The Experts below are selected from a list of 132 Experts worldwide ranked by ideXlab platform
Jill P Smith - One of the best experts on this subject based on the ideXlab platform.
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abstract 5326 cholecystokinin receptor antagonist decreases fibrosis in pancreatic cancer microenvironment to improve uptake and efficacy of chemotherapy
Cancer Research, 2020Co-Authors: Zoe X Malchiodi, Narayan Shivapurkar, Hong Cao, Sunil Bansal, Benjamin A Weinberg, Amrita K Cheema, Jill P SmithAbstract:Background: Although pancreatic cancer cells respond to chemotherapeutic agents in cell culture, many of these drugs are less effective in vivo. This decreased response to chemotherapy in animal models and human subjects is in part attributed to the dense stroma of the pancreatic tumor microenvironment (TME) that impedes penetration of drugs. Pancreatic stellate cells and tissue fibroblasts have cholecystokinin (CCK) receptors and when these receptors are activated, they promote collagen deposition and increase fibrosis in the TME. We have previously shown that CCK receptor antagonists can decrease fibrosis and change the T-cell infiltrates of the TME in pancreatic tumors. We hypothesized that an oral CCK receptor antagonist, Proglumide, would improve the efficacy of gemcitabine by decreasing fibrosis in the TME and improving uptake of chemotherapy. Methods: 500,000 mT3 murine pancreatic cancer cells were injected subcutaneously into the right flank of 40 C57/BL6 female mice. One week after the mice had measurable tumors (baseline), mice were divided into 4 groups (N=10 mice each) with equal mean tumor volumes. Treatment groups included: PBS control (100µl IP twice weekly); Proglumide in drinking water (0.1 mg/ml); gemcitabine (100mg/kg, 100µl IP twice weekly); and combination of gemcitabine and Proglumide. Tumors were measured weekly and the volumes were calculated. Mice were euthanized per protocol when the tumor diameter reached 20mm; tumors were removed, then flash frozen for gemcitabine measurement via mass spectrometry. Results: Tumor volumes demonstrated a rapid growth rate in the PBS control mice with a slope of 184.2±2 (mm3/week), whereas growth rates for Proglumide (75±2) and gemcitabine monotherapy (72±14) were 2.6-fold slower, and also 3.4-fold slower for mice treated with both gemcitabine and Proglumide (55.6±12; p Conclusion: CCK receptor blockade with Proglumide decreases fibrosis in pancreatic cancer TME allowing greater tumor uptake of gemcitabine and improving efficacy by slowing tumor growth and improving survival. Strategies to improve first-line therapies for patients with pancreatic cancer may improve overall survival of this disease. Citation Format: Zoe X. Malchiodi, Hong Cao, Martha Gay, Sunil Bansal, Benjamin A. Weinberg, Amrita Cheema, Narayan Shivapurkar, Jill P. Smith. Cholecystokinin receptor antagonist decreases fibrosis in pancreatic cancer microenvironment to improve uptake and efficacy of chemotherapy [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5326.
