Integration of pro-inflammatory cytokines, 12-lipoxygenase and NOX-1 in pancreatic islet beta cell dysfunction
► Inflammatory cytokines elevate reactive species, 12-LO and induce islet dysfunction. ► NADPH oxidase 1 is induced in islets and beta cell lines by inflammatory cytokines. ► Inhibitors of NADPH oxidase preserve markers of beta cell function. ► 12-LO activates islet NOX-1 and inhibitors of 12-LO blo...
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| Veröffentlicht in: | Molecular and cellular endocrinology 2012-07, Vol.358 (1), p.88-95 |
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| creator | Weaver, Jessica R. Holman, Theodore R. Imai, Yumi Jadhav, Ajit Kenyon, Victor Maloney, David J. Nadler, Jerry L. Rai, Ganesha Simeonov, Anton Taylor-Fishwick, David A. |
| description | ► Inflammatory cytokines elevate reactive species, 12-LO and induce islet dysfunction. ► NADPH oxidase 1 is induced in islets and beta cell lines by inflammatory cytokines. ► Inhibitors of NADPH oxidase preserve markers of beta cell function. ► 12-LO activates islet NOX-1 and inhibitors of 12-LO block cytokine induced NOX-1. ► Integrated pathway of inflammatory cytokine-induced beta cell dysfunction identified.
Elevated cellular reactive species, which can be produced by diabetic serum conditions such as elevated inflammatory cytokines, lipotoxicity or glucotoxicity contribute to islet beta cell dysfunction and cell death. Cellular pathways that result in beta cell oxidative stress are poorly resolved. In this study, stimulation of human donor islets, primary mouse islets or homogeneous beta cell lines with a cocktail of inflammatory cytokines (TNFα, IL-1β, and INFγ) significantly induced NADPH oxidase-1 (NOX-1) gene expression (p |
| doi_str_mv | 10.1016/j.mce.2012.03.004 |
| format | Article |
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Elevated cellular reactive species, which can be produced by diabetic serum conditions such as elevated inflammatory cytokines, lipotoxicity or glucotoxicity contribute to islet beta cell dysfunction and cell death. Cellular pathways that result in beta cell oxidative stress are poorly resolved. In this study, stimulation of human donor islets, primary mouse islets or homogeneous beta cell lines with a cocktail of inflammatory cytokines (TNFα, IL-1β, and INFγ) significantly induced NADPH oxidase-1 (NOX-1) gene expression (p<0.05). This pro-inflammatory cytokine cocktail concomitantly induced loss of islet glucose stimulated insulin response (p<0.05), elevated expression of MCP-1 (p<0.01), increased cellular reactive oxygen species (ROS) and induced cell death. Inhibitors of NADPH oxidase, apocynin and diphenyleneiodonium, and a dual selective NOX1/4 inhibitor, blocked ROS generation (p<0.01) and induction of MCP-1 (p<0.05) by pro-inflammatory cytokines in beta cells. It has previously been reported that pro-inflammatory cytokine stimulation induces 12-lipoxygenase (12-LO) expression in human islets. 12-Hydroxyeicosatetraenoic acid (12-HETE), a product of 12-LO activity, stimulated NOX-1 expression in human islets (p<0.05). A novel selective inhibitor of 12-LO blocked induction of NOX-1, production of ROS and pro-caspase 3 cleavage by pro-inflammatory cytokines in INS-1 beta cells (p<0.01). Inhibition was not seen with a structurally related but inactive analog. Importantly, islets from human type 2 diabetic donors have an elevated expression of NOX-1 (p<0.05). This study describes an integrated pathway in beta cells that links beta cell dysfunction induced by pro-inflammatory cytokines with 12-lipoxygenase and NADPH oxidase (NOX-1) activation. Inhibitors of this pathway may provide a new therapeutic strategy to preserve beta cell mass in diabetes.]]