Apigenin inhibits pancreatic stellate cell activity in pancreatitis

Abstract Background Chronic pancreatitis (CP) is characterized by recurrent pancreatic injury, resulting in inflammation, necrosis, and fibrosis. There are currently no drugs limiting pancreatic fibrosis associated with CP, and there is a definite need to fill this void in patient care. Materials an...

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Veröffentlicht in:The Journal of surgical research 2015-06, Vol.196 (1), p.8-16
Hauptverfasser: Mrazek, Amy A., MD, Porro, Laura J., MD, Bhatia, Vandanajay, PhD, Falzon, Miriam, PhD, Spratt, Heidi, PhD, Zhou, Jia, PhD, Chao, Celia, MD, Hellmich, Mark R., PhD
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container_end_page 16
container_issue 1
container_start_page 8
container_title The Journal of surgical research
container_volume 196
creator Mrazek, Amy A., MD
Porro, Laura J., MD
Bhatia, Vandanajay, PhD
Falzon, Miriam, PhD
Spratt, Heidi, PhD
Zhou, Jia, PhD
Chao, Celia, MD
Hellmich, Mark R., PhD
description Abstract Background Chronic pancreatitis (CP) is characterized by recurrent pancreatic injury, resulting in inflammation, necrosis, and fibrosis. There are currently no drugs limiting pancreatic fibrosis associated with CP, and there is a definite need to fill this void in patient care. Materials and methods Pancreatitis was induced in C57/BL6 mice using supraphysiologic doses of cerulein, and apigenin treatment (once daily, 50 μg per mouse by oral gavage) was initiated 1 wk into the recurrent acute pancreatitis (RAP) protocol. Pancreata were harvested after 4 wk of RAP. Immunostaining with fibronectin antibody was used to quantify the extent of pancreatic fibrosis. To assess how apigenin may decrease organ fibrosis, we evaluated the effect of apigenin on the proliferation and apoptosis of human pancreatic stellate cells (PSCs) in vitro . Finally, we assessed apigenin's effect on the gene expression in PSCs stimulated with parathyroid hormone–related protein, a profibrotic and proinflammatory mediator of pancreatitis, using reverse transcription-polymerase chain reaction. Results After 4 wk of RAP, apigenin significantly reduced the fibrotic response to injury while preserving acinar units. Apigenin inhibited viability and induced apoptosis of PSCs in a time- and dose-dependent manner. Finally, apigenin reduced parathyroid hormone–related protein–stimulated increases in the PSC messenger RNA expression levels of extracellular matrix proteins collagen 1A1 and fibronectin, proliferating cell nuclear antigen, transforming growth factor-beta, and interleukin-6. Conclusions These in vivo and in vitro studies provide novel insights regarding apigenin's mechanism(s) of action in reducing the severity of RAP. Additional preclinical testing of apigenin analogs is warranted to develop a therapeutic agent for patients at risk for CP.
doi_str_mv 10.1016/j.jss.2015.02.032
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There are currently no drugs limiting pancreatic fibrosis associated with CP, and there is a definite need to fill this void in patient care. Materials and methods Pancreatitis was induced in C57/BL6 mice using supraphysiologic doses of cerulein, and apigenin treatment (once daily, 50 μg per mouse by oral gavage) was initiated 1 wk into the recurrent acute pancreatitis (RAP) protocol. Pancreata were harvested after 4 wk of RAP. Immunostaining with fibronectin antibody was used to quantify the extent of pancreatic fibrosis. To assess how apigenin may decrease organ fibrosis, we evaluated the effect of apigenin on the proliferation and apoptosis of human pancreatic stellate cells (PSCs) in vitro . Finally, we assessed apigenin's effect on the gene expression in PSCs stimulated with parathyroid hormone–related protein, a profibrotic and proinflammatory mediator of pancreatitis, using reverse transcription-polymerase chain reaction. Results After 4 wk of RAP, apigenin significantly reduced the fibrotic response to