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abstract 5193 cholecystokinin b receptor mediates growth of hepatocellular carcinoma
Cancer Research, 2020Co-Authors: Anita Safronenka, Robin D Tucker, Narayan Shivapurkar, Hong Cao, Jill P SmithAbstract:Background: The fastest-growing cause of cancer-related death is hepatocellular carcinoma (HCC), which is in part attributable to the obesity epidemic and nonalcoholic steatohepatitis (NASH). The gastrointestinal (GI) peptides, gastrin and cholecystokinin (CCK), regulate digestive functions and growth of the GI tract through the G-protein coupled receptors CCK- receptors (CCK-Rs). Both peptides activate the CCK-B receptor (CCK-BR) whereas only CCK peptide activates the CCK-A receptor (CCK-AR). CCK-Rs and gastrin are low or absent in normal mouse hepatocytes. We have previously shown that CCK blood levels increase and CCK-Rs become overexpressed in the livers of mice eating a high saturated fat diet that induced NASH and HCC. Hypothesis: CCK and gastrin mediate the growth of HCC through the CCK-R and that interruption of this signaling pathway could decrease growth of HCC. Methods: RNA was extracted from murine Hepa1-6, RIL-175, and human HepG2 cells and was evaluated by qRT-PCR for expression of CCK-AR, CCK-BR, and gastrin. CCK-R protein expression was analyzed by flow cytometry. In order to determine which CCK-R mediated the growth effects, growth was studied in vitro using selective receptor antagonists or CRISPR Cas9 technology to knock-out each receptor. HCC cells were treated in vitro with CCK peptide (1-10nM), the CCK-AR antagonist (L364,718), or the CCK-BR antagonist (L365,260). Proliferation of selective CCK-R KO cells was compared to that of wild-type cells. To determine the effect of a CCK-R antagonist on tumor growth in vivo, two cohorts of mice bearing subcutaneous Hepa1-6 or RIL-175 HCC tumors were treated with an oral bioavailable CCK-R antagonist, Proglumide (1 mg/ml) or untreated water (controls) for 3-4 weeks. The mice bearing Hepa1-6 tumors were placed on a high-fat diet to raise blood CCK levels. Mice bearing RIL-175 tumors were fed standard chow to determine if Proglumide could block autocrine growth by gastrin. Results: The mRNA expression of CCK-AR, CCK-BR and gastrin were increased 80-90-fold in all HCC cell lines compared to that of normal liver. CCK-BRs were detected on >85% of the cells by flow cytometry. CCK peptide (1nM) stimulated HCC growth in vitro in both wild-type cells and in CCK-AR KO cells but not in CCK-BR KO cells. CCK-BR antagonist blocked CCK-stimulated growth in vitro but the CCK-AR antagonist did not, suggesting that the CCK-BR was responsible for mediating proliferation. In vivo tumor growth was significantly reduced with Proglumide treatment by 70% (p Conclusion: CCK-Rs are overexpressed in HCC and proliferation appears to be mediated through the CCK-BR. Downregulation with CRISPR Cas9 or blockade of the CCK-BR with an antagonist decreases growth in vitro and Proglumide therapy decreases tumor growth in vivo. Strategies that block signaling at the CCK-BR may provide a novel therapeutic option for HCC treatment. Citation Format: Martha D. Gay, Anita Safronenka, Hong Cao, Robin Tucker, Narayan Shivapurkar, Jill P. Smith. Cholecystokinin-B receptor mediates growth of hepatocellular carcinoma [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5193.
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cholecystokinin receptor antagonist halts progression of pancreatic cancer precursor lesions and fibrosis in mice
Pancreas, 2014Co-Authors: Jill P Smith, Timothy K Cooper, Christopher O Mcgovern, Evan L Gilius, Qing Zhong, Jiangang Liao, Alfredo A Molinolo, Silvio J Gutkind, Gail L MattersAbstract:Objectives Exogenous administration of cholecystokinin (CCK) induces hypertrophy and hyperplasia of the pancreas with an increase in DNA content. We hypothesized that endogenous CCK is involved in the malignant progression of pancreatic intraepithelial neoplasia (PanIN) lesions and the fibrosis associated with pancreatic cancer. Methods The presence of CCK receptors in early PanIN lesions was examined by immunohistochemistry in mouse and human pancreas. Pdx1-Cre/LSL-KrasG12D transgenic mice were randomized to receive either untreated drinking water or water supplemented with a CCK receptor antagonist (Proglumide, 0.1 mg/mL). Pancreas from the mice were removed and examined histologically for number and grade of PanINs after 1, 2, or 4 months of antagonist therapy. Results Both CCK-A and CCK-B receptors were identified in early stage PanINs from mouse and human pancreas. The grade of PanIN lesions was reversed, and progression to advanced lesions arrested in mice treated with Proglumide compared with the controls (P = 0.004). Furthermore, pancreatic fibrosis was significantly reduced in antagonist-treated animals compared with vehicle (P Conclusions These findings demonstrate that endogenous CCK is in part responsible for the development and progression of pancreatic cancer. The use of CCK receptor antagonists may have a role in cancer prophylaxis in high-risk subjects and may reduce fibrosis in the microenvironment.
