The Experts below are selected from a list of 40392 Experts worldwide ranked by ideXlab platform
Ingrid B Renes - One of the best experts on this subject based on the ideXlab platform.
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Threonine metabolism in the intestine of mice: loss of Mucin 2 induces the threonine catabolic pathway.
Journal of Pediatric Gastroenterology and Nutrition, 2009Co-Authors: Maria Van Der Sluis, Anna Velcich, Barbara A E De Koning, Maaike W Schaart, Ingrid B Renes, Henk Schierbeek, Johannes B. Van GoudoeverAbstract:Objectives: Previous studies have shown that the intestine uses a major part of the dietary threonine intake for the synthesis of the structural component of the protective intestinal mucus layer, the secretory Mucin Muc2. In this context, the high intestinal demand for dietary threonine probably results from its incorporation into secretory Mucins rich in threonine residues. Therefore, we compared threonine utilization in the colon of Muc2 knockout (Muc2-/-) and wild-type (Muc2+/+) mice to investigate the intestinal dietary threonine metabolism in the absence of Muc2, which results in inflammation of the colon. Materials and Methods: Concentrations and isotopic enrichment of threonine were measured by gas chromatographyisotope ratio mass spectrometry in the serum, colon, and colonic content of mice given a bolus [U-13C]threonine enterally. Results: We retrieved 37.8% and 40.9% of dietary threonine in Muc2+/+and Muc2-/-mice, respectively, either as free or incorporated threonine. There were no major differences in the availability and concentration of free or incorporated threonine recovered in both serum and colon in both types of mice. However, the Muc2-/-mice did show overall significantly higher threonine oxidation rates compared with Muc2+/+mice. Conclusions: In the absence of Muc2, dietary threonine is mainly used for constitutive protein synthesis or becomes a substrate for metabolic oxidation. This indicates that inflammation also requires high threonine amounts. JPGN 49:99-107, 2009.
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Combined defects in epithelial and immunoregulatory factors exacerbate the pathogenesis of inflammation: Mucin 2-interleukin 10-deficient mice.
Laboratory Investigation, 2008Co-Authors: Maria Van Der Sluis, Anna Velcich, Hans A. Büller, Alexandra W. C. Einerhand, Johannes B. Van Goudoever, Isabelle Van Seuningen, Janneke Bouma, Audrey Vincent, Kermit L. Carraway, Ingrid B RenesAbstract:Expression of the Mucin MUC2, the structural component of the colonic mucus layer, is lowered in ulcerative colitis. Furthermore, interleukin (IL)-10 knockout (IL-10-/-) mice develop colitis and have reduced Muc2 levels. Our aim was to obtain insight into the role of Muc2 and IL-10 in epithelial protection. Muc2-IL-10 double-knockout (Muc2/IL-10(DKO)) mice were characterized and compared to Muc2 knockout (Muc2-/-), IL-10-/- and wild-type (WT) mice. Clinical symptoms, intestinal morphology and differences in epithelial-specific protein levels were analyzed. In addition, levels of the pro-inflammatory cytokines in colonic tissue and serum were determined. IL-10-/- mice were indistinguishable from WT mice throughout this experiment and showed no clinical or histological signs of colitis. Muc2/IL-10(DKO) and Muc2-/- mice showed significant growth retardation and clinical signs of colitis at 4 and 5 weeks, respectively. Muc2/IL-10(DKO) mice had a high mortality rate (50% survival/5 weeks) compared to the other types of mice (100% survival). Microscopic analysis of the colon of Muc2/IL-10(DKO) mice showed mucosal thickening, increased proliferation, superficial erosions and a diminished Muc4 expression. Furthermore, pro-inflammatory cytokines were significantly upregulated, both in tissue (mRNA) and systemically in Muc2/IL-10(DKO) mice. In conclusion, Muc2/IL-10(DKO) mice develop colitis, which is more severe in every aspect compared to Muc2-/- and IL-10-/- mice. These data indicate that (i) in case of Muc2 deficiency, the anti-inflammatory cytokine IL-10 can control epithelial damage, though to a limited extent and (ii) the mucus layer is most likely a key factor determining colitis.