injury while preserving acinar units. Apigenin inhibited viability and induced apoptosis of PSCs in a time- and dose-dependent manner. Finally, apigenin reduced parathyroid hormone–related protein–stimulated increases in the PSC messenger RNA expression levels of extracellular matrix proteins collagen 1A1 and fibronectin, proliferating cell nuclear antigen, transforming growth factor-beta, and interleukin-6. Conclusions These in vivo and in vitro studies provide novel insights regarding apigenin's mechanism(s) of action in reducing the severity of RAP. Additional preclinical testing of apigenin analogs is warranted to develop a therapeutic agent for patients at risk for CP.</description><identifier>ISSN: 0022-4804</identifier><identifier>EISSN: 1095-8673</identifier><identifier>DOI: 10.1016/j.jss.2015.02.032</identifier><identifier>PMID: 25799526</identifier><language>eng</language><publisher>United States: Elsevier Inc</publisher><subject>Animals ; Apigenin ; Apigenin - pharmacology ; Apigenin - therapeutic use ; Cell Survival - drug effects ; Cells, Cultured ; Chronic pancreatitis ; Disease Models, Animal ; Female ; Humans ; Male ; Mice ; Mice, Inbred C57BL ; Pancreatic stellate cells ; Pancreatic Stellate Cells - drug effects ; Pancreatic Stellate Cells - pathology ; Pancreatitis, Chronic - drug therapy ; Pancreatitis, Chronic - metabolism ; Pancreatitis, Chronic - pathology ; Parathyroid Hormone-Related Protein - pharmacology ; Parathyroid hormone–related protein ; Surgery</subject><ispartof>The Journal of surgical research, 2015-06, Vol.196 (1), p.8-16</ispartof><rights>Elsevier Inc.</rights><rights>2015 Elsevier Inc.</rights><rights>Copyright © 2015 Elsevier Inc. All rights reserved.</rights><rights>2015 Published by Elsevier Inc. 2015</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c576t-283b903ba29f83ae798546e9336fe41525f7565829177894ca92809b6ecb923c3</citedby><cites>FETCH-LOGICAL-c576t-283b903ba29f83ae798546e9336fe41525f7565829177894ca92809b6ecb923c3</cites><orcidid>0000-0001-8725-4908</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://dx.doi.org/10.1016/j.jss.2015.02.032$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>230,314,780,784,885,3550,27924,27925,45995</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/25799526$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Mrazek, Amy A., MD</creatorcontrib><creatorcontrib>Porro, Laura J., MD</creatorcontrib><creatorcontrib>Bhatia, Vandanajay, PhD</creatorcontrib><creatorcontrib>Falzon, Miriam, PhD</creatorcontrib><creatorcontrib>Spratt, Heidi, PhD</creatorcontrib><creatorcontrib>Zhou, Jia, PhD</creatorcontrib><creatorcontrib>Chao, Celia, MD</creatorcontrib><creatorcontrib>Hellmich, Mark R., PhD</creatorcontrib><title>Apigenin inhibits pancreatic stellate cell activity in pancreatitis</title><title>The Journal of surgical research</title><addtitle>J Surg Res</addtitle><description>Abstract Background Chronic pancreatitis (CP) is characterized by recurrent pancreatic injury, resulting in inflammation, necrosis, and fibrosis. There are currently no drugs limiting pancreatic fibrosis associated with CP, and there is a definite need to fill this void in patient care. Materials and methods Pancreatitis was induced in C57/BL6 mice using supraphysiologic doses of cerulein, and apigenin treatment (once daily, 50 μg per mouse by oral gavage) was initiated 1 wk into the recurrent acute pancreatitis (RAP) protocol. Pancreata were harvested after 4 wk of RAP. Immunostaining with fibronectin antibody was used to quantify the extent of pancreatic fibrosis. To assess how apigenin may decrease organ fibrosis, we evaluated the effect of apigenin on the proliferation and apoptosis of human pancreatic stellate cells (PSCs) in vitro . Finally, we assessed apigenin's effect on the gene expression in PSCs stimulated with parathyroid hormone–related protein, a profibrotic and proinflammatory mediator of pancreatitis, using reverse transcription-polymerase chain reaction. Results After 4 