Narayan Shivapurkar - One of the best experts on this subject based on the ideXlab platform.
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abstract 5326 cholecystokinin receptor antagonist decreases fibrosis in pancreatic cancer microenvironment to improve uptake and efficacy of chemotherapy
Cancer Research, 2020Co-Authors: Zoe X Malchiodi, Narayan Shivapurkar, Hong Cao, Sunil Bansal, Benjamin A Weinberg, Amrita K Cheema, Jill P SmithAbstract:Background: Although pancreatic cancer cells respond to chemotherapeutic agents in cell culture, many of these drugs are less effective in vivo. This decreased response to chemotherapy in animal models and human subjects is in part attributed to the dense stroma of the pancreatic tumor microenvironment (TME) that impedes penetration of drugs. Pancreatic stellate cells and tissue fibroblasts have cholecystokinin (CCK) receptors and when these receptors are activated, they promote collagen deposition and increase fibrosis in the TME. We have previously shown that CCK receptor antagonists can decrease fibrosis and change the T-cell infiltrates of the TME in pancreatic tumors. We hypothesized that an oral CCK receptor antagonist, Proglumide, would improve the efficacy of gemcitabine by decreasing fibrosis in the TME and improving uptake of chemotherapy. Methods: 500,000 mT3 murine pancreatic cancer cells were injected subcutaneously into the right flank of 40 C57/BL6 female mice. One week after the mice had measurable tumors (baseline), mice were divided into 4 groups (N=10 mice each) with equal mean tumor volumes. Treatment groups included: PBS control (100µl IP twice weekly); Proglumide in drinking water (0.1 mg/ml); gemcitabine (100mg/kg, 100µl IP twice weekly); and combination of gemcitabine and Proglumide. Tumors were measured weekly and the volumes were calculated. Mice were euthanized per protocol when the tumor diameter reached 20mm; tumors were removed, then flash frozen for gemcitabine measurement via mass spectrometry. Results: Tumor volumes demonstrated a rapid growth rate in the PBS control mice with a slope of 184.2±2 (mm3/week), whereas growth rates for Proglumide (75±2) and gemcitabine monotherapy (72±14) were 2.6-fold slower, and also 3.4-fold slower for mice treated with both gemcitabine and Proglumide (55.6±12; p Conclusion: CCK receptor blockade with Proglumide decreases fibrosis in pancreatic cancer TME allowing greater tumor uptake of gemcitabine and improving efficacy by slowing tumor growth and improving survival. Strategies to improve first-line therapies for patients with pancreatic cancer may improve overall survival of this disease. Citation Format: Zoe X. Malchiodi, Hong Cao, Martha Gay, Sunil Bansal, Benjamin A. Weinberg, Amrita Cheema, Narayan Shivapurkar, Jill P. Smith. Cholecystokinin receptor antagonist decreases fibrosis in pancreatic cancer microenvironment to improve uptake and efficacy of chemotherapy [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5326.