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methotrexate induced mucositis in Mucin 2 deficient mice
Journal of Cellular Physiology, 2007Co-Authors: Barbara De Koning, Anna Velcich, Maria Van Der Sluis, Rob Pieters, Hans A. Büller, Alexandra W. C. Einerhand, Dicky J Lindenberghkortleve, Ingrid B RenesAbstract:The Mucin Muc2 or Mycin2 (Muc2), which is the main structural component of the protective mucus layer, has shown to be upregulated during chemotherapy-induced mucositis. As Muc2 has shown to have protective capacities, upregulation of Muc2 may be a counter reaction of the intestine protecting against mucositis. Therefore, increasing Muc2 protein levels could be a therapeutic target in mucositis prevention or reduction. Our aim was to determine the role of Muc2 in chemotherapy-induced mucositis. Mucositis was induced in Muc2 knockout (Muc2(-/-)) and wild type (Muc2(+/+)) mice by injecting methotrexate (MTX). Animals were weighed and sacrificed on Days 2-6 after MTX treatment and jejunal segments were analyzed. Before MTX treatment, the small intestine of Muc2(+/+) and Muc2(-/-) mice were similar with respect to epithelial morphology and proliferation. Moreover, sucrase-isomaltase and trefoil factor-3 protein expression levels were comparable between Muc2(+/+) and Muc2(-/-) mice. Up to Day 3 after MTX treatment, percentages of weight-loss did not differ. Thereafter, Muc2(+/+) mice showed a trend towards regaining weight, whereas Muc2(-/-) mice continued to lose weight. Surprisingly, MTX-induced intestinal damage of Muc2(-/-) and Muc2(+/+) mice was comparable. Prior to MTX-injection, tumor necrosis factor-alpha and interleukin-10 mRNAs were upregulated in Muc2(-/-) mice, probably due to continuous exposure of the intestine to luminal antigens. Muc2 deficiency does not lead to an increase in chemotherapy-induced mucositis. A possible explanation is the mechanism by which Muc2 deficiency may trigger the immune system to release interleukin-10, an anti-inflammatory cytokine before MTX-treatment.
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Methotrexate-induced mucositis in Mucin 2-deficient mice.
Journal of Cellular Physiology, 2006Co-Authors: Barbara A E De Koning, Anna Velcich, Maria Van Der Sluis, Dicky J. Lindenbergh-kortleve, Rob Pieters, Hans A. Büller, Alexandra W. C. Einerhand, Ingrid B RenesAbstract:The Mucin Muc2 or Mycin2 (Muc2), which is the main structural component of the protective mucus layer, has shown to be upregulated during chemotherapy-induced mucositis. As Muc2 has shown to have protective capacities, upregulation of Muc2 may be a counter reaction of the intestine protecting against mucositis. Therefore, increasing Muc2 protein levels could be a therapeutic target in mucositis prevention or reduction. Our aim was to determine the role of Muc2 in chemotherapy-induced mucositis. Mucositis was induced in Muc2 knockout (Muc2−/−) and wild type (Muc2+/+) mice by injecting methotrexate (MTX). Animals were weighed and sacrificed on Days 2–6 after MTX treatment and jejunal segments were analyzed. Before MTX treatment, the small intestine of Muc2+/+ and Muc2−/− mice were similar with respect to epithelial morphology and proliferation. Moreover, sucrase-isomaltase and trefoil factor-3 protein expression levels were comparable between Muc2+/+ and Muc2−/− mice. Up to Day 3 after MTX treatment, percentages of weight-loss did not differ. Thereafter, Muc2+/+ mice showed a trend towards regaining weight, whereas Muc2−/− mice continued to lose weight. Surprisingly, MTX-induced intestinal damage of Muc2−/− and Muc2+/+ mice was comparable. Prior to MTX-injection, tumor necrosis factor-α and interleukin-10 mRNAs were upregulated in Muc2−/− mice, probably due to continuous exposure of the intestine to luminal antigens. Muc2 deficiency does not lead to an increase in chemotherapy-induced mucositis. A possible explanation is the mechanism by which Muc2 deficiency may trigger the immune system to release interleukin-10, an anti-inflammatory cytokine before MTX-treatment. J. Cell. Physiol. 210: 144–152, 2007. © 2006 Wiley-Liss, Inc.
Reino Heikkilä - One of the best experts on this subject based on the ideXlab platform.
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prognostic relevance of occult metastases detected by cytokeratin 20 and Mucin 2 mrna levels in sentinel lymph nodes from colon cancer patients
Annals of Surgical Oncology, 2012Co-Authors: Oddmund Nordgård, Satu Oltedal, Ole Gunnar Aasprong, Kjersti Tjensvoll, Bjørnar Gilje, Jon Arne Søreide, Kjetil Søreide, Reino HeikkiläAbstract:To investigate the prognostic value of occult metastases detected by quantitative measurements of candidate biomarkers in sentinel lymph nodes (SLNs) from patients curatively resected for colon cancer. Resection specimens from consecutive patients undergoing surgery for localized colon cancer were subjected to ex vivo SLN mapping. SLNs were examined for the presence of metastases by routine hematoxylin–erythrosin–safranin staining and by cytokeratin 20 (CK20) and Mucin 2 (MUC2) mRNA quantification. The patients were stratified according to KRAS and BRAF mutation status and microsatellite instability status in their primary tumors. Survival end points were analyzed by Kaplan–Meier survival estimates and log-rank tests. A total of 817 SLNs were identified in 206 (97 %) of the 213 included patients. Routine histological examination of SLNs and other regional lymph nodes identified 63 patients with positive nodes (pN+), of which 42 (67 %) were positive in one or more SLNs (sensitivity 67 %, false-negative rate 33 %). On the basis of the CK20 and MUC2 mRNA levels in SLNs, occult metastases were suggested in 86 (60 %) and 52 (36 %) of the 143 otherwise LN-negative (pN0) patients, respectively. Survival analysis with a median 3.6-year follow-up revealed that MUC2 mRNA quantification had significant prognostic value in SLNs from all patients; however, occult SLN metastasis detection did not. Occult SLN metastases detected by CK20 and MUC2 mRNA quantification had limited prognostic value.
