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Juan L. Iovanna - One of the best experts on this subject based on the ideXlab platform.
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The Pancreatitis-Associated Protein VMP1, a key regulator of inducible autophagy, promotes Kras(G12D)-mediated pancreatic cancer initiation.
Cell Death & Disease, 2016Co-Authors: C Loncle, Nelson Dusetti, M I Molejon, S Lac, J I Tellechea, G Lomberk, L Gramatica, R Urrutia, M F Fernandez Zapico, Juan L. IovannaAbstract:Both clinical and experimental evidence have firmly established that chronic Pancreatitis, in particular in the context of Kras oncogenic mutations, predisposes to pancreatic ductal adenocarcinoma (PDAC). However, the repertoire of molecular mediators of Pancreatitis involved in Kras-mediated initiation of pancreatic carcinogenesis remains to be fully defined. In this study we demonstrate a novel role for vacuole membrane Protein 1 (VMP1), a Pancreatitis-Associated Protein critical for inducible autophagy, in the regulation of Kras-induced PDAC initiation. Using a newly developed genetically engineered model, we demonstrate that VMP1 increases the ability of Kras to give rise to preneoplastic lesions, pancreatic intraepithelial neoplasias (PanINs). This promoting effect of VMP1 on PanIN formation is due, at least in part, by an increase in cell proliferation combined with a decrease in apoptosis. Using chloroquine, an inhibitor of autophagy, we show that this drug antagonizes the effect of VMP1 on PanIN formation. Thus, we conclude that VMP1-mediated autophagy cooperate with Kras to promote PDAC initiation. These findings are of significant medical relevance, molecules targeting autophagy are currently being tested along chemotherapeutic agents to treat PDAC and other tumors in human trials.
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The Pancreatitis-Associated Protein VMP1, a key regulator of inducible autophagy, promotes Kras^G12D-mediated pancreatic cancer initiation
Cell Death & Disease, 2016Co-Authors: C Loncle, Nelson Dusetti, M I Molejon, S Lac, J I Tellechea, G Lomberk, L Gramatica, M F Fernandez Zapico, R Urrutia, Juan L. IovannaAbstract:Both clinical and experimental evidence have firmly established that chronic Pancreatitis, in particular in the context of Kras oncogenic mutations, predisposes to pancreatic ductal adenocarcinoma (PDAC). However, the repertoire of molecular mediators of Pancreatitis involved in Kras-mediated initiation of pancreatic carcinogenesis remains to be fully defined. In this study we demonstrate a novel role for vacuole membrane Protein 1 (VMP1), a Pancreatitis-Associated Protein critical for inducible autophagy, in the regulation of Kras-induced PDAC initiation. Using a newly developed genetically engineered model, we demonstrate that VMP1 increases the ability of Kras to give rise to preneoplastic lesions, pancreatic intraepithelial neoplasias (PanINs). This promoting effect of VMP1 on PanIN formation is due, at least in part, by an increase in cell proliferation combined with a decrease in apoptosis. Using chloroquine, an inhibitor of autophagy, we show that this drug antagonizes the effect of VMP1 on PanIN formation. Thus, we conclude that VMP1-mediated autophagy cooperate with Kras to promote PDAC initiation. These findings are of significant medical relevance, molecules targeting autophagy are currently being tested along chemotherapeutic agents to treat PDAC and other tumors in human trials.
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Pancreatitis-Associated Protein Does Not Predict Disease Relapse in Inflammatory Bowel Disease Patients
PLoS ONE, 2014Co-Authors: Tiago Nunes, Juan L. Iovanna, Maria Josefina Etchevers, Maria José Sandi, Susana Pinó Donnay, Teddy Grandjean, Maria Pellise, Julián Panés, Elena Ricart, Jean-charles DagornAbstract:Background The Pancreatitis-Associated Protein (PAP) is increased in the serum of active inflammatory bowel disease (IBD) patients and its levels seem to be correlated with disease activity. Our aim was to evaluate the usefulness of serum and fecal PAP measurements to predict relapse in patients with inactive IBD.