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abstract 5193 cholecystokinin b receptor mediates growth of hepatocellular carcinoma
Cancer Research, 2020Co-Authors: Anita Safronenka, Robin D Tucker, Narayan Shivapurkar, Hong Cao, Jill P SmithAbstract:Background: The fastest-growing cause of cancer-related death is hepatocellular carcinoma (HCC), which is in part attributable to the obesity epidemic and nonalcoholic steatohepatitis (NASH). The gastrointestinal (GI) peptides, gastrin and cholecystokinin (CCK), regulate digestive functions and growth of the GI tract through the G-protein coupled receptors CCK- receptors (CCK-Rs). Both peptides activate the CCK-B receptor (CCK-BR) whereas only CCK peptide activates the CCK-A receptor (CCK-AR). CCK-Rs and gastrin are low or absent in normal mouse hepatocytes. We have previously shown that CCK blood levels increase and CCK-Rs become overexpressed in the livers of mice eating a high saturated fat diet that induced NASH and HCC. Hypothesis: CCK and gastrin mediate the growth of HCC through the CCK-R and that interruption of this signaling pathway could decrease growth of HCC. Methods: RNA was extracted from murine Hepa1-6, RIL-175, and human HepG2 cells and was evaluated by qRT-PCR for expression of CCK-AR, CCK-BR, and gastrin. CCK-R protein expression was analyzed by flow cytometry. In order to determine which CCK-R mediated the growth effects, growth was studied in vitro using selective receptor antagonists or CRISPR Cas9 technology to knock-out each receptor. HCC cells were treated in vitro with CCK peptide (1-10nM), the CCK-AR antagonist (L364,718), or the CCK-BR antagonist (L365,260). Proliferation of selective CCK-R KO cells was compared to that of wild-type cells. To determine the effect of a CCK-R antagonist on tumor growth in vivo, two cohorts of mice bearing subcutaneous Hepa1-6 or RIL-175 HCC tumors were treated with an oral bioavailable CCK-R antagonist, Proglumide (1 mg/ml) or untreated water (controls) for 3-4 weeks. The mice bearing Hepa1-6 tumors were placed on a high-fat diet to raise blood CCK levels. Mice bearing RIL-175 tumors were fed standard chow to determine if Proglumide could block autocrine growth by gastrin. Results: The mRNA expression of CCK-AR, CCK-BR and gastrin were increased 80-90-fold in all HCC cell lines compared to that of normal liver. CCK-BRs were detected on >85% of the cells by flow cytometry. CCK peptide (1nM) stimulated HCC growth in vitro in both wild-type cells and in CCK-AR KO cells but not in CCK-BR KO cells. CCK-BR antagonist blocked CCK-stimulated growth in vitro but the CCK-AR antagonist did not, suggesting that the CCK-BR was responsible for mediating proliferation. In vivo tumor growth was significantly reduced with Proglumide treatment by 70% (p Conclusion: CCK-Rs are overexpressed in HCC and proliferation appears to be mediated through the CCK-BR. Downregulation with CRISPR Cas9 or blockade of the CCK-BR with an antagonist decreases growth in vitro and Proglumide therapy decreases tumor growth in vivo. Strategies that block signaling at the CCK-BR may provide a novel therapeutic option for HCC treatment. Citation Format: Martha D. Gay, Anita Safronenka, Hong Cao, Robin Tucker, Narayan Shivapurkar, Jill P. Smith. Cholecystokinin-B receptor mediates growth of hepatocellular carcinoma [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5193.
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a cholecystokinin receptor antagonist halts nonalcoholic steatohepatitis and prevents hepatocellular carcinoma
Digestive Diseases and Sciences, 2020Co-Authors: Robin D Tucker, Sandeep Nadella, Narayan Shivapurkar, Hong Cao, Victor Ciofoaia, Bhaskar Kallakury, Matthew Huber, Anita Safronenka, Annie J Kruger, Alexander KroemerAbstract:Nonalcoholic steatohepatitis (NASH) is a common inflammatory liver condition that may lead to cirrhosis and hepatocellular carcinoma (HCC). Risk factors for NASH include a saturated fat diet, altered lipid metabolism, and genetic and epigenetic factors, including microRNAs. Serum levels of cholecystokinin (CCK) are elevated in mice and humans that consume a high-saturated fat diet. CCK receptors (CCK-Rs) have been reported on fibroblasts which when activated can induce fibrosis; however, their role in hepatic fibrosis remains unknown. We hypothesized that elevated levels of CCK acting on the CCK-Rs play a role in the development of NASH and in NASH-associated HCC. We performed a NASH Prevention study and Reversal study in mice fed a saturated fat 75% choline-deficient–ethionine-supplemented (CDE) diet for 12 or 18 weeks. In each study, half of the mice received untreated drinking water, while the other half received water supplemented with the CCK-R antagonist Proglumide. CCK-R expression was evaluated in mouse liver and murine HCC cells. CCK receptor antagonist treatment not only prevented NASH but also reversed hepatic inflammation, fibrosis, and steatosis and normalized hepatic transaminases after NASH was established. Thirty-five percent of the mice on the CDE diet developed HCC compared with none in the Proglumide-treated group. We found that CCK-BR expression was markedly upregulated in mouse CDE liver and HCC cells compared with normal hepatic parenchymal cells, and this expression was epigenetically regulated by microRNA-148a. These results support the novel role of CCK receptors in the pathogenesis of NASH and HCC.