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prognostic relevance of occult metastases detected by cytokeratin 20 and Mucin 2 mrna levels in sentinel lymph nodes from colon cancer patients
Annals of Surgical Oncology, 2012Co-Authors: Oddmund Nordgård, Satu Oltedal, Ole Gunnar Aasprong, Kjersti Tjensvoll, Bjørnar Gilje, Jon Arne Søreide, Kjetil Søreide, Reino HeikkiläAbstract:Purpose To investigate the prognostic value of occult metastases detected by quantitative measurements of candidate biomarkers in sentinel lymph nodes (SLNs) from patients curatively resected for colon cancer.
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Abstract 4548: Prognostic value of occult metastases detected by cytokeratin 20 and Mucin 2 mRNA quantification in sentinel lymph nodes from colon cancer patients
Cancer Research, 2012Co-Authors: Oddmund Nordgård, Satu Oltedal, Ole Gunnar Aasprong, Kjersti Tjensvoll, Bjørnar Gilje, Reino Heikkilä, Jon Arne Søreide, Kjetil Søreide, Marianne Guriby, Ragnhild A. LotheAbstract:Proceedings: AACR 103rd Annual Meeting 2012‐‐ Mar 31‐Apr 4, 2012; Chicago, IL BACKGROUND: Lymph node (LN) metastasis status is among the strongest prognostic factors in colon cancer. Despite this, 20-30% of LN negative patients experience disease recurrence. These patients may have occult LN metastases that are not detected by routine microscopy. The aim of the present study was to investigate the prognostic value of occult metastases detected by cytokeratin 20 (CK20) and Mucin 2 (MUC2) mRNA quantification in sentinel lymph nodes (SLNs) from patients curatively resected for colon cancer. METHODS: Resection specimens from consecutive patients undergoing surgery for localized colon cancer were subjected to ex vivo SLN mapping. The isolated SLNs were examined for the presence of metastases by routine HES staining and quantitative CK20 and MUC2 mRNA measurements. Primary tumor microsatelite instability- (MSI), KRAS and BRAF mutation status were determined for the included patients. Recurrence-free and disease-specific survivals were analyzed by Kaplan-Meier survival estimates and log rank tests. RESULTS: SLNs were identified in 206 (97%) of the 213 included patients. Routine histological analysis of SLNs and other regional lymph nodes revealed LN metastases in 63 patients (pN+), of which 42 (67%) had metastases detected in one or more SLNs (sensitivity 67%, false negative rate 33%). When analyzing the SLNs by CK20 and MUC2 mRNA quantification, occult metastases were suggested in 86 (60%) and 52 (36%) of the 143 otherwise LN negative (pN0) patients, respectively. Survival analysis with a median 3.6 year follow-up revealed a significant prognostic value of MUC2 mRNA quantification in SLNs from all the patients, but not for the pN0 patients. For CK20 mRNA levels in SLNs we observed no statistically significant survival differences. Patient stratification according to primary tumor MSI, KRAS mutation and BRAF mutation status did not reveal any significant survival differences related to the suggested occult SLN metastases, neither. CONCLUSIONS: Occult SLN metastases detected by quantitative CK20 and MUC2 mRNA measurements did not demonstrate any prognostic value in this study. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4548. doi:1538-7445.AM2012-4548
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the potential of cytokeratin 20 and Mucin 2 mrna as metastasis markers in regional lymph nodes of colon cancer patients investigated by quantitative rt pcr
International Journal of Colorectal Disease, 2009Co-Authors: Oddmund Nordgård, Satu Oltedal, Ole Gunnar Aasprong, Kjersti Tjensvoll, Bjørnar Gilje, Hartwig Korner, Reino HeikkiläAbstract:The presence of regional lymph node metastases is one of the most important prognostic factors in colon cancer. Nevertheless, up to 30% of the lymph node negative patients experience disease recurrence. Possibly, this patient group may be identified by more sensitive techniques than routine histopathological examination of the lymph nodes. In the present study, we have evaluated the detection of colon cancer lymph node metastases by real-time RT-PCR quantitation of the epithelial-specific cytokeratin 20 (CK20) and Mucin 2 (MUC2) mRNAs. Both assays were able to detect dilutions of tumor cells down to one tumor cell in 106 normal lymphocytes. CK20 and MUC2 mRNA were quantitated in 52 normal lymph nodes from 12 patients undergoing surgery for benign bowel diseases and in 144 primary colon tumors. The median tumor level of both markers were more than 104-fold higher than the highest level in normal lymph nodes, indicating that the markers had a potential for metastasis detection in a clinical context. We applied the assays to 61 lymph nodes with known metastases detected by routine staining. Elevated CK20 or MUC2 mRNA levels were detected in 57 (95%) of the 61 LNs. Thus, CK20 and MUC2 quantitation by real-time RT-PCR seems to be a promising, sensitive tool to detect metastases in regional lymph nodes from colon cancer patients.