></description><identifier>ISSN: 0303-7207</identifier><identifier>EISSN: 1872-8057</identifier><identifier>DOI: 10.1016/j.mce.2012.03.004</identifier><identifier>PMID: 22502743</identifier><language>eng</language><publisher>Ireland: Elsevier Ireland Ltd</publisher><subject>12-Lipoxygenase ; Acetophenones - pharmacology ; Animals ; Apoptosis - drug effects ; Arachidonate 12-Lipoxygenase - metabolism ; blood serum ; Caspase 3 - metabolism ; cell death ; Chemokine CCL2 - biosynthesis ; Cytokines ; Diabetes ; Diabetes Mellitus - metabolism ; Diabetes Mellitus - pathology ; Eicosapentaenoic Acid - analogs & derivatives ; Eicosapentaenoic Acid - antagonists & inhibitors ; Eicosapentaenoic Acid - pharmacology ; Enzyme Activation ; gene expression ; glucose ; Humans ; Inhibitors ; insulin ; Insulin-Secreting Cells - metabolism ; Insulin-Secreting Cells - pathology ; interferon-gamma ; Interferon-gamma - pharmacology ; interleukin-1beta ; Interleukin-1beta - pharmacology ; Islet beta cell ; islets of Langerhans ; Mice ; NAD(P)H oxidase (H2O2-forming) ; NADH, NADPH Oxidoreductases - antagonists & inhibitors ; NADH, NADPH Oxidoreductases - metabolism ; NADPH oxidase ; NADPH Oxidase 1 ; noninsulin-dependent diabetes mellitus ; Onium Compounds - pharmacology ; oxidative stress ; Oxidative Stress - drug effects ; reactive oxygen species ; Reactive Oxygen Species - metabolism ; tumor necrosis factor-alpha ; Tumor Necrosis Factor-alpha - pharmacology</subject><ispartof>Molecular and cellular endocrinology, 2012-07, Vol.358 (1), p.88-95</ispartof><rights>2012 Elsevier Ireland Ltd</rights><rights>Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c453t-ba757f77f51574ea1aaa6902ffd486dec180410ade16e2bdb87f386352cc1f1e3</citedby><cites>FETCH-LOGICAL-c453t-ba757f77f51574ea1aaa6902ffd486dec180410ade16e2bdb87f386352cc1f1e3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://www.sciencedirect.com/science/article/pii/S0303720712001670$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>314,776,780,3537,27901,27902,65306</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/22502743$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Weaver, Jessica R.</creatorcontrib><creatorcontrib>Holman, Theodore R.</creatorcontrib><creatorcontrib>Imai, Yumi</creatorcontrib><creatorcontrib>Jadhav, Ajit</creatorcontrib><creatorcontrib>Kenyon, Victor</creatorcontrib><creatorcontrib>Maloney, David J.</creatorcontrib><creatorcontrib>Nadler, Jerry L.</creatorcontrib><creatorcontrib>Rai, Ganesha</creatorcontrib><creatorcontrib>Simeonov, Anton</creatorcontrib><creatorcontrib>Taylor-Fishwick, David A.</creatorcontrib><title>Integration of pro-inflammatory cytokines, 12-lipoxygenase and NOX-1 in pancreatic islet beta cell dysfunction</title><title>Molecular and cellular endocrinology</title><addtitle>Mol Cell Endocrinol</addtitle><description><![CDATA[► Inflammatory cytokines elevate reactive species, 12-LO and induce islet dysfunction. ► NADPH oxidase 1 is induced in islets and beta cell lines by inflammatory cytokines. ► Inhibitors of NADPH oxidase preserve markers of beta cell function. ► 12-LO activates islet NOX-1 and inhibitors of 12-LO block cytokine induced NOX-1. ► Integrated pathway of inflammatory cytokine-induced beta cell dysfunction identified.