Hong Cao - One of the best experts on this subject based on the ideXlab platform.
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abstract 5326 cholecystokinin receptor antagonist decreases fibrosis in pancreatic cancer microenvironment to improve uptake and efficacy of chemotherapy
Cancer Research, 2020Co-Authors: Zoe X Malchiodi, Narayan Shivapurkar, Hong Cao, Sunil Bansal, Benjamin A Weinberg, Amrita K Cheema, Jill P SmithAbstract:Background: Although pancreatic cancer cells respond to chemotherapeutic agents in cell culture, many of these drugs are less effective in vivo. This decreased response to chemotherapy in animal models and human subjects is in part attributed to the dense stroma of the pancreatic tumor microenvironment (TME) that impedes penetration of drugs. Pancreatic stellate cells and tissue fibroblasts have cholecystokinin (CCK) receptors and when these receptors are activated, they promote collagen deposition and increase fibrosis in the TME. We have previously shown that CCK receptor antagonists can decrease fibrosis and change the T-cell infiltrates of the TME in pancreatic tumors. We hypothesized that an oral CCK receptor antagonist, Proglumide, would improve the efficacy of gemcitabine by decreasing fibrosis in the TME and improving uptake of chemotherapy. Methods: 500,000 mT3 murine pancreatic cancer cells were injected subcutaneously into the right flank of 40 C57/BL6 female mice. One week after the mice had measurable tumors (baseline), mice were divided into 4 groups (N=10 mice each) with equal mean tumor volumes. Treatment groups included: PBS control (100µl IP twice weekly); Proglumide in drinking water (0.1 mg/ml); gemcitabine (100mg/kg, 100µl IP twice weekly); and combination of gemcitabine and Proglumide. Tumors were measured weekly and the volumes were calculated. Mice were euthanized per protocol when the tumor diameter reached 20mm; tumors were removed, then flash frozen for gemcitabine measurement via mass spectrometry. Results: Tumor volumes demonstrated a rapid growth rate in the PBS control mice with a slope of 184.2±2 (mm3/week), whereas growth rates for Proglumide (75±2) and gemcitabine monotherapy (72±14) were 2.6-fold slower, and also 3.4-fold slower for mice treated with both gemcitabine and Proglumide (55.6±12; p Conclusion: CCK receptor blockade with Proglumide decreases fibrosis in pancreatic cancer TME allowing greater tumor uptake of gemcitabine and improving efficacy by slowing tumor growth and improving survival. Strategies to improve first-line therapies for patients with pancreatic cancer may improve overall survival of this disease. Citation Format: Zoe X. Malchiodi, Hong Cao, Martha Gay, Sunil Bansal, Benjamin A. Weinberg, Amrita Cheema, Narayan Shivapurkar, Jill P. Smith. Cholecystokinin receptor antagonist decreases fibrosis in pancreatic cancer microenvironment to improve uptake and efficacy of chemotherapy [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5326.