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the potential of cytokeratin 20 and Mucin 2 mrna as metastasis markers in regional lymph nodes of colon cancer patients investigated by quantitative rt pcr
International Journal of Colorectal Disease, 2009Co-Authors: Oddmund Nordgård, Satu Oltedal, Ole Gunnar Aasprong, Kjersti Tjensvoll, Bjørnar Gilje, Hartwig Korner, Reino HeikkiläAbstract:Purpose The presence of regional lymph node metastases is one of the most important prognostic factors in colon cancer. Nevertheless, up to 30% of the lymph node negative patients experience disease recurrence. Possibly, this patient group may be identified by more sensitive techniques than routine histopathological examination of the lymph nodes.
Oddmund Nordgård - One of the best experts on this subject based on the ideXlab platform.
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prognostic relevance of occult metastases detected by cytokeratin 20 and Mucin 2 mrna levels in sentinel lymph nodes from colon cancer patients
Annals of Surgical Oncology, 2012Co-Authors: Oddmund Nordgård, Satu Oltedal, Ole Gunnar Aasprong, Kjersti Tjensvoll, Bjørnar Gilje, Jon Arne Søreide, Kjetil Søreide, Reino HeikkiläAbstract:To investigate the prognostic value of occult metastases detected by quantitative measurements of candidate biomarkers in sentinel lymph nodes (SLNs) from patients curatively resected for colon cancer. Resection specimens from consecutive patients undergoing surgery for localized colon cancer were subjected to ex vivo SLN mapping. SLNs were examined for the presence of metastases by routine hematoxylin–erythrosin–safranin staining and by cytokeratin 20 (CK20) and Mucin 2 (MUC2) mRNA quantification. The patients were stratified according to KRAS and BRAF mutation status and microsatellite instability status in their primary tumors. Survival end points were analyzed by Kaplan–Meier survival estimates and log-rank tests. A total of 817 SLNs were identified in 206 (97 %) of the 213 included patients. Routine histological examination of SLNs and other regional lymph nodes identified 63 patients with positive nodes (pN+), of which 42 (67 %) were positive in one or more SLNs (sensitivity 67 %, false-negative rate 33 %). On the basis of the CK20 and MUC2 mRNA levels in SLNs, occult metastases were suggested in 86 (60 %) and 52 (36 %) of the 143 otherwise LN-negative (pN0) patients, respectively. Survival analysis with a median 3.6-year follow-up revealed that MUC2 mRNA quantification had significant prognostic value in SLNs from all patients; however, occult SLN metastasis detection did not. Occult SLN metastases detected by CK20 and MUC2 mRNA quantification had limited prognostic value.
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prognostic relevance of occult metastases detected by cytokeratin 20 and Mucin 2 mrna levels in sentinel lymph nodes from colon cancer patients
Annals of Surgical Oncology, 2012Co-Authors: Oddmund Nordgård, Satu Oltedal, Ole Gunnar Aasprong, Kjersti Tjensvoll, Bjørnar Gilje, Jon Arne Søreide, Kjetil Søreide, Reino HeikkiläAbstract:Purpose To investigate the prognostic value of occult metastases detected by quantitative measurements of candidate biomarkers in sentinel lymph nodes (SLNs) from patients curatively resected for colon cancer.
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Abstract 4548: Prognostic value of occult metastases detected by cytokeratin 20 and Mucin 2 mRNA quantification in sentinel lymph nodes from colon cancer patients
Cancer Research, 2012Co-Authors: Oddmund Nordgård, Satu Oltedal, Ole Gunnar Aasprong, Kjersti Tjensvoll, Bjørnar Gilje, Reino Heikkilä, Jon Arne Søreide, Kjetil Søreide, Marianne Guriby, Ragnhild A. LotheAbstract:Proceedings: AACR 103rd Annual Meeting 2012‐‐ Mar 31‐Apr 4, 2012; Chicago, IL BACKGROUND: Lymph node (LN) metastasis status is among the strongest prognostic factors in colon cancer. Despite this, 20-30% of LN negative patients experience disease recurrence. These patients may have occult LN metastases that are not detected by routine microscopy. The aim of the present study was to investigate the prognostic value of occult metastases detected by cytokeratin 20 (CK20) and Mucin 2 (MUC2) mRNA quantification in sentinel lymph nodes (SLNs) from patients curatively resected for colon cancer. METHODS: Resection specimens from consecutive patients undergoing surgery for localized colon cancer were subjected to ex vivo SLN mapping. The isolated SLNs were examined for the presence of metastases by routine HES staining and quantitative CK20 and MUC2 mRNA measurements. Primary tumor microsatelite instability- (MSI), KRAS and BRAF mutation status were determined for the included patients. Recurrence-free and disease-specific survivals were analyzed by Kaplan-Meier survival estimates and log rank tests. RESULTS: SLNs were identified in 206 (97%) of the 213 included patients. Routine histological analysis of SLNs and other regional lymph nodes revealed LN metastases in 63 patients (pN+), of which 42 (67%) had metastases detected in one or more SLNs (sensitivity 67%, false negative rate 33%). When analyzing the SLNs by CK20 and MUC2 mRNA quantification, occult metastases were suggested in 86 (60%) and 52 (36%) of the 143 otherwise LN negative (pN0) patients, respectively. Survival analysis with a median 3.6 year follow-up revealed a significant prognostic value of MUC2 mRNA quantification in SLNs from all the patients, but not for the pN0 patients. For CK20 mRNA levels in SLNs we observed no statistically significant survival differences. Patient stratification according to primary tumor MSI, KRAS mutation and BRAF mutation status did not reveal any significant survival differences related to the suggested occult SLN metastases, neither. CONCLUSIONS: Occult SLN metastases detected by quantitative CK20 and MUC2 mRNA measurements did not demonstrate any prognostic value in this study. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4548. doi:1538-7445.AM2012-4548
