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Dimethyl Fumarate Protects Pancreatic Islet Cells and Non-Endocrine Tissue in L-Arginine-Induced Chronic Pancreatitis

BACKGROUND: Chronic pancreatitis (CP) is a progressive disorder resulting in the destruction and fibrosis of the pancreatic parenchyma which ultimately leads to impairment of the endocrine and exocrine functions. Dimethyl Fumarate (DMF) was recently approved by FDA for treatment of patients with mul...

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Autores principales: Robles, Lourdes, Vaziri, Nosratola D., Li, Shiri, Masuda, Yuichi, Takasu, Chie, Takasu, Mizuki, Vo, Kelly, Farzaneh, Seyed H., Stamos, Michael J., Ichii, Hirohito
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2014
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4157838/
https://www.ncbi.nlm.nih.gov/pubmed/25198679
http://dx.doi.org/10.1371/journal.pone.0107111
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author Robles, Lourdes
Vaziri, Nosratola D.
Li, Shiri
Masuda, Yuichi
Takasu, Chie
Takasu, Mizuki
Vo, Kelly
Farzaneh, Seyed H.
Stamos, Michael J.
Ichii, Hirohito
author_facet Robles, Lourdes
Vaziri, Nosratola D.
Li, Shiri
Masuda, Yuichi
Takasu, Chie
Takasu, Mizuki
Vo, Kelly
Farzaneh, Seyed H.
Stamos, Michael J.
Ichii, Hirohito
author_sort Robles, Lourdes
collection PubMed
description BACKGROUND: Chronic pancreatitis (CP) is a progressive disorder resulting in the destruction and fibrosis of the pancreatic parenchyma which ultimately leads to impairment of the endocrine and exocrine functions. Dimethyl Fumarate (DMF) was recently approved by FDA for treatment of patients with multiple sclerosis. DMF's unique anti-oxidant and anti-inflammatory properties make it an interesting drug to test on other inflammatory conditions. This study was undertaken to determine the effects of DMF on islet cells and non-endocrine tissue in a rodent model of L-Arginine-induced CP. METHODS: Male Wistar rats fed daily DMF (25 mg/kg) or vehicle by oral gavage were given 5 IP injections of L-Arginine (250 mg/100 g×2, 1 hr apart). Rats were assessed with weights and intra-peritoneal glucose tolerance tests (IPGTT, 2 g/kg). Islets were isolated and assessed for islet mass and viability with flow cytometry. Non-endocrine tissue was assessed for histology, myeloperoxidase (MPO), and lipid peroxidation level (MDA). In vitro assessments included determination of heme oxygenase (HO-1) protein expression by Western blot. RESULTS: Weight gain was significantly reduced in untreated CP group at 6 weeks. IPGTT revealed significant impairment in untreated CP group and its restoration with DMF therapy (P <0.05). Untreated CP rats had pancreatic atrophy, severe acinar architectural damage, edema, and fatty infiltration as well as elevated MDA and MPO levels, which were significantly improved by DMF treatment. After islet isolation, the volume of non-endocrine tissue was significantly smaller in untreated CP group. Although islet counts were similar in the two groups, islet viability was significantly reduced in untreated CP group and improved with DMF treatment. In vitro incubation of human pancreatic tissue with DMF significantly increased HO-1 expression. CONCLUSION: Administration of DMF attenuated L-Arginine-induced CP and islet function in rats. DMF treatment could be a possible strategy to improve clinical outcome in patients with CP.
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spelling pubmed-41578382014-09-09 Dimethyl Fumarate Protects Pancreatic Islet Cells and Non-Endocrine Tissue in L-Arginine-Induced Chronic Pancreatitis Robles, Lourdes Vaziri, Nosratola D. Li, Shiri Masuda, Yuichi Takasu, Chie Takasu, Mizuki Vo, Kelly Farzaneh, Seyed H. Stamos, Michael J. Ichii, Hirohito PLoS One Research Article BACKGROUND: Chronic pancreatitis (CP) is a progressive disorder resulting in the destruction and fibrosis of the pancreatic parenchyma which ultimately leads to impairment of the endocrine and exocrine functions. Dimethyl Fumarate (DMF) was recently approved by FDA for treatment of patients with multiple sclerosis. DMF's unique anti-oxidant and anti-inflammatory properties make it an interesting drug to test on other inflammatory conditions. This study was undertaken to determine the effects of DMF on islet cells and non-endocrine tissue in a rodent model of L-Arginine-induced CP. METHODS: Male Wistar rats fed daily DMF (25 mg/kg) or vehicle by oral gavage were given 5 IP injections of L-Arginine (250 mg/100 g×2, 1 hr apart). Rats were assessed with weights and intra-peritoneal glucose tolerance tests (IPGTT, 2 g/kg). Islets were isolated and assessed for islet mass and viability with flow cytometry. Non-endocrine tissue was assessed for histology, myeloperoxidase (MPO), and lipid peroxidation level (MDA). In vitro assessments included determination of heme oxygenase (HO-1) protein expression by Western blot. RESULTS: Weight gain was significantly reduced in untreated CP group at 6 weeks. IPGTT revealed significant impairment in untreated CP group and its restoration with DMF therapy (P <0.05). Untreated CP rats had pancreatic atrophy, severe acinar architectural damage, edema, and fatty infiltration as well as elevated MDA and MPO levels, which were significantly improved by DMF treatment. After islet isolation, the volume of non-endocrine tissue was significantly smaller in untreated CP group. Although islet counts were similar in the two groups, islet viability was significantly reduced in untreated CP group and improved with DMF treatment. In vitro incubation of human pancreatic tissue with DMF significantly increased HO-1 expression. CONCLUSION: Administration of DMF attenuated L-Arginine-induced CP and islet function in rats. DMF treatment could be a possible strategy to improve clinical outcome in patients with CP. Public Library of Science 2014-09-08 /pmc/articles/PMC4157838/ /pubmed/25198679 http://dx.doi.org/10.1371/journal.pone.0107111 Text en © 2014 Robles et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Robles, Lourdes
Vaziri, Nosratola D.
Li, Shiri
Masuda, Yuichi
Takasu, Chie
Takasu, Mizuki
Vo, Kelly
Farzaneh, Seyed H.
Stamos, Michael J.
Ichii, Hirohito
Dimethyl Fumarate Protects Pancreatic Islet Cells and Non-Endocrine Tissue in L-Arginine-Induced Chronic Pancreatitis
title Dimethyl Fumarate Protects Pancreatic Islet Cells and Non-Endocrine Tissue in L-Arginine-Induced Chronic Pancreatitis
title_full Dimethyl Fumarate Protects Pancreatic Islet Cells and Non-Endocrine Tissue in L-Arginine-Induced Chronic Pancreatitis
title_fullStr Dimethyl Fumarate Protects Pancreatic Islet Cells and Non-Endocrine Tissue in L-Arginine-Induced Chronic Pancreatitis
title_full_unstemmed Dimethyl Fumarate Protects Pancreatic Islet Cells and Non-Endocrine Tissue in L-Arginine-Induced Chronic Pancreatitis
title_short Dimethyl Fumarate Protects Pancreatic Islet Cells and Non-Endocrine Tissue in L-Arginine-Induced Chronic Pancreatitis
title_sort dimethyl fumarate protects pancreatic islet cells and non-endocrine tissue in l-arginine-induced chronic pancreatitis
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4157838/
https://www.ncbi.nlm.nih.gov/pubmed/25198679
http://dx.doi.org/10.1371/journal.pone.0107111
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