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abstract 5193 cholecystokinin b receptor mediates growth of hepatocellular carcinoma
Cancer Research, 2020Co-Authors: Anita Safronenka, Robin D Tucker, Narayan Shivapurkar, Hong Cao, Jill P SmithAbstract:Background: The fastest-growing cause of cancer-related death is hepatocellular carcinoma (HCC), which is in part attributable to the obesity epidemic and nonalcoholic steatohepatitis (NASH). The gastrointestinal (GI) peptides, gastrin and cholecystokinin (CCK), regulate digestive functions and growth of the GI tract through the G-protein coupled receptors CCK- receptors (CCK-Rs). Both peptides activate the CCK-B receptor (CCK-BR) whereas only CCK peptide activates the CCK-A receptor (CCK-AR). CCK-Rs and gastrin are low or absent in normal mouse hepatocytes. We have previously shown that CCK blood levels increase and CCK-Rs become overexpressed in the livers of mice eating a high saturated fat diet that induced NASH and HCC. Hypothesis: CCK and gastrin mediate the growth of HCC through the CCK-R and that interruption of this signaling pathway could decrease growth of HCC. Methods: RNA was extracted from murine Hepa1-6, RIL-175, and human HepG2 cells and was evaluated by qRT-PCR for expression of CCK-AR, CCK-BR, and gastrin. CCK-R protein expression was analyzed by flow cytometry. In order to determine which CCK-R mediated the growth effects, growth was studied in vitro using selective receptor antagonists or CRISPR Cas9 technology to knock-out each receptor. HCC cells were treated in vitro with CCK peptide (1-10nM), the CCK-AR antagonist (L364,718), or the CCK-BR antagonist (L365,260). Proliferation of selective CCK-R KO cells was compared to that of wild-type cells. To determine the effect of a CCK-R antagonist on tumor growth in vivo, two cohorts of mice bearing subcutaneous Hepa1-6 or RIL-175 HCC tumors were treated with an oral bioavailable CCK-R antagonist, Proglumide (1 mg/ml) or untreated water (controls) for 3-4 weeks. The mice bearing Hepa1-6 tumors were placed on a high-fat diet to raise blood CCK levels. Mice bearing RIL-175 tumors were fed standard chow to determine if Proglumide could block autocrine growth by gastrin. Results: The mRNA expression of CCK-AR, CCK-BR and gastrin were increased 80-90-fold in all HCC cell lines compared to that of normal liver. CCK-BRs were detected on >85% of the cells by flow cytometry. CCK peptide (1nM) stimulated HCC growth in vitro in both wild-type cells and in CCK-AR KO cells but not in CCK-BR KO cells. CCK-BR antagonist blocked CCK-stimulated growth in vitro but the CCK-AR antagonist did not, suggesting that the CCK-BR was responsible for mediating proliferation. In vivo tumor growth was significantly reduced with Proglumide treatment by 70% (p Conclusion: CCK-Rs are overexpressed in HCC and proliferation appears to be mediated through the CCK-BR. Downregulation with CRISPR Cas9 or blockade of the CCK-BR with an antagonist decreases growth in vitro and Proglumide therapy decreases tumor growth in vivo. Strategies that block signaling at the CCK-BR may provide a novel therapeutic option for HCC treatment. Citation Format: Martha D. Gay, Anita Safronenka, Hong Cao, Robin Tucker, Narayan Shivapurkar, Jill P. Smith. Cholecystokinin-B receptor mediates growth of hepatocellular carcinoma [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5193.
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a cholecystokinin receptor antagonist halts nonalcoholic steatohepatitis and prevents hepatocellular carcinoma
Digestive Diseases and Sciences, 2020Co-Authors: Robin D Tucker, Sandeep Nadella, Narayan Shivapurkar, Hong Cao, Victor Ciofoaia, Bhaskar Kallakury, Matthew Huber, Anita Safronenka, Annie J Kruger, Alexander KroemerAbstract:Nonalcoholic steatohepatitis (NASH) is a common inflammatory liver condition that may lead to cirrhosis and hepatocellular carcinoma (HCC). Risk factors for NASH include a saturated fat diet, altered lipid metabolism, and genetic and epigenetic factors, including microRNAs. Serum levels of cholecystokinin (CCK) are elevated in mice and humans that consume a high-saturated fat diet. CCK receptors (CCK-Rs) have been reported on fibroblasts which when activated can induce fibrosis; however, their role in hepatic fibrosis remains unknown. We hypothesized that elevated levels of CCK acting on the CCK-Rs play a role in the development of NASH and in NASH-associated HCC. We performed a NASH Prevention study and Reversal study in mice fed a saturated fat 75% choline-deficient–ethionine-supplemented (CDE) diet for 12 or 18 weeks. In each study, half of the mice received untreated drinking water, while the other half received water supplemented with the CCK-R antagonist Proglumide. CCK-R expression was evaluated in mouse liver and murine HCC cells. CCK receptor antagonist treatment not only prevented NASH but also reversed hepatic inflammation, fibrosis, and steatosis and normalized hepatic transaminases after NASH was established. Thirty-five percent of the mice on the CDE diet developed HCC compared with none in the Proglumide-treated group. We found that CCK-BR expression was markedly upregulated in mouse CDE liver and HCC cells compared with normal hepatic parenchymal cells, and this expression was epigenetically regulated by microRNA-148a. These results support the novel role of CCK receptors in the pathogenesis of NASH and HCC.