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the potential of cytokeratin 20 and Mucin 2 mrna as metastasis markers in regional lymph nodes of colon cancer patients investigated by quantitative rt pcr
International Journal of Colorectal Disease, 2009Co-Authors: Oddmund Nordgård, Satu Oltedal, Ole Gunnar Aasprong, Kjersti Tjensvoll, Bjørnar Gilje, Hartwig Korner, Reino HeikkiläAbstract:The presence of regional lymph node metastases is one of the most important prognostic factors in colon cancer. Nevertheless, up to 30% of the lymph node negative patients experience disease recurrence. Possibly, this patient group may be identified by more sensitive techniques than routine histopathological examination of the lymph nodes. In the present study, we have evaluated the detection of colon cancer lymph node metastases by real-time RT-PCR quantitation of the epithelial-specific cytokeratin 20 (CK20) and Mucin 2 (MUC2) mRNAs. Both assays were able to detect dilutions of tumor cells down to one tumor cell in 106 normal lymphocytes. CK20 and MUC2 mRNA were quantitated in 52 normal lymph nodes from 12 patients undergoing surgery for benign bowel diseases and in 144 primary colon tumors. The median tumor level of both markers were more than 104-fold higher than the highest level in normal lymph nodes, indicating that the markers had a potential for metastasis detection in a clinical context. We applied the assays to 61 lymph nodes with known metastases detected by routine staining. Elevated CK20 or MUC2 mRNA levels were detected in 57 (95%) of the 61 LNs. Thus, CK20 and MUC2 quantitation by real-time RT-PCR seems to be a promising, sensitive tool to detect metastases in regional lymph nodes from colon cancer patients.
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the potential of cytokeratin 20 and Mucin 2 mrna as metastasis markers in regional lymph nodes of colon cancer patients investigated by quantitative rt pcr
International Journal of Colorectal Disease, 2009Co-Authors: Oddmund Nordgård, Satu Oltedal, Ole Gunnar Aasprong, Kjersti Tjensvoll, Bjørnar Gilje, Hartwig Korner, Reino HeikkiläAbstract:Purpose The presence of regional lymph node metastases is one of the most important prognostic factors in colon cancer. Nevertheless, up to 30% of the lymph node negative patients experience disease recurrence. Possibly, this patient group may be identified by more sensitive techniques than routine histopathological examination of the lymph nodes.
Maria Van Der Sluis - One of the best experts on this subject based on the ideXlab platform.
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Threonine metabolism in the intestine of mice: loss of Mucin 2 induces the threonine catabolic pathway.
Journal of Pediatric Gastroenterology and Nutrition, 2009Co-Authors: Maria Van Der Sluis, Anna Velcich, Barbara A E De Koning, Maaike W Schaart, Ingrid B Renes, Henk Schierbeek, Johannes B. Van GoudoeverAbstract:Objectives: Previous studies have shown that the intestine uses a major part of the dietary threonine intake for the synthesis of the structural component of the protective intestinal mucus layer, the secretory Mucin Muc2. In this context, the high intestinal demand for dietary threonine probably results from its incorporation into secretory Mucins rich in threonine residues. Therefore, we compared threonine utilization in the colon of Muc2 knockout (Muc2-/-) and wild-type (Muc2+/+) mice to investigate the intestinal dietary threonine metabolism in the absence of Muc2, which results in inflammation of the colon. Materials and Methods: Concentrations and isotopic enrichment of threonine were measured by gas chromatographyisotope ratio mass spectrometry in the serum, colon, and colonic content of mice given a bolus [U-13C]threonine enterally. Results: We retrieved 37.8% and 40.9% of dietary threonine in Muc2+/+and Muc2-/-mice, respectively, either as free or incorporated threonine. There were no major differences in the availability and concentration of free or incorporated threonine recovered in both serum and colon in both types of mice. However, the Muc2-/-mice did show overall significantly higher threonine oxidation rates compared with Muc2+/+mice. Conclusions: In the absence of Muc2, dietary threonine is mainly used for constitutive protein synthesis or becomes a substrate for metabolic oxidation. This indicates that inflammation also requires high threonine amounts. JPGN 49:99-107, 2009.