wk of RAP, apigenin significantly reduced the fibrotic response to injury while preserving acinar units. Apigenin inhibited viability and induced apoptosis of PSCs in a time- and dose-dependent manner. Finally, apigenin reduced parathyroid hormone–related protein–stimulated increases in the PSC messenger RNA expression levels of extracellular matrix proteins collagen 1A1 and fibronectin, proliferating cell nuclear antigen, transforming growth factor-beta, and interleukin-6. Conclusions These in vivo and in vitro studies provide novel insights regarding apigenin's mechanism(s) of action in reducing the severity of RAP. Additional preclinical testing of apigenin analogs is warranted to develop a therapeutic agent for patients at risk for CP.</description><subject>Animals</subject><subject>Apigenin</subject><subject>Apigenin - pharmacology</subject><subject>Apigenin - therapeutic use</subject><subject>Cell Survival - drug effects</subject><subject>Cells, Cultured</subject><subject>Chronic pancreatitis</subject><subject>Disease Models, Animal</subject><subject>Female</subject><subject>Humans</subject><subject>Male</subject><subject>Mice</subject><subject>Mice, Inbred C57BL</subject><subject>Pancreatic stellate cells</subject><subject>Pancreatic Stellate Cells - drug effects</subject><subject>Pancreatic Stellate Cells - pathology</subject><subject>Pancreatitis, Chronic - drug therapy</subject><subject>Pancreatitis, Chronic - metabolism</subject><subject>Pancreatitis, Chronic - pathology</subject><subject>Parathyroid Hormone-Related Protein - pharmacology</subject><subject>Parathyroid hormone–related protein</subject><subject>Surgery</subject><issn>0022-4804</issn><issn>1095-8673</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2015</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kdtq3DAQhkVpaDZpH6A3xS9gZ3SyLQqBsKRNIdCLttdC1o6TcR15kZSFffto2TQ9XPRqEPq_X-gbxt5zaDjw9mJqppQaAVw3IBqQ4hVbcTC67ttOvmYrACFq1YM6ZWcpTVDOppNv2KnQnTFatCu2vtrSHQYKFYV7GiinauuCj-gy-SplnGeXsfJlVs5n2lHel-jvUKb0lp2Mbk747nmesx-frr-vb-rbr5-_rK9ua6-7Nteil4MBOThhxl467EyvVYtGynZExbXQY6db3QvDu643yjsjejBDi34wQnp5zi6PvdvH4QE3HkOObrbbSA8u7u3iyP59E-je3i07q5QEBaoU8GOBj0tKEccXloM9GLWTLUbtwagFYYvRwnz489EX4pfCEvh4DGD5-o4w2uQJg8cNRfTZbhb6b_3lP7SfKZB380_cY5qWxxiKU8ttKoD9dljpYaNcA3AFnXwCQM2caw</recordid><startdate>20150601</startdate><enddate>20150601</enddate><creator>Mrazek, Amy A., MD</creator><creator>Porro, Laura J., MD</creator><creator>Bhatia, Vandanajay, PhD</creator><creator>Falzon, Miriam, PhD</creator><creator>Spratt, Heidi, PhD</creator><creator>Zhou, Jia, PhD</creator><creator>Chao, Celia, MD</creator><creator>Hellmich, Mark R., PhD</creator><general>Elsevier Inc</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0001-8725-4908</orcidid></search><sort><creationdate>20150601</creationdate><title>Apigenin inhibits pancreatic stellate cell activity in pancreatitis</title><author>Mrazek, Amy A., MD ; Porro, Laura J., MD ; Bhatia, Vandanajay, PhD ; Falzon, Miriam, PhD ; Spratt, Heidi, PhD ; Zhou, Jia, PhD ; Chao, Celia, MD ; Hellmich, Mark R., PhD</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c576t-283b903ba29f83ae798546e9336fe41525f7565829177894ca92809b6ecb923c3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2015</creationdate><topic>Animals</topic><topic>Apigenin</topic><topic>Apigenin - pharmacology</topic><topic>Apigenin - therapeutic use</topic><topic>Cell Survival - drug effects</topic><topic>Cells, Cultured</topic><topic>Chronic pancreatitis</topic><topic>Disease Models, Animal</topic><topic>Female</topic><topic>Humans</topic><topic>Male</topic><topic>Mice</topic><topic>Mice, Inbred C57BL</topic><topic>Pancreatic stellate cells</topic><topic>Pancreatic Stellate Cells - drug effects</topic><topic>Pancreatic Stellate Cells - pathology</topic><topic>Pancreatitis, Chronic - drug therapy</topic><topic>Pancreatitis, Chronic - metabolism</topic><topic>Pancreatitis, Chronic - pathology</topic><topic>Parathyroid Hormone-Related Protein - pharmacology</topic><topic>Parathyroid