Elevated cellular reactive species, which can be produced by diabetic serum conditions such as elevated inflammatory cytokines, lipotoxicity or glucotoxicity contribute to islet beta cell dysfunction and cell death. Cellular pathways that result in beta cell oxidative stress are poorly resolved. In this study, stimulation of human donor islets, primary mouse islets or homogeneous beta cell lines with a cocktail of inflammatory cytokines (TNFα, IL-1β, and INFγ) significantly induced NADPH oxidase-1 (NOX-1) gene expression (p<0.05). This pro-inflammatory cytokine cocktail concomitantly induced loss of islet glucose stimulated insulin response (p<0.05), elevated expression of MCP-1 (p<0.01), increased cellular reactive oxygen species (ROS) and induced cell death. Inhibitors of NADPH oxidase, apocynin and diphenyleneiodonium, and a dual selective NOX1/4 inhibitor, blocked ROS generation (p<0.01) and induction of MCP-1 (p<0.05) by pro-inflammatory cytokines in beta cells. It has previously been reported that pro-inflammatory cytokine stimulation induces 12-lipoxygenase (12-LO) expression in human islets. 12-Hydroxyeicosatetraenoic acid (12-HETE), a product of 12-LO activity, stimulated NOX-1 expression in human islets (p<0.05). A novel selective inhibitor of 12-LO blocked induction of NOX-1, production of ROS and pro-caspase 3 cleavage by pro-inflammatory cytokines in INS-1 beta cells (p<0.01). Inhibition was not seen with a structurally related but inactive analog. Importantly, islets from human type 2 diabetic donors have an elevated expression of NOX-1 (p<0.05). This study describes an integrated pathway in beta cells that links beta cell dysfunction induced by pro-inflammatory cytokines with 12-lipoxygenase and NADPH oxidase (NOX-1) activation. Inhibitors of this pathway may provide a new therapeutic strategy to preserve beta cell mass in diabetes.]]></description><subject>12-Lipoxygenase</subject><subject>Acetophenones - pharmacology</subject><subject>Animals</subject><subject>Apoptosis - drug effects</subject><subject>Arachidonate 12-Lipoxygenase - metabolism</subject><subject>blood serum</subject><subject>Caspase 3 - metabolism</subject><subject>cell death</subject><subject>Chemokine CCL2 - biosynthesis</subject><subject>Cytokines</subject><subject>Diabetes</subject><subject>Diabetes Mellitus - metabolism</subject><subject>Diabetes Mellitus - pathology</subject><subject>Eicosapentaenoic Acid - analogs & derivatives</subject><subject>Eicosapentaenoic Acid - antagonists & inhibitors</subject><subject>Eicosapentaenoic Acid - pharmacology</subject><subject>Enzyme Activation</subject><subject>gene expression</subject><subject>glucose</subject><subject>Humans</subject><subject>Inhibitors</subject><subject>insulin</subject><subject>Insulin-Secreting Cells - metabolism</subject><subject>Insulin-Secreting Cells - pathology</subject><subject>interferon-gamma</subject><subject>Interferon-gamma - pharmacology</subject><subject>interleukin-1beta</subject><subject>Interleukin-1beta - pharmacology</subject><subject>Islet beta cell</subject><subject>islets of Langerhans</subject><subject>Mice</subject><subject>NAD(P)H oxidase (H2O2-forming)</subject><subject>NADH, NADPH Oxidoreductases - antagonists & inhibitors</subject><subject>NADH, NADPH Oxidoreductases - metabolism</subject><subject>NADPH oxidase</subject><subject>NADPH Oxidase 1</subject><subject>noninsulin-dependent diabetes mellitus</subject><subject>Onium Compounds - pharmacology</subject><subject>oxidative stress</subject><subject>Oxidative Stress - drug effects</subject><subject>reactive oxygen species</subject><subject>Reactive Oxygen Species - metabolism</subject><subject>tumor necrosis factor-alpha</subject><subject>Tumor Necrosis Factor-alpha - pharmacology</subject><issn>0303-7207</issn><issn>1872-8057</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2012</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqNkT-P1DAQxS0E4paDD0ADLilIGNtx7BUVOvHnpBNXwEl0luOMV14Se7GziHx7vNqDElFN83tv3swj5DmDlgHr3-zb2WHLgfEWRAvQPSAbphVvNEj1kGxAgGgUB3VBnpSyBwAluX5MLjiXwFUnNiRexwV32S4hRZo8PeTUhOgnO892SXmlbl3S9xCxvKaMN1M4pF_rDqMtSG0c6efbbw2jIdKDjS5j9XE0lAkXOuBiqcNpouNa_DG604qn5JG3U8Fn9_OS3H14__XqU3Nz-_H66t1N4zoplmawSiqvlJdMqg4ts9b2W-Dej53uR3RMQ8fAjsh65MM4aOWF7oXkzjHPUFySV2ffes-PI5bFzKGcwtiI6VgMA6F5t5Wd-g-UMdlxveUVZWfU5VRKRm8OOcw2rxU6cb3Zm9qIOTViQJjaSNW8uLc_DjOOfxV_KqjAyzPgbTJ2l0Mxd1-qgwRguubsK_H2TGD92M-A2RQXMDocQ0a3mDGFfwT4DWW9pSg</recordid><startdate>20120706</startdate><enddate>20120706</enddate><creator>Weaver, Jessica R.</creator><creator>Holman, Theodore R.