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Combined defects in epithelial and immunoregulatory factors exacerbate the pathogenesis of inflammation: Mucin 2-interleukin 10-deficient mice.
Laboratory Investigation, 2008Co-Authors: Maria Van Der Sluis, Anna Velcich, Hans A. Büller, Alexandra W. C. Einerhand, Johannes B. Van Goudoever, Isabelle Van Seuningen, Janneke Bouma, Audrey Vincent, Kermit L. Carraway, Ingrid B RenesAbstract:Expression of the Mucin MUC2, the structural component of the colonic mucus layer, is lowered in ulcerative colitis. Furthermore, interleukin (IL)-10 knockout (IL-10-/-) mice develop colitis and have reduced Muc2 levels. Our aim was to obtain insight into the role of Muc2 and IL-10 in epithelial protection. Muc2-IL-10 double-knockout (Muc2/IL-10(DKO)) mice were characterized and compared to Muc2 knockout (Muc2-/-), IL-10-/- and wild-type (WT) mice. Clinical symptoms, intestinal morphology and differences in epithelial-specific protein levels were analyzed. In addition, levels of the pro-inflammatory cytokines in colonic tissue and serum were determined. IL-10-/- mice were indistinguishable from WT mice throughout this experiment and showed no clinical or histological signs of colitis. Muc2/IL-10(DKO) and Muc2-/- mice showed significant growth retardation and clinical signs of colitis at 4 and 5 weeks, respectively. Muc2/IL-10(DKO) mice had a high mortality rate (50% survival/5 weeks) compared to the other types of mice (100% survival). Microscopic analysis of the colon of Muc2/IL-10(DKO) mice showed mucosal thickening, increased proliferation, superficial erosions and a diminished Muc4 expression. Furthermore, pro-inflammatory cytokines were significantly upregulated, both in tissue (mRNA) and systemically in Muc2/IL-10(DKO) mice. In conclusion, Muc2/IL-10(DKO) mice develop colitis, which is more severe in every aspect compared to Muc2-/- and IL-10-/- mice. These data indicate that (i) in case of Muc2 deficiency, the anti-inflammatory cytokine IL-10 can control epithelial damage, though to a limited extent and (ii) the mucus layer is most likely a key factor determining colitis.
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methotrexate induced mucositis in Mucin 2 deficient mice
Journal of Cellular Physiology, 2007Co-Authors: Barbara De Koning, Anna Velcich, Maria Van Der Sluis, Rob Pieters, Hans A. Büller, Alexandra W. C. Einerhand, Dicky J Lindenberghkortleve, Ingrid B RenesAbstract:The Mucin Muc2 or Mycin2 (Muc2), which is the main structural component of the protective mucus layer, has shown to be upregulated during chemotherapy-induced mucositis. As Muc2 has shown to have protective capacities, upregulation of Muc2 may be a counter reaction of the intestine protecting against mucositis. Therefore, increasing Muc2 protein levels could be a therapeutic target in mucositis prevention or reduction. Our aim was to determine the role of Muc2 in chemotherapy-induced mucositis. Mucositis was induced in Muc2 knockout (Muc2(-/-)) and wild type (Muc2(+/+)) mice by injecting methotrexate (MTX). Animals were weighed and sacrificed on Days 2-6 after MTX treatment and jejunal segments were analyzed. Before MTX treatment, the small intestine of Muc2(+/+) and Muc2(-/-) mice were similar with respect to epithelial morphology and proliferation. Moreover, sucrase-isomaltase and trefoil factor-3 protein expression levels were comparable between Muc2(+/+) and Muc2(-/-) mice. Up to Day 3 after MTX treatment, percentages of weight-loss did not differ. Thereafter, Muc2(+/+) mice showed a trend towards regaining weight, whereas Muc2(-/-) mice continued to lose weight. Surprisingly, MTX-induced intestinal damage of Muc2(-/-) and Muc2(+/+) mice was comparable. Prior to MTX-injection, tumor necrosis factor-alpha and interleukin-10 mRNAs were upregulated in Muc2(-/-) mice, probably due to continuous exposure of the intestine to luminal antigens. Muc2 deficiency does not lead to an increase in chemotherapy-induced mucositis. A possible explanation is the mechanism by which Muc2 deficiency may trigger the immune system to release interleukin-10, an anti-inflammatory cytokine before MTX-treatment.
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Methotrexate-induced mucositis in Mucin 2-deficient mice.