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Pancreatitis-Associated Protein Does Not Predict Disease Relapse in Inflammatory Bowel Disease Patients
PloS one, 2014Co-Authors: Tiago Nunes, Juan L. Iovanna, Maria Josefina Etchevers, Maria José Sandi, Susana Pinó Donnay, Teddy Grandjean, Maria Pellise, Julián Panés, Elena Ricart, Jean-charles DagornAbstract:The Pancreatitis-Associated Protein (PAP) is increased in the serum of active inflammatory bowel disease (IBD) patients and its levels seem to be correlated with disease activity. Our aim was to evaluate the usefulness of serum and fecal PAP measurements to predict relapse in patients with inactive IBD. We undertook a 12-month prospective study that included 66 Crohn's disease (CD) and 74 ulcerative colitis (UC) patients. At inclusion, patients were in clinical remission, defined by a Harvey-Bradshaw (HB) Index≤4 (CD) or a partial Mayo Score (MS)<3 (UC), along with a normal serum C reactive Protein (CRP) and fecal calprotectin. Patients were followed every 3 months. Blood and stool samples were collected and a clinical evaluation was performed at each visit. Serum PAP and CRP levels as well as fecal concentrations of PAP and calprotectin were assessed. Active CD patients had an increased mean serum PAP at the diagnosis of the flare (104.1 ng/ml) and 3 months prior to activity (22.68 ng/ml) compared with patients in remission (13.26 ng/ml), p<0.05. No significant change in serum PAP levels in UC and fecal PAP levels in CD and UC were detected during disease activity. In CD, serum PAP was a poor diagnostic predictor of disease activity, with an AUC of 0.69. In patients in remission, fecal PAP was barely detectable in UC compared with CD patients. Serum PAP is increased only in active CD patients, but this marker does not predict disease activity. Inactive UC patients have marked low levels of PAP in fecal samples compared with CD patients.
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Urinary levels of Hepatocarcinoma-intestine-pancreas/Pancreatitis-Associated Protein as a diagnostic biomarker in patients with bladder cancer
BMC urology, 2012Co-Authors: Yujiro Nitta, Juan L. Iovanna, Hiroyuki Konishi, Tetsuya Makino, Hidenori Kawashima, Tatsuya Nakatani, Tomoaki Tanaka, Hiroshi KiyamaAbstract:To assess the possibility of hepatocarcinoma-intestine-pancreas/Pancreatitis-Associated Protein (HIP/PAP) as a biological marker for detecting Bladder cancer (BCa), we examined the expression of HIP/PAP in both BCa specimens and BCa cell lines and measured HIP/PAP levels in urine from patients with BCa. HIP/PAP expression in BCa samples was evaluated by western blot analysis, and urinary levels of HIP/PAP in patients with BCa were measured by enzyme-linked immunosorbent assay. Urine samples were collected from 10 healthy volunteers and 109 with benign urological disorders as controls, and from 101 patients who were diagnosed with BCa. HIP/PAP was highly expressed in BCa samples as compared with control bladder. Urinary HIP/PAP concentrations were significantly higher in BCa patients than in controls (median value; 3.184 pg/mL vs. 55.200 pg/mL, P <0.0001, by Mann-Whitney U test). Urinary HIP/PAP levels in BCa patients correlated positively with pathological T stages and progression-risk groups among non-muscle invasive BCa (P = 0.0008, by Kruskal-Wallis test). Regarding the recurrence-risk classifications of non-muscle invasive BCa, the urinary levels of HIP/PAP were significantly higher in the intermediate than in the low risk group (P = 0.0002, by Mann-Whitney U test). Based on a cut-off of 8.5 pg/mL, the ability of urinary HIP/PAP levels to detect BCa had a sensitivity of 80.2%, specificity of 78.2%, positive predictive value (PPV) of 75.7%, and negative predictive value (NPV) of 82.3%. HIP/PAP was abundantly expressed in BCa, and the urinary levels of HIP/PAP could be a novel and potent biomarker for detection of BCa, and also for predicting the risks of recurrence- and progression-risk of non-muscle invasive BCa. A large scale study will be needed to establish the usefulness of this biomarker.
Jean-charles Dagorn - One of the best experts on this subject based on the ideXlab platform.
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Pancreatitis-Associated Protein Does Not Predict Disease Relapse in Inflammatory Bowel Disease Patients
PLoS ONE, 2014Co-Authors: Tiago Nunes, Juan L. Iovanna, Maria Josefina Etchevers, Maria José Sandi, Susana Pinó Donnay, Teddy Grandjean, Maria Pellise, Julián Panés, Elena Ricart, Jean-charles DagornAbstract:Background The Pancreatitis-Associated Protein (PAP) is increased in the serum of active inflammatory bowel disease (IBD) patients and its levels seem to be correlated with disease activity. Our aim was to evaluate the usefulness of serum and fecal PAP measurements to predict relapse in patients with inactive IBD.