Saleh Al Deeb - One of the best experts on this subject based on the ideXlab platform.
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Proglumide a cholecystokinin receptor antagonist exacerbates β β iminodipropionitrile induced dyskinetic syndrome in rats
Neurotoxicology and Teratology, 1998Co-Authors: Mohammad Tariq, Haseeb A Khan, Zehra Rehana, Khalaf Al Moutaery, Saleh Al DeebAbstract:The present investigation was undertaken to study the effect of Proglumide, a cholecystokinin (CCK) receptor antagonist, on iminodipropionitrile (IDPN)-induced excitation, chorea, and circling (ECC) syndrome in rats. The animals were exposed to IDPN in the dose of 100 mg/kg/day IP for 9 days. Proglumide (PG) was administered IP daily 1 h before IDPN in the doses of 250, 500, and 750 mg/kg body weight in three different groups of rats. The animals were observed daily for neurobehavioral abnormalities including dyskinetic head movements, circling, tail hanging, air righting reflex, locomotor activity, and contact inhibition of the righting reflex. After behavioral studies, blood and brain samples were collected for the analysis of malondialdehyde (MDA), conjugated dienes, vitamin E, and glutathione peroxidase (GSH-Px). The temporal bones were also collected for inner ear histopathology. Our results showed that Proglumide significantly and dose-dependently exacerbated the incidence and the severity of IDPN-induced ECC syndrome during the treatment period as well as up to 3 weeks of postdosing. Administration of IDPN produced a significant increase in MDA and conjugated dienes and a decrease in vitamin E and GSH-Px, suggesting the role of oxygen-derived free radicals (ODFR) in IDPN-induced neurotoxicity. Concomitant treatment with Proglumide potentiated IDPN-induced oxidative stress. The histopathology of the inner ear showed significantly high degeneration of sensory hair cells in the crista ampullaris of the rats treated with IDPN plus Proglumide compared to IDPN-alone-treated animals. Further studies are warranted to determine the role of CCK in nitrile toxicity and drug-induced dyskinesia.
Gail L Matters - One of the best experts on this subject based on the ideXlab platform.
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cholecystokinin receptor antagonist halts progression of pancreatic cancer precursor lesions and fibrosis in mice
Pancreas, 2014Co-Authors: Jill P Smith, Timothy K Cooper, Christopher O Mcgovern, Evan L Gilius, Qing Zhong, Jiangang Liao, Alfredo A Molinolo, Silvio J Gutkind, Gail L MattersAbstract:Objectives Exogenous administration of cholecystokinin (CCK) induces hypertrophy and hyperplasia of the pancreas with an increase in DNA content. We hypothesized that endogenous CCK is involved in the malignant progression of pancreatic intraepithelial neoplasia (PanIN) lesions and the fibrosis associated with pancreatic cancer. Methods The presence of CCK receptors in early PanIN lesions was examined by immunohistochemistry in mouse and human pancreas. Pdx1-Cre/LSL-KrasG12D transgenic mice were randomized to receive either untreated drinking water or water supplemented with a CCK receptor antagonist (Proglumide, 0.1 mg/mL). Pancreas from the mice were removed and examined histologically for number and grade of PanINs after 1, 2, or 4 months of antagonist therapy. Results Both CCK-A and CCK-B receptors were identified in early stage PanINs from mouse and human pancreas. The grade of PanIN lesions was reversed, and progression to advanced lesions arrested in mice treated with Proglumide compared with the controls (P = 0.004). Furthermore, pancreatic fibrosis was significantly reduced in antagonist-treated animals compared with vehicle (P Conclusions These findings demonstrate that endogenous CCK is in part responsible for the development and progression of pancreatic cancer. The use of CCK receptor antagonists may have a role in cancer prophylaxis in high-risk subjects and may reduce fibrosis in the microenvironment.