Journal of Cellular Physiology, 2006Co-Authors: Barbara A E De Koning, Anna Velcich, Maria Van Der Sluis, Dicky J. Lindenbergh-kortleve, Rob Pieters, Hans A. Büller, Alexandra W. C. Einerhand, Ingrid B RenesAbstract:The Mucin Muc2 or Mycin2 (Muc2), which is the main structural component of the protective mucus layer, has shown to be upregulated during chemotherapy-induced mucositis. As Muc2 has shown to have protective capacities, upregulation of Muc2 may be a counter reaction of the intestine protecting against mucositis. Therefore, increasing Muc2 protein levels could be a therapeutic target in mucositis prevention or reduction. Our aim was to determine the role of Muc2 in chemotherapy-induced mucositis. Mucositis was induced in Muc2 knockout (Muc2−/−) and wild type (Muc2+/+) mice by injecting methotrexate (MTX). Animals were weighed and sacrificed on Days 2–6 after MTX treatment and jejunal segments were analyzed. Before MTX treatment, the small intestine of Muc2+/+ and Muc2−/− mice were similar with respect to epithelial morphology and proliferation. Moreover, sucrase-isomaltase and trefoil factor-3 protein expression levels were comparable between Muc2+/+ and Muc2−/− mice. Up to Day 3 after MTX treatment, percentages of weight-loss did not differ. Thereafter, Muc2+/+ mice showed a trend towards regaining weight, whereas Muc2−/− mice continued to lose weight. Surprisingly, MTX-induced intestinal damage of Muc2−/− and Muc2+/+ mice was comparable. Prior to MTX-injection, tumor necrosis factor-α and interleukin-10 mRNAs were upregulated in Muc2−/− mice, probably due to continuous exposure of the intestine to luminal antigens. Muc2 deficiency does not lead to an increase in chemotherapy-induced mucositis. A possible explanation is the mechanism by which Muc2 deficiency may trigger the immune system to release interleukin-10, an anti-inflammatory cytokine before MTX-treatment. J. Cell. Physiol. 210: 144–152, 2007. © 2006 Wiley-Liss, Inc.
Anna Velcich - One of the best experts on this subject based on the ideXlab platform.
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Threonine metabolism in the intestine of mice: loss of Mucin 2 induces the threonine catabolic pathway.
Journal of Pediatric Gastroenterology and Nutrition, 2009Co-Authors: Maria Van Der Sluis, Anna Velcich, Barbara A E De Koning, Maaike W Schaart, Ingrid B Renes, Henk Schierbeek, Johannes B. Van GoudoeverAbstract:Objectives: Previous studies have shown that the intestine uses a major part of the dietary threonine intake for the synthesis of the structural component of the protective intestinal mucus layer, the secretory Mucin Muc2. In this context, the high intestinal demand for dietary threonine probably results from its incorporation into secretory Mucins rich in threonine residues. Therefore, we compared threonine utilization in the colon of Muc2 knockout (Muc2-/-) and wild-type (Muc2+/+) mice to investigate the intestinal dietary threonine metabolism in the absence of Muc2, which results in inflammation of the colon. Materials and Methods: Concentrations and isotopic enrichment of threonine were measured by gas chromatographyisotope ratio mass spectrometry in the serum, colon, and colonic content of mice given a bolus [U-13C]threonine enterally. Results: We retrieved 37.8% and 40.9% of dietary threonine in Muc2+/+and Muc2-/-mice, respectively, either as free or incorporated threonine. There were no major differences in the availability and concentration of free or incorporated threonine recovered in both serum and colon in both types of mice. However, the Muc2-/-mice did show overall significantly higher threonine oxidation rates compared with Muc2+/+mice. Conclusions: In the absence of Muc2, dietary threonine is mainly used for constitutive protein synthesis or becomes a substrate for metabolic oxidation. This indicates that inflammation also requires high threonine amounts. JPGN 49:99-107, 2009.
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Combined defects in epithelial and immunoregulatory factors exacerbate the pathogenesis of inflammation: Mucin 2-interleukin 10-deficient mice.
Laboratory Investigation, 2008Co-Authors: Maria Van Der Sluis, Anna Velcich, Hans A. Büller, Alexandra W. C. Einerhand, Johannes B. Van Goudoever, Isabelle Van Seuningen, Janneke Bouma, Audrey Vincent, Kermit L. Carraway, Ingrid B RenesAbstract:Expression of the Mucin MUC2, the structural component of the colonic mucus layer, is lowered in ulcerative colitis. Furthermore, interleukin (IL)-10 knockout (IL-10-/-) mice develop colitis and have reduced Muc2 levels. Our aim was to obtain insight into the role of Muc2 and IL-10 in epithelial protection. Muc2-IL-10 double-knockout (Muc2/IL-10(DKO)) mice were characterized and compared to Muc2 knockout (Muc2-/-), IL-10-/- and wild-type (WT) mice. Clinical symptoms, intestinal morphology and differences in epithelial-specific protein levels were analyzed. In addition, levels of the pro-inflammatory cytokines in colonic tissue and serum were determined. IL-10-/- mice were indistinguishable from WT mice throughout this experiment and showed no clinical or histological signs of colitis. Muc2/IL-10(DKO) and Muc2-/- mice showed significant growth retardation and clinical signs of colitis at 4 and 5 weeks, respectively. Muc2/IL-10(DKO) mice had a high mortality rate (50% survival/5 weeks) compared to the other types of mice (100% survival). Microscopic analysis of the colon of Muc2/IL-10(DKO) mice showed mucosal thickening, increased proliferation, superficial erosions and a diminished Muc4 expression. Furthermore, pro-inflammatory cytokines were significantly upregulated, both in tissue (mRNA) and systemically in Muc2/IL-10(DKO) mice. In conclusion, Muc2/IL-10(DKO) mice develop colitis, which is more severe in every aspect compared to Muc2-/- and IL-10-/- mice. These data indicate that (i) in case of Muc2 deficiency, the anti-inflammatory cytokine IL-10 can control epithelial damage, though to a limited extent and (ii) the mucus layer is most likely a key factor determining colitis.