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Pancreatitis-Associated Protein Does Not Predict Disease Relapse in Inflammatory Bowel Disease Patients
PloS one, 2014Co-Authors: Tiago Nunes, Juan L. Iovanna, Maria Josefina Etchevers, Maria José Sandi, Susana Pinó Donnay, Teddy Grandjean, Maria Pellise, Julián Panés, Elena Ricart, Jean-charles DagornAbstract:The Pancreatitis-Associated Protein (PAP) is increased in the serum of active inflammatory bowel disease (IBD) patients and its levels seem to be correlated with disease activity. Our aim was to evaluate the usefulness of serum and fecal PAP measurements to predict relapse in patients with inactive IBD. We undertook a 12-month prospective study that included 66 Crohn's disease (CD) and 74 ulcerative colitis (UC) patients. At inclusion, patients were in clinical remission, defined by a Harvey-Bradshaw (HB) Index≤4 (CD) or a partial Mayo Score (MS)<3 (UC), along with a normal serum C reactive Protein (CRP) and fecal calprotectin. Patients were followed every 3 months. Blood and stool samples were collected and a clinical evaluation was performed at each visit. Serum PAP and CRP levels as well as fecal concentrations of PAP and calprotectin were assessed. Active CD patients had an increased mean serum PAP at the diagnosis of the flare (104.1 ng/ml) and 3 months prior to activity (22.68 ng/ml) compared with patients in remission (13.26 ng/ml), p<0.05. No significant change in serum PAP levels in UC and fecal PAP levels in CD and UC were detected during disease activity. In CD, serum PAP was a poor diagnostic predictor of disease activity, with an AUC of 0.69. In patients in remission, fecal PAP was barely detectable in UC compared with CD patients. Serum PAP is increased only in active CD patients, but this marker does not predict disease activity. Inactive UC patients have marked low levels of PAP in fecal samples compared with CD patients.
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Usefulness of Pancreatitis-Associated Protein, a Novel Biomarker, to Predict Severity of Disease in Ambulatory Patients With Heart Failure
The American Journal of Cardiology, 2014Co-Authors: Timothy P. Fitzgibbons, Jean-charles Dagorn, Jonathan Paolino, Theo E. MeyerAbstract:Pancreatitis-Associated Protein (PAP) is a novel cytokine with putative anti-inflammatory effects. PAP gene expression has been found to be increased in the myocardium of rats with decompensated pressure-overload hypertrophy. A prospective pilot study was performed to test the hypotheses that PAP is elevated in ambulatory patients with heart failure (HF) and that concentrations correlate with the severity of disease. Blood samples were obtained from patients with HF (n = 70) and normal controls (n = 17). Patients with New York Heart Association class III and IV symptoms had a greater mean PAP than patients with class I and II symptoms (35.5 ± 4.0 vs 10.3 ± 1.0 μg/L, p
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Pancreatitis Associated Protein i suppresses nf κb activation through a jak stat mediated mechanism in epithelial cells
Journal of Immunology, 2006Co-Authors: Emma Folchpuy, Juan L. Iovanna, Jean-charles Dagorn, Susana Granell, Daniel ClosaAbstract:Pancreatitis-Associated Protein I (PAP I), also known as HIP, p23, or Reg2 Protein, has recently been implicated in the endogenous regulation of inflammation. Although it was initially characterized as a Protein that is overexpressed in acute Pancreatitis, PAP I has also been Associated with a number of inflammatory diseases, such as Crohn’s disease. Knowing that PAP I and IL-10 responses share several features, we have used a pancreatic acinar cell line (AR42J) to assess the extent to which their expression is reciprocally regulated, and whether the JAK/STAT and NF-κB signaling pathways are involved in the suppression of inflammation mediated by PAP I. We observed that PAP I is induced in epithelial cells by IL-10 and by PAP I itself. In contrast, we found phosphorylation and nuclear translocation of STAT3 and induction of suppressor of cytokine signaling 3 in response to PAP I exposure. Finally, a JAK-specific inhibitor, tyrphostin AG490, markedly prevented PAP I-induced NF-κB inhibition, pointing to a cross-talk between JAK/STAT3 and NF-κB signaling pathways. Together, these findings indicate that PAP I inhibits the inflammatory response by blocking NF-κB activation through a STAT3-dependent mechanism. Important functional similarities to the anti-inflammatory cytokine IL-10 suggest that PAP I could play a role similar to that of IL-10 in epithelial cells.