</creator><creator>Imai, Yumi</creator><creator>Jadhav, Ajit</creator><creator>Kenyon, Victor</creator><creator>Maloney, David J.</creator><creator>Nadler, Jerry L.</creator><creator>Rai, Ganesha</creator><creator>Simeonov, Anton</creator><creator>Taylor-Fishwick, David A.</creator><general>Elsevier Ireland Ltd</general><scope>FBQ</scope><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>7X8</scope><scope>7T5</scope><scope>H94</scope></search><sort><creationdate>20120706</creationdate><title>Integration of pro-inflammatory cytokines, 12-lipoxygenase and NOX-1 in pancreatic islet beta cell dysfunction</title><author>Weaver, Jessica R. ; Holman, Theodore R. ; Imai, Yumi ; Jadhav, Ajit ; Kenyon, Victor ; Maloney, David J. ; Nadler, Jerry L. ; Rai, Ganesha ; Simeonov, Anton ; Taylor-Fishwick, David A.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c453t-ba757f77f51574ea1aaa6902ffd486dec180410ade16e2bdb87f386352cc1f1e3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2012</creationdate><topic>12-Lipoxygenase</topic><topic>Acetophenones - pharmacology</topic><topic>Animals</topic><topic>Apoptosis - drug effects</topic><topic>Arachidonate 12-Lipoxygenase - metabolism</topic><topic>blood serum</topic><topic>Caspase 3 - metabolism</topic><topic>cell death</topic><topic>Chemokine CCL2 - biosynthesis</topic><topic>Cytokines</topic><topic>Diabetes</topic><topic>Diabetes Mellitus - metabolism</topic><topic>Diabetes Mellitus - pathology</topic><topic>Eicosapentaenoic Acid - analogs & derivatives</topic><topic>Eicosapentaenoic Acid - antagonists & inhibitors</topic><topic>Eicosapentaenoic Acid - pharmacology</topic><topic>Enzyme Activation</topic><topic>gene expression</topic><topic>glucose</topic><topic>Humans</topic><topic>Inhibitors</topic><topic>insulin</topic><topic>Insulin-Secreting Cells - metabolism</topic><topic>Insulin-Secreting Cells - pathology</topic><topic>interferon-gamma</topic><topic>Interferon-gamma - pharmacology</topic><topic>interleukin-1beta</topic><topic>Interleukin-1beta - pharmacology</topic><topic>Islet beta cell</topic><topic>islets of Langerhans</topic><topic>Mice</topic><topic>NAD(P)H oxidase (H2O2-forming)</topic><topic>NADH, NADPH Oxidoreductases - antagonists & inhibitors</topic><topic>NADH, NADPH Oxidoreductases - metabolism</topic><topic>NADPH oxidase</topic><topic>NADPH Oxidase 1</topic><topic>noninsulin-dependent diabetes mellitus</topic><topic>Onium Compounds - pharmacology</topic><topic>oxidative stress</topic><topic>Oxidative Stress - drug effects</topic><topic>reactive oxygen species</topic><topic>Reactive Oxygen Species - metabolism</topic><topic>tumor necrosis factor-alpha</topic><topic>Tumor Necrosis Factor-alpha - pharmacology</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Weaver, Jessica R.</creatorcontrib><creatorcontrib>Holman, Theodore R.</creatorcontrib><creatorcontrib>Imai, Yumi</creatorcontrib><creatorcontrib>Jadhav, Ajit</creatorcontrib><creatorcontrib>Kenyon, Victor</creatorcontrib><creatorcontrib>Maloney, David J.</creatorcontrib><creatorcontrib>Nadler, Jerry L.</creatorcontrib><creatorcontrib>Rai, Ganesha</creatorcontrib><creatorcontrib>Simeonov, Anton</creatorcontrib><creatorcontrib>Taylor-Fishwick, David A.</creatorcontrib><collection>AGRIS</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><collection>Immunology Abstracts</collection><collection>AIDS and Cancer Research Abstracts</collection><jtitle>Molecular and cellular endocrinology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Weaver, Jessica R.</au><au>Holman, Theodore R.</au><au>Imai, Yumi</au><au>Jadhav, Ajit</au><au>Kenyon, Victor</au><au>Maloney, David J.</au><au>Nadler, Jerry L.</au><au>Rai, Ganesha</au><au>Simeonov, Anton</au><au>Taylor-Fishwick, David A.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Integration of pro-inflammatory cytokines, 12-lipoxygenase and NOX-1 in pancreatic islet beta cell dysfunction</atitle><jtitle>Molecular and cellular endocrinology</jtitle><addtitle>Mol Cell Endocrinol</addtitle><date>2012-07-06</date><risdate>2012</risdate><volume>358</volume><issue>1</issue><spage>88</spage><epage>95</epage><pages>88-95</pages><issn>0303-7207</issn><eissn>1872-8057</eissn><abstract><![CDATA[► Inflammatory cytokines elevate reactive species, 12-LO and induce islet dysfunction. ► NADPH oxidase 1 is induced in islets and beta cell lines by inflammatory cytokines. ► Inhibitors of NADPH oxidase preserve markers of beta cell function. ► 12-LO activates islet NOX-1 and inhibitors of 12-LO block cytokine induced NOX-1. ► Integrated pathway of inflammatory cytokine-induced beta cell dysfunction identified.
