fluoride in a novel, rapid one-step reaction at ambient temperature. [ 18 F]Marimastat-aryltrifluoroborate localized to the tumors, with labeling being blocked in control animals first loaded with >10-fold excess unlabeled Marimastat. The labeled drug cleared primarily via the hepatobiliary and gastrointestinal tract, with multiple animals imaged in independent experiments, confirming the ease of this new labeling strategy. Cancer Res; 70(19); 7562–9. ©2010 AACR.
Mark Puder - One of the best experts on this subject based on the ideXlab platform.
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Broad-Spectrum Matrix Metalloproteinase Inhibition Curbs Inflammation and Liver Injury but Aggravates Experimental Liver Fibrosis in Mice
2013Co-Authors: Vincent E De Meijer, Deanna Y Sverdlov, Yury Popov, Jonathan A Meisel, Vânia Nose, Mark PuderAbstract:Background: Liver fibrosis is characterized by excessive synthesis of extracellular matrix proteins, which prevails over their enzymatic degradation, primarily by matrix metalloproteinases (MMPs). The effect of pharmacological MMP inhibition on fibrogenesis, however, is largely unexplored. Inflammation is considered a prerequisite and important co-contributor to fibrosis and is, in part, mediated by tumor necrosis factor (TNF)-a-converting enzyme (TACE). We hypothesized that treatment with a broad-spectrum MMP and TACE-inhibitor (Marimastat) would ameliorate injury and inflammation, leading to decreased fibrogenesis during repeated hepatotoxin-induced liver injury. Methodology/Principal Findings: Liver fibrosis was induced in mice by repeated carbon tetrachloride (CCl4) administration, during which the mice received either Marimastat or vehicle twice daily. A single dose of CCl4 was administered to investigate acute liver injury in mice pretreated with Marimastat, mice deficient in Mmp9, or mice deficient in both TNF-a receptors. Liver injury was quantified by alanine aminotransferase (ALT) levels and confirmed by histology. Hepatic collagen was determined as hydroxyproline, and expression of fibrogenesis and fibrolysis-related transcripts was determined by quantitative reverse-transcription polymerase chain reaction. Marimastat-treated animals demonstrated significantly attenuated liver injury and inflammation but a 25 % increase in collagen deposition. Transcripts related to fibrogenesis were significantly less upregulated compared to vehicle-treated animals, while MMP expression and activity analysis reveale
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Marimastat treatment increased hepatic fibrosis following repeated carbon tetrachloride (CCl4) administration.
2013Co-Authors: Vincent E De Meijer, Detlef Schuppan, Deanna Y Sverdlov, Yury Popov, Jonathan A Meisel, Vânia Nose, Mark PuderAbstract:In mice treated with Marimastat, the liver to body weight ratio (A), as well as the spleen to body weight ratio (B) were increased. Masson trichrome staining of liver sections for collagen (blue; C) revealed bridging portal fibrosis. Livers from Marimastat treated animals showed occasional focal cirrhosis; however, advanced fibrosis was predominant (C). Livers from Marimastat treated mice exhibited increased collagen deposition as determined biochemically as relative hydroxyproline content and total hydroxyproline content in liver samples from two different lobes (D, E). Relative fibrotic area was increased in livers from mice treated with Marimastat, as quantified using morphometric analysis of Sirius Red stained liver sections (F). Oil, non-fibrotic control group; CCl4, fibrotic mice; VEH, vehicle treated control group; MAR, Marimastat treated experimental group; *, P
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Marimastat treatment downregulates matrix metalloproteinase (MMP) gene expression and MMP-activities.
2013Co-Authors: Vincent E De Meijer, Detlef Schuppan, Deanna Y Sverdlov, Yury Popov, Jonathan A Meisel, Vânia Nose, Mark PuderAbstract:Following repeated carbon tetrachloride (CCl4) administration, Marimastat did not affect hepatic transcript levels of MMP-2 (A), or MMP-3 (B) as quantified by real-time RT-PCR. Hepatic MMP-8 (C) and MMP-9 (D) transcripts were significantly upregulated in livers from Marimastat treated animals, whereas hepatic MMP-13 mRNA was significantly higher in the vehicle treated animals (E). Marimastat inhibits interstitial collagenolytic and gelatinolytic activity in a dose-dependent matter (F). Relative gelatinase and interstitial collagenase activities after 4 hours in liver homogenates supplemented with increasing concentrations of Marimastat, as determined by degradation of DQ-gelatin and collagen (black and grey squares, respectively). Oil, non-fibrotic control group; CCl4, fibrotic mice; VEH, vehicle treated control group; MAR, Marimastat treated experimental group; TNF, tumor necrosis factor; MMP, matrix metalloproteinase; *, P
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Marimastat treatment ameliorated hepatic injury and the inflammatory response following repeated carbon tetrachloride (CCl4) administration.