hormone–related protein</topic><topic>Surgery</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Mrazek, Amy A., MD</creatorcontrib><creatorcontrib>Porro, Laura J., MD</creatorcontrib><creatorcontrib>Bhatia, Vandanajay, PhD</creatorcontrib><creatorcontrib>Falzon, Miriam, PhD</creatorcontrib><creatorcontrib>Spratt, Heidi, PhD</creatorcontrib><creatorcontrib>Zhou, Jia, PhD</creatorcontrib><creatorcontrib>Chao, Celia, MD</creatorcontrib><creatorcontrib>Hellmich, Mark R., PhD</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>The Journal of surgical research</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Mrazek, Amy A., MD</au><au>Porro, Laura J., MD</au><au>Bhatia, Vandanajay, PhD</au><au>Falzon, Miriam, PhD</au><au>Spratt, Heidi, PhD</au><au>Zhou, Jia, PhD</au><au>Chao, Celia, MD</au><au>Hellmich, Mark R., PhD</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Apigenin inhibits pancreatic stellate cell activity in pancreatitis</atitle><jtitle>The Journal of surgical research</jtitle><addtitle>J Surg Res</addtitle><date>2015-06-01</date><risdate>2015</risdate><volume>196</volume><issue>1</issue><spage>8</spage><epage>16</epage><pages>8-16</pages><issn>0022-4804</issn><eissn>1095-8673</eissn><abstract>Abstract Background Chronic pancreatitis (CP) is characterized by recurrent pancreatic injury, resulting in inflammation, necrosis, and fibrosis. There are currently no drugs limiting pancreatic fibrosis associated with CP, and there is a definite need to fill this void in patient care. Materials and methods Pancreatitis was induced in C57/BL6 mice using supraphysiologic doses of cerulein, and apigenin treatment (once daily, 50 μg per mouse by oral gavage) was initiated 1 wk into the recurrent acute pancreatitis (RAP) protocol. Pancreata were harvested after 4 wk of RAP. Immunostaining with fibronectin antibody was used to quantify the extent of pancreatic fibrosis. To assess how apigenin may decrease organ fibrosis, we evaluated the effect of apigenin on the proliferation and apoptosis of human pancreatic stellate cells (PSCs) in vitro . Finally, we assessed apigenin's effect on the gene expression in PSCs stimulated with parathyroid hormone–related protein, a profibrotic and proinflammatory mediator of pancreatitis, using reverse transcription-polymerase chain reaction. Results After 4 wk of RAP, apigenin significantly reduced the fibrotic response to injury while preserving acinar units. Apigenin inhibited viability and induced apoptosis of PSCs in a time- and dose-dependent manner. Finally, apigenin reduced parathyroid hormone–related protein–stimulated increases in the PSC messenger RNA expression levels of extracellular matrix proteins collagen 1A1 and fibronectin, proliferating cell nuclear antigen, transforming growth factor-beta, and interleukin-6. Conclusions These in vivo and in vitro studies provide novel insights regarding apigenin's mechanism(s) of action in reducing the severity of RAP. Additional preclinical testing of apigenin analogs is warranted to develop a therapeutic agent for patients at risk for CP.</abstract><cop>United States</cop><pub>Elsevier Inc</pub><pmid>25799526</pmid><doi>10.1016/j.jss.2015.02.032</doi><tpages>9</tpages><orcidid>https://orcid.org/0000-0001-8725-4908</orcidid><oa>free_for_read</oa></addata></record>
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subjects Animals
Apigenin
Apigenin - pharmacology
Apigenin - therapeutic use
Cell Survival - drug effects
Cells, Cultured
Chronic pancreatitis
Disease Models, Animal
Female
Humans
Male
Mice
Mice, Inbred C57BL
Pancreatic stellate cells
Pancreatic Stellate Cells - drug effects
Pancreatic Stellate Cells - pathology
Pancreatitis, Chronic - drug therapy
Pancreatitis, Chronic - metabolism
Pancreatitis, Chronic - pathology
Parathyroid Hormone-Related Protein - pharmacology
Parathyroid hormone–related protein
Surgery
title Apigenin inhibits pancreatic stellate cell activity in pancreatitis
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