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methotrexate induced mucositis in Mucin 2 deficient mice
Journal of Cellular Physiology, 2007Co-Authors: Barbara De Koning, Anna Velcich, Maria Van Der Sluis, Rob Pieters, Hans A. Büller, Alexandra W. C. Einerhand, Dicky J Lindenberghkortleve, Ingrid B RenesAbstract:The Mucin Muc2 or Mycin2 (Muc2), which is the main structural component of the protective mucus layer, has shown to be upregulated during chemotherapy-induced mucositis. As Muc2 has shown to have protective capacities, upregulation of Muc2 may be a counter reaction of the intestine protecting against mucositis. Therefore, increasing Muc2 protein levels could be a therapeutic target in mucositis prevention or reduction. Our aim was to determine the role of Muc2 in chemotherapy-induced mucositis. Mucositis was induced in Muc2 knockout (Muc2(-/-)) and wild type (Muc2(+/+)) mice by injecting methotrexate (MTX). Animals were weighed and sacrificed on Days 2-6 after MTX treatment and jejunal segments were analyzed. Before MTX treatment, the small intestine of Muc2(+/+) and Muc2(-/-) mice were similar with respect to epithelial morphology and proliferation. Moreover, sucrase-isomaltase and trefoil factor-3 protein expression levels were comparable between Muc2(+/+) and Muc2(-/-) mice. Up to Day 3 after MTX treatment, percentages of weight-loss did not differ. Thereafter, Muc2(+/+) mice showed a trend towards regaining weight, whereas Muc2(-/-) mice continued to lose weight. Surprisingly, MTX-induced intestinal damage of Muc2(-/-) and Muc2(+/+) mice was comparable. Prior to MTX-injection, tumor necrosis factor-alpha and interleukin-10 mRNAs were upregulated in Muc2(-/-) mice, probably due to continuous exposure of the intestine to luminal antigens. Muc2 deficiency does not lead to an increase in chemotherapy-induced mucositis. A possible explanation is the mechanism by which Muc2 deficiency may trigger the immune system to release interleukin-10, an anti-inflammatory cytokine before MTX-treatment.
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Methotrexate-induced mucositis in Mucin 2-deficient mice.
Journal of Cellular Physiology, 2006Co-Authors: Barbara A E De Koning, Anna Velcich, Maria Van Der Sluis, Dicky J. Lindenbergh-kortleve, Rob Pieters, Hans A. Büller, Alexandra W. C. Einerhand, Ingrid B RenesAbstract:The Mucin Muc2 or Mycin2 (Muc2), which is the main structural component of the protective mucus layer, has shown to be upregulated during chemotherapy-induced mucositis. As Muc2 has shown to have protective capacities, upregulation of Muc2 may be a counter reaction of the intestine protecting against mucositis. Therefore, increasing Muc2 protein levels could be a therapeutic target in mucositis prevention or reduction. Our aim was to determine the role of Muc2 in chemotherapy-induced mucositis. Mucositis was induced in Muc2 knockout (Muc2−/−) and wild type (Muc2+/+) mice by injecting methotrexate (MTX). Animals were weighed and sacrificed on Days 2–6 after MTX treatment and jejunal segments were analyzed. Before MTX treatment, the small intestine of Muc2+/+ and Muc2−/− mice were similar with respect to epithelial morphology and proliferation. Moreover, sucrase-isomaltase and trefoil factor-3 protein expression levels were comparable between Muc2+/+ and Muc2−/− mice. Up to Day 3 after MTX treatment, percentages of weight-loss did not differ. Thereafter, Muc2+/+ mice showed a trend towards regaining weight, whereas Muc2−/− mice continued to lose weight. Surprisingly, MTX-induced intestinal damage of Muc2−/− and Muc2+/+ mice was comparable. Prior to MTX-injection, tumor necrosis factor-α and interleukin-10 mRNAs were upregulated in Muc2−/− mice, probably due to continuous exposure of the intestine to luminal antigens. Muc2 deficiency does not lead to an increase in chemotherapy-induced mucositis. A possible explanation is the mechanism by which Muc2 deficiency may trigger the immune system to release interleukin-10, an anti-inflammatory cytokine before MTX-treatment. J. Cell. Physiol. 210: 144–152, 2007. © 2006 Wiley-Liss, Inc.