2013Co-Authors: Vincent E De Meijer, Detlef Schuppan, Deanna Y Sverdlov, Yury Popov, Jonathan A Meisel, Vânia Nose, Mark PuderAbstract:Marimastat treatment significantly reduced serum alkaline phosphatase levels (A), and resulted in a 14-fold decrease of serum ALT (B), indicating decreased hepatic injury. Serum TNF-α receptor II (p75) levels as measured by ELISA decreased following Marimastat treatment, suggesting successful inhibition of TNF-α converting enzyme (TACE) and an ameliorated inflammatory response. IL-6 serum levels as measured by ELISA increased following Marimastat treatment, suggesting hepatoprotection and stimulated liver regeneration (D). Oil, non-fibrotic control group; CCl4, fibrotic mice; VEH, vehicle treated control group; MAR, Marimastat treated experimental group; ALT, alanine aminotransferase; TNF, tumor necrosis factor; IL, interleukin; *, P
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Marimastat decreases hepatic stellate cell (HSC) activation, but increases recruitment of inflammatory cells.
2013Co-Authors: Vincent E De Meijer, Detlef Schuppan, Deanna Y Sverdlov, Yury Popov, Jonathan A Meisel, Vânia Nose, Mark PuderAbstract:Chronic carbon tetrachloride (CCl4) administration in animals treated with Marimastat resulted in a decreased activation of HSCs, as identified by alpha-smooth muscle actin (α-SMA) staining (A). Quantification revealed that following chronic CCl4 administration, Marimastat treated animals had a 74% decrease of activated HSCs, compared to controls (B). Liver sections from animals that were chronically challenged with CCl4 showed that resident T cells (CD3, C,D) and macrophages (F4/80, E,F) counts increased up to 2-fold upon Marimastat treatment. Oil, non-fibrotic control group; CCl4, fibrotic mice; VEH, vehicle treated control group; MAR, Marimastat treated experimental group; α-SMA, alpha-smooth muscle actin; *, P
Vincent E De Meijer - One of the best experts on this subject based on the ideXlab platform.
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Tumor Necrosis Factor a-Converting Enzyme Inhibition Reverses Hepatic Steatosis and Improves Insulin Sensitivity Markers and Surgical Outcome in Mice
2016Co-Authors: Vincent E De Meijer, Jonathan A Meisel, Anisha K. Sharma, Yury PopovAbstract:Background: Hepatic steatosis is an established risk factor for complications following major hepatic resection. Pharmacological options to reverse steatosis prior to surgery, however, are lacking. We hypothesized that treatment with the pharmacologic tumor necrosis factor-a converting enzyme (TACE)-inhibitor Marimastat would reverse established steatosis, leading to improved outcome following hepatectomy. Methodology/Principal Findings: C57BL/6 male mice were fed a high fat diet for 9 weeks to establish obesity, hepatic steatosis and insulin resistance, and were administered either Marimastat or vehicle for an additional 2 or 4 weeks. Leptin deficient, hyperinsulinemic ob/ob mice were treated with Marimastat for 4 weeks. Hepatic steatosis was quantified by magnetic resonance spectroscopy and confirmed by histology. After two weeks, Marimastat-treated animals significantly improved surrogate markers for insulin sensitivity and liver histology, and experienced a 66 % decrease in steatosis (P = 0.010). These findings were confirmed in ob/ob mice. Transcripts related to fatty acid synthesis were significantly downregulated in Marimastat-treated animals. Following pre-treatment with Marimastat or vehicle for two weeks, high fat fed C57BL/6 mice were subjected to two-thirds hepatectomy. Post-operative liver injury as quantified by serum aspartate aminotransferase levels and alanine aminotransferase levels was significantly decreased by 57 % (P = 0.020) and 44% (P = 0.032) respectively, compared to controls
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Broad-Spectrum Matrix Metalloproteinase Inhibition Curbs Inflammation and Liver Injury but Aggravates Experimental Liver Fibrosis in Mice
2013Co-Authors: Vincent E De Meijer, Deanna Y Sverdlov, Yury Popov, Jonathan A Meisel, Vânia Nose, Mark PuderAbstract:Background: Liver fibrosis is characterized by excessive synthesis of extracellular matrix proteins, which prevails over their enzymatic degradation, primarily by matrix metalloproteinases (MMPs). The effect of pharmacological MMP inhibition on fibrogenesis, however, is largely unexplored. Inflammation is considered a prerequisite and important co-contributor to fibrosis and is, in part, mediated by tumor necrosis factor (TNF)-a-converting enzyme (TACE). We hypothesized that treatment with a broad-spectrum MMP and TACE-inhibitor (Marimastat) would ameliorate injury and inflammation, leading to decreased fibrogenesis during repeated hepatotoxin-induced liver injury. Methodology/Principal Findings: Liver fibrosis was induced in mice by repeated carbon tetrachloride (CCl4) administration, during which the mice received either Marimastat or vehicle twice daily. A single dose of CCl4 was administered to investigate acute liver injury in mice pretreated with Marimastat, mice deficient in Mmp9, or mice deficient in both TNF-a receptors. Liver injury was quantified by alanine aminotransferase (ALT) levels and confirmed by histology. Hepatic collagen was determined as hydroxyproline, and expression of fibrogenesis and fibrolysis-related transcripts was determined by quantitative reverse-transcription polymerase chain reaction. Marimastat-treated animals demonstrated significantly attenuated liver injury and inflammation but a 25 % increase in collagen deposition. Transcripts related to fibrogenesis were significantly less upregulated compared to vehicle-treated animals, while MMP expression and activity analysis reveale
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Marimastat treatment increased hepatic fibrosis following repeated carbon tetrachloride (CCl4) administration.