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Pancreatitis-Associated Protein I Suppresses NF-κB Activation through a JAK/STAT-Mediated Mechanism in Epithelial Cells
The Journal of Immunology, 2006Co-Authors: Emma Folch-puy, Juan L. Iovanna, Jean-charles Dagorn, Susana Granell, Daniel ClosaAbstract:Pancreatitis-Associated Protein I (PAP I), also known as HIP, p23, or Reg2 Protein, has recently been implicated in the endogenous regulation of inflammation. Although it was initially characterized as a Protein that is overexpressed in acute Pancreatitis, PAP I has also been Associated with a number of inflammatory diseases, such as Crohn’s disease. Knowing that PAP I and IL-10 responses share several features, we have used a pancreatic acinar cell line (AR42J) to assess the extent to which their expression is reciprocally regulated, and whether the JAK/STAT and NF-κB signaling pathways are involved in the suppression of inflammation mediated by PAP I. We observed that PAP I is induced in epithelial cells by IL-10 and by PAP I itself. In contrast, we found phosphorylation and nuclear translocation of STAT3 and induction of suppressor of cytokine signaling 3 in response to PAP I exposure. Finally, a JAK-specific inhibitor, tyrphostin AG490, markedly prevented PAP I-induced NF-κB inhibition, pointing to a cross-talk between JAK/STAT3 and NF-κB signaling pathways. Together, these findings indicate that PAP I inhibits the inflammatory response by blocking NF-κB activation through a STAT3-dependent mechanism. Important functional similarities to the anti-inflammatory cytokine IL-10 suggest that PAP I could play a role similar to that of IL-10 in epithelial cells.
Hiroshi Kiyama - One of the best experts on this subject based on the ideXlab platform.
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N-terminal cleaved Pancreatitis-Associated Protein-III (PAP-III) serves as a scaffold for neurites and promotes neurite outgrowth.
Journal of Biological Chemistry, 2013Co-Authors: Hiroyuki Konishi, Kazuhiko Namikawa, Sakiko Matsumoto, Hiroshi KiyamaAbstract:Pancreatitis-Associated Protein (PAP)-III, also known as regenerating gene/regenerating islet-derived (Reg)-IIIγ, is a small secretory Protein whose expression is substantially induced in injured nerves. Here, we found that PAP-III Protein underwent proteolytic N-terminal processing by trypsin-like protease(s) in injured sciatic nerves after axotomy. In vitro studies demonstrated that the N terminus-truncated PAP-III (ΔN-PAP-III) polymerized into a filament with a relatively uniform diameter of 10-20 nm, and the filaments formed higher order structures in a Na(+) concentration-dependent manner. When the ΔN-PAP-III fibers were added to the culture media, the ΔN-PAP-III fibers were tightly attached to neurites and somata of primary cortical neurons in vitro. In contrast, little association with glial cells was observed. When dense matrices of ΔN-PAP-III fibers were sheeted on a culture dish, neurites preferentially adhered to the fibers, and neurite extension was enhanced. This neurite outgrowth activity was significantly suppressed by preincubation with antibodies against PAP-III. These results imply that the released PAP-III might be cleaved and forms ΔN-PAP-III fibers at the nerve injury sites. Consequently, these resulting fibers would provide regenerating axons with a platform for extension.