Elevated cellular reactive species, which can be produced by diabetic serum conditions such as elevated inflammatory cytokines, lipotoxicity or glucotoxicity contribute to islet beta cell dysfunction and cell death. Cellular pathways that result in beta cell oxidative stress are poorly resolved. In this study, stimulation of human donor islets, primary mouse islets or homogeneous beta cell lines with a cocktail of inflammatory cytokines (TNFα, IL-1β, and INFγ) significantly induced NADPH oxidase-1 (NOX-1) gene expression (p<0.05). This pro-inflammatory cytokine cocktail concomitantly induced loss of islet glucose stimulated insulin response (p<0.05), elevated expression of MCP-1 (p<0.01), increased cellular reactive oxygen species (ROS) and induced cell death. Inhibitors of NADPH oxidase, apocynin and diphenyleneiodonium, and a dual selective NOX1/4 inhibitor, blocked ROS generation (p<0.01) and induction of MCP-1 (p<0.05) by pro-inflammatory cytokines in beta cells. It has previously been reported that pro-inflammatory cytokine stimulation induces 12-lipoxygenase (12-LO) expression in human islets. 12-Hydroxyeicosatetraenoic acid (12-HETE), a product of 12-LO activity, stimulated NOX-1 expression in human islets (p<0.05). A novel selective inhibitor of 12-LO blocked induction of NOX-1, production of ROS and pro-caspase 3 cleavage by pro-inflammatory cytokines in INS-1 beta cells (p<0.01). Inhibition was not seen with a structurally related but inactive analog. Importantly, islets from human type 2 diabetic donors have an elevated expression of NOX-1 (p<0.05). This study describes an integrated pathway in beta cells that links beta cell dysfunction induced by pro-inflammatory cytokines with 12-lipoxygenase and NADPH oxidase (NOX-1) activation. Inhibitors of this pathway may provide a new therapeutic strategy to preserve beta cell mass in diabetes.]]></abstract><cop>Ireland</cop><pub>Elsevier Ireland Ltd</pub><pmid>22502743</pmid><doi>10.1016/j.mce.2012.03.004</doi><tpages>8</tpages><oa>free_for_read</oa></addata></record> |
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| ispartof | Molecular and cellular endocrinology, 2012-07, Vol.358 (1), p.88-95 |
| issn | 0303-7207 1872-8057 |
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| subjects | 12-Lipoxygenase Acetophenones - pharmacology Animals Apoptosis - drug effects Arachidonate 12-Lipoxygenase - metabolism blood serum Caspase 3 - metabolism cell death Chemokine CCL2 - biosynthesis Cytokines Diabetes Diabetes Mellitus - metabolism Diabetes Mellitus - pathology Eicosapentaenoic Acid - analogs & derivatives Eicosapentaenoic Acid - antagonists & inhibitors Eicosapentaenoic Acid - pharmacology Enzyme Activation gene expression glucose Humans Inhibitors insulin Insulin-Secreting Cells - metabolism Insulin-Secreting Cells - pathology interferon-gamma Interferon-gamma - pharmacology interleukin-1beta Interleukin-1beta - pharmacology Islet beta cell islets of Langerhans Mice NAD(P)H oxidase (H2O2-forming) NADH, NADPH Oxidoreductases - antagonists & inhibitors NADH, NADPH Oxidoreductases - metabolism NADPH oxidase NADPH Oxidase 1 noninsulin-dependent diabetes mellitus Onium Compounds - pharmacology oxidative stress Oxidative Stress - drug effects reactive oxygen species Reactive Oxygen Species - metabolism tumor necrosis factor-alpha Tumor Necrosis Factor-alpha - pharmacology |
| title | Integration of pro-inflammatory cytokines, 12-lipoxygenase and NOX-1 in pancreatic islet beta cell dysfunction |
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