2013Co-Authors: Vincent E De Meijer, Detlef Schuppan, Deanna Y Sverdlov, Yury Popov, Jonathan A Meisel, Vânia Nose, Mark PuderAbstract:In mice treated with Marimastat, the liver to body weight ratio (A), as well as the spleen to body weight ratio (B) were increased. Masson trichrome staining of liver sections for collagen (blue; C) revealed bridging portal fibrosis. Livers from Marimastat treated animals showed occasional focal cirrhosis; however, advanced fibrosis was predominant (C). Livers from Marimastat treated mice exhibited increased collagen deposition as determined biochemically as relative hydroxyproline content and total hydroxyproline content in liver samples from two different lobes (D, E). Relative fibrotic area was increased in livers from mice treated with Marimastat, as quantified using morphometric analysis of Sirius Red stained liver sections (F). Oil, non-fibrotic control group; CCl4, fibrotic mice; VEH, vehicle treated control group; MAR, Marimastat treated experimental group; *, P
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Marimastat treatment downregulates matrix metalloproteinase (MMP) gene expression and MMP-activities.
2013Co-Authors: Vincent E De Meijer, Detlef Schuppan, Deanna Y Sverdlov, Yury Popov, Jonathan A Meisel, Vânia Nose, Mark PuderAbstract:Following repeated carbon tetrachloride (CCl4) administration, Marimastat did not affect hepatic transcript levels of MMP-2 (A), or MMP-3 (B) as quantified by real-time RT-PCR. Hepatic MMP-8 (C) and MMP-9 (D) transcripts were significantly upregulated in livers from Marimastat treated animals, whereas hepatic MMP-13 mRNA was significantly higher in the vehicle treated animals (E). Marimastat inhibits interstitial collagenolytic and gelatinolytic activity in a dose-dependent matter (F). Relative gelatinase and interstitial collagenase activities after 4 hours in liver homogenates supplemented with increasing concentrations of Marimastat, as determined by degradation of DQ-gelatin and collagen (black and grey squares, respectively). Oil, non-fibrotic control group; CCl4, fibrotic mice; VEH, vehicle treated control group; MAR, Marimastat treated experimental group; TNF, tumor necrosis factor; MMP, matrix metalloproteinase; *, P
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Marimastat treatment ameliorated hepatic injury and the inflammatory response following repeated carbon tetrachloride (CCl4) administration.
2013Co-Authors: Vincent E De Meijer, Detlef Schuppan, Deanna Y Sverdlov, Yury Popov, Jonathan A Meisel, Vânia Nose, Mark PuderAbstract:Marimastat treatment significantly reduced serum alkaline phosphatase levels (A), and resulted in a 14-fold decrease of serum ALT (B), indicating decreased hepatic injury. Serum TNF-α receptor II (p75) levels as measured by ELISA decreased following Marimastat treatment, suggesting successful inhibition of TNF-α converting enzyme (TACE) and an ameliorated inflammatory response. IL-6 serum levels as measured by ELISA increased following Marimastat treatment, suggesting hepatoprotection and stimulated liver regeneration (D). Oil, non-fibrotic control group; CCl4, fibrotic mice; VEH, vehicle treated control group; MAR, Marimastat treated experimental group; ALT, alanine aminotransferase; TNF, tumor necrosis factor; IL, interleukin; *, P