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Urinary levels of Hepatocarcinoma-intestine-pancreas/Pancreatitis-Associated Protein as a diagnostic biomarker in patients with bladder cancer
BMC Urology, 2012Co-Authors: Yujiro Nitta, Juan L. Iovanna, Hiroyuki Konishi, Tetsuya Makino, Hidenori Kawashima, Tatsuya Nakatani, Tomoaki Tanaka, Hiroshi KiyamaAbstract:To assess the possibility of hepatocarcinoma-intestine-pancreas/Pancreatitis-Associated Protein (HIP/PAP) as a biological marker for detecting Bladder cancer (BCa), we examined the expression of HIP/PAP in both BCa specimens and BCa cell lines and measured HIP/PAP levels in urine from patients with BCa. HIP/PAP expression in BCa samples was evaluated by western blot analysis, and urinary levels of HIP/PAP in patients with BCa were measured by enzyme-linked immunosorbent assay. Urine samples were collected from 10 healthy volunteers and 109 with benign urological disorders as controls, and from 101 patients who were diagnosed with BCa. HIP/PAP was highly expressed in BCa samples as compared with control bladder. Urinary HIP/PAP concentrations were significantly higher in BCa patients than in controls (median value; 3.184 pg/mL vs. 55.200 pg/mL, P
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urinary levels of hepatocarcinoma intestine pancreas Pancreatitis Associated Protein as a diagnostic biomarker in patients with bladder cancer
BMC Urology, 2012Co-Authors: Yujiro Nitta, Juan L. Iovanna, Hiroyuki Konishi, Tetsuya Makino, Hidenori Kawashima, Tatsuya Nakatani, Tomoaki Tanaka, Hiroshi KiyamaAbstract:To assess the possibility of hepatocarcinoma-intestine-pancreas/Pancreatitis-Associated Protein (HIP/PAP) as a biological marker for detecting Bladder cancer (BCa), we examined the expression of HIP/PAP in both BCa specimens and BCa cell lines and measured HIP/PAP levels in urine from patients with BCa. HIP/PAP expression in BCa samples was evaluated by western blot analysis, and urinary levels of HIP/PAP in patients with BCa were measured by enzyme-linked immunosorbent assay. Urine samples were collected from 10 healthy volunteers and 109 with benign urological disorders as controls, and from 101 patients who were diagnosed with BCa. HIP/PAP was highly expressed in BCa samples as compared with control bladder. Urinary HIP/PAP concentrations were significantly higher in BCa patients than in controls (median value; 3.184 pg/mL vs. 55.200 pg/mL, P <0.0001, by Mann–Whitney U test). Urinary HIP/PAP levels in BCa patients correlated positively with pathological T stages and progression-risk groups among non-muscle invasive BCa (P = 0.0008, by Kruskal-Wallis test). Regarding the recurrence-risk classifications of non-muscle invasive BCa, the urinary levels of HIP/PAP were significantly higher in the intermediate than in the low risk group (P = 0.0002, by Mann–Whitney U test). Based on a cut-off of 8.5 pg/mL, the ability of urinary HIP/PAP levels to detect BCa had a sensitivity of 80.2%, specificity of 78.2%, positive predictive value (PPV) of 75.7%, and negative predictive value (NPV) of 82.3%. HIP/PAP was abundantly expressed in BCa, and the urinary levels of HIP/PAP could be a novel and potent biomarker for detection of BCa, and also for predicting the risks of recurrence- and progression-risk of non-muscle invasive BCa. A large scale study will be needed to establish the usefulness of this biomarker.
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Urinary levels of Hepatocarcinoma-intestine-pancreas/Pancreatitis-Associated Protein as a diagnostic biomarker in patients with bladder cancer
BMC urology, 2012Co-Authors: Yujiro Nitta, Juan L. Iovanna, Hiroyuki Konishi, Tetsuya Makino, Hidenori Kawashima, Tatsuya Nakatani, Tomoaki Tanaka, Hiroshi KiyamaAbstract:To assess the possibility of hepatocarcinoma-intestine-pancreas/Pancreatitis-Associated Protein (HIP/PAP) as a biological marker for detecting Bladder cancer (BCa), we examined the expression of HIP/PAP in both BCa specimens and BCa cell lines and measured HIP/PAP levels in urine from patients with BCa. HIP/PAP expression in BCa samples was evaluated by western blot analysis, and urinary levels of HIP/PAP in patients with BCa were measured by enzyme-linked immunosorbent assay. Urine samples were collected from 10 healthy volunteers and 109 with benign urological disorders as controls, and from 101 patients who were diagnosed with BCa. HIP/PAP was highly expressed in BCa samples as compared with control bladder. Urinary HIP/PAP concentrations were significantly higher in BCa patients than in controls (median value; 3.184 pg/mL vs. 55.200 pg/mL, P <0.0001, by Mann-Whitney U test). Urinary HIP/PAP levels in BCa patients correlated positively with pathological T stages and progression-risk groups among non-muscle invasive BCa (P = 0.0008, by Kruskal-Wallis test). Regarding the recurrence-risk classifications of non-muscle invasive BCa, the urinary levels of HIP/PAP were significantly higher in the intermediate than in the low risk group (P = 0.0002, by Mann-Whitney U test). Based on a cut-off of 8.5 pg/mL, the ability of urinary HIP/PAP levels to detect BCa had a sensitivity of 80.2%, specificity of 78.2%, positive predictive value (PPV) of 75.7%, and negative predictive value (NPV) of 82.3%. HIP/PAP was abundantly expressed in BCa, and the urinary levels of HIP/PAP could be a novel and potent biomarker for detection of BCa, and also for predicting the risks of recurrence- and progression-risk of non-muscle invasive BCa. A large scale study will be needed to establish the usefulness of this biomarker.
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Urinary levels of Hepatocarcinoma-intestine-pancreas/Pancreatitis-Associated Protein as a diagnostic biomarker in patients with bladder cancer.
BMC Urology, 2012Co-Authors: Yujiro Nitta, Juan L. Iovanna, Hiroyuki Konishi, Tetsuya Makino, Hidenori Kawashima, Tatsuya Nakatani, Tomoaki Tanaka, Hiroshi KiyamaAbstract:UNLABELLED: ABSTRACT: BACKGROUND: To assess the possibility of hepatocarcinoma-intestine-pancreas/Pancreatitis-Associated Protein (HIP/PAP) as a biological marker for detecting Bladder cancer (BCa), we examined the expression of HIP/PAP in both BCa specimens and BCa cell lines and measured HIP/PAP levels in urine from patients with BCa. METHODS: HIP/PAP expression in BCa samples was evaluated by western blot analysis, and urinary levels of HIP/PAP in patients with BCa were measured by enzyme-linked immunosorbent assay. Urine samples were collected from 10 healthy volunteers and 109 with benign urological disorders as controls, and from 101 patients who were diagnosed with BCa. RESULTS: HIP/PAP was highly expressed in BCa samples as compared with control bladder. Urinary HIP/PAP concentrations were significantly higher in BCa patients than in controls (median value; 3.184 pg/mL vs. 55.200 pg/mL, P
Zhiming Hao - One of the best experts on this subject based on the ideXlab platform.
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adenovirus mediated hepatocarcinoma intestine pancreas Pancreatitis Associated Protein suppresses dextran sulfate sodium induced acute ulcerative colitis in rats
Inflammatory Bowel Diseases, 2012Co-Authors: Xiaofei Yang, Yongwei Huo, Hong Tian, Yan Yin, Zhiming HaoAbstract:Background: Although increased expression of hepatocarcinoma-intestine-pancreas/Pancreatitis-Associated Protein (HIP/PAP) has been reported in ulcerative colitis (UC), its role in UC remains unclear. This study was designed to assess the function of HIP/PAP in experimental UC and further to explore its underlying mechanisms. Methods: Recombinant adenovirus was prepared to mediate ectopic expression of HIP/PAP in the colon of rats. The effect of HIP/PAP on dextran sodium sulfate (DSS)-induced colitis was assessed by disease activity index (DAI), macroscopic, and histological evaluations. Superoxide dismutase (SOD) and myeloperoxidase (MPO) activities, malondialdehyde (MDA) content, and tumor necrosis factor α (TNF-α) and interleukin-6 (IL-6) production were determined in colonic mucosa. Proliferation cell nuclear antigen (PCNA) was immunostained to reflect the proliferation of colonic epithelia. The effects of HIP/PAP on proliferation and H2O2-induced apoptosis of SW480 and LoVo colonic adenocarcinoma cells were also determined. Gene expression profiles in SW480 after HIP/PAP overexpression were analyzed by microarray analysis. Results: The protective effect of HIP/PAP against DSS-induced colitis in rats was confirmed. Ectopic expression of HIP/PAP resulted in attenuation of oxidative damage, reduction of TNF-α and IL-6 expression, and elevation of epithelial proliferation in colonic mucosa and led to decreased apoptosis and increased proliferation in colonic adenocarcinoma cells. Microarray analysis revealed altered expression of inflammation-related molecules, growth factors, proliferation-related molecules, and antioxidant enzymes under overexpression of HIP/PAP. Conclusions: HIP/PAP has a protective effect against DSS-induced colitis in rats via inhibiting inflammation, alleviating oxidative damage, and promoting colonic epithelium regeneration. HIP/PAP might represent a new promising therapeutic strategy in UC. (Inflamm Bowel Dis 2012)
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Adenovirus-mediated hepatocarcinoma-intestine-pancreas/Pancreatitis-Associated Protein suppresses dextran sulfate sodium-induced acute ulcerative colitis in rats.
Inflammatory bowel diseases, 2012Co-Authors: Xiaofei Yang, Yongwei Huo, Hong Tian, Yan Yin, Zhiming HaoAbstract:Although increased expression of hepatocarcinoma-intestine-pancreas/Pancreatitis-Associated Protein (HIP/PAP) has been reported in ulcerative colitis (UC), its role in UC remains unclear. This study was designed to assess the function of HIP/PAP in experimental UC and further to explore its underlying mechanisms. Recombinant adenovirus was prepared to mediate ectopic expression of HIP/PAP in the colon of rats. The effect of HIP/PAP on dextran sodium sulfate (DSS)-induced colitis was assessed by disease activity index (DAI), macroscopic, and histological evaluations. Superoxide dismutase (SOD) and myeloperoxidase (MPO) activities, malondialdehyde (MDA) content, and tumor necrosis factor α (TNF-α) and interleukin-6 (IL-6) production were determined in colonic mucosa. Proliferation cell nuclear antigen (PCNA) was immunostained to reflect the proliferation of colonic epithelia. The effects of HIP/PAP on proliferation and H(2)O(2) -induced apoptosis of SW480 and LoVo colonic adenocarcinoma cells were also determined. Gene expression profiles in SW480 after HIP/PAP overexpression were analyzed by microarray analysis. The protective effect of HIP/PAP against DSS-induced colitis in rats was confirmed. Ectopic expression of HIP/PAP resulted in attenuation of oxidative damage, reduction of TNF-α and IL-6 expression, and elevation of epithelial proliferation in colonic mucosa and led to decreased apoptosis and increased proliferation in colonic adenocarcinoma cells. Microarray analysis revealed altered expression of inflammation-related molecules, growth factors, proliferation-related molecules, and antioxidant enzymes under overexpression of HIP/PAP. HIP/PAP has a protective effect against DSS-induced colitis in rats via inhibiting inflammation, alleviating oxidative damage, and promoting colonic epithelium regeneration. HIP/PAP might represent a new promising therapeutic strategy in UC. Copyright © 2012 Crohn's & Colitis Foundation of America, Inc.
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Adenovirus-mediated hepatocarcinoma-intestine-pancreas/Pancreatitis-Associated Protein suppresses dextran sulfate sodium-induced acute ulcerative colitis in rats.
Inflammatory Bowel Diseases, 2012Co-Authors: Xiaofei Yang, Yongwei Huo, Hong Tian, Yan Yin, Zhiming HaoAbstract:Background: Although increased expression of hepatocarcinoma-intestine-pancreas/Pancreatitis-Associated Protein (HIP/PAP) has been reported in ulcerative colitis (UC), its role in UC remains unclear. This study was designed to assess the function of HIP/PAP in experimental UC and further to explore its underlying mechanisms. Methods: Recombinant adenovirus was prepared to mediate ectopic expression of HIP/PAP in the colon of rats. The effect of HIP/PAP on dextran sodium sulfate (DSS)-induced colitis was assessed by disease activity index (DAI), macroscopic, and histological evaluations. Superoxide dismutase (SOD) and myeloperoxidase (MPO) activities, malondialdehyde (MDA) content, and tumor necrosis factor α (TNF-α) and interleukin-6 (IL-6) production were determined in colonic mucosa. Proliferation cell nuclear antigen (PCNA) was immunostained to reflect the proliferation of colonic epithelia. The effects of HIP/PAP on proliferation and H2O2-induced apoptosis of SW480 and LoVo colonic adenocarcinoma cells were also determined. Gene expression profiles in SW480 after HIP/PAP overexpression were analyzed by microarray analysis. Results: The protective effect of HIP/PAP against DSS-induced colitis in rats was confirmed. Ectopic expression of HIP/PAP resulted in attenuation of oxidative damage, reduction of TNF-α and IL-6 expression, and elevation of epithelial proliferation in colonic mucosa and led to decreased apoptosis and increased proliferation in colonic adenocarcinoma cells. Microarray analysis revealed altered expression of inflammation-related molecules, growth factors, proliferation-related molecules, and antioxidant enzymes under overexpression of HIP/PAP. Conclusions: HIP/PAP has a protective effect against DSS-induced colitis in rats via inhibiting inflammation, alleviating oxidative damage, and promoting colonic epithelium regeneration. HIP/PAP might represent a new promising therapeutic strategy in UC. (Inflamm Bowel Dis 2012)
Rolf Graf - One of the best experts on this subject based on the ideXlab platform.
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Pancreatitis-Associated Protein Inhibits Human Pancreatic Stellate Cell MMP-1 and -2, TIMP-1 and -2 Secretion and RECK Expression
Pancreatology, 2009Co-Authors: Max G Bachem, Daniel Bimmler, Shaoxia Zhou, Zilin Sun, Jinfei Chen, Marco Siech, Rolf GrafAbstract:Background/Aims: Pancreatic stellate cells (PSCs) play a key role in fibrogenesis Associated with acute and chronic Pancreatitis. Pancreatitis-Associated Protein (PAP), an acute-phas
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Pancreatitis-Associated Protein inhibits human pancreatic stellate cell MMP-1 and -2, TIMP-1 and -2 secretion and RECK expression.
Pancreatology, 2009Co-Authors: Max G Bachem, Daniel Bimmler, Shaoxia Zhou, Zilin Sun, Jinfei Chen, Marco Siech, Rolf GrafAbstract:Pancreatic stellate cells (PSCs) play a key role in fibrogenesis Associated with acute and chronic Pancreatitis. Pancreatitis-Associated Protein (PAP), an acute-phase Protein, is dramatically upregulated during acute and chronic Pancreatitis. Assuming a protective role of PAP, we investigated its effects on human PSCs. PSCs were obtained by outgrowth from fibrotic human pancreas tissue. PAP was expressed in the yeast Pichia pastoris. PAP was added at 10 ng/ml to cultured PSCs. Cell proliferation was determined by bromodeoxyuridine incorporation. PSC migration was assessed by a wound healing assay. Collagen types I and III, fibronectin, matrix metalloProteinases (MMPs), tissue inhibitors of MMPs (TIMPs) and reversion-inducing cysteine-rich Protein with Kazal motifs (RECK) were demonstrated on Protein and mRNA level. PAP had no significant effect on PSC proliferation and migration. Cell-Associated fibrillar collagen types I and III and fibronectin increased after addition of PAP to PSCs. PAP diminished the expression of MMP-1 and -2 and TIMP-1 and -2 and their concentrations in PSC supernatants. RECK was detected on the surface of PSCs and its expression was reduced after PAP application. Our data offer new insights into the biological functions of PAP, which may play an important role in wound healing response and cell-matrix interactions. Copyright 2008 S. Karger AG, Basel and IAP.
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Conformational changes of Pancreatitis-Associated Protein (PAP) activated by trypsin lead to insoluble Protein aggregates.
Pancreas, 2001Co-Authors: Marc Schiesser, Daniel Bimmler, Thomas W. Frick, Rolf GrafAbstract:Summary: Pancreatitis-Associated Protein (PAP), a secretory acute-phase Protein of the pancreatic acinar cell, is highly upregulated early in acute Pancreatitis. PAP expression returns to undetectable levels when the pancreas recovers. In the rat, three isoforms of PAP are known, all of which are upregulated during acute Pancreatitis. Their functions remain obscure. Pancreatic stone Protein (PSP/ reg), which shows strong sequence homology to PAP, is secreted into pancreatic juice under physiologic and pathologic conditions. PSP/ reg is highly susceptible to trypsin cleavage at its ARG11–ILE12 bond. Cleavage results in an N-terminal undecapeptide and a C-terminal peptide called pancreatic thread Protein (PTP). PTP forms oligomeric fibrillar structures, which spontaneously sediment in vitro. PTP can be found in Protein plugs or stones from patients with chronic Pancreatitis. Rat PAP contains a trypsin cleavage site at the same position as PSP/ reg. We hypothesize that PAP is susceptible to tryptic cleavage, and that the C-terminal cleavage product of PAP spontaneously precipitates at neutral pH. To test our hypothesis, we generated and purified recombinant PAP. Here we report the production of rat PAP I, II, and III in a yeast expression system using Pichia pastoris. We demonstrate in vitro the tryptic cleavage of rat PAP and the formation of a spontaneously precipitating peptide, which we call Pancreatitis-Associated thread Protein (PATP). PATP displays pH-dependent solubility characteristics very similar to those of PTP.
