Protective Effects of Necrostatin-1 in Acute Pancreatitis : Partial Involvement of Receptor Interacting Protein Kinase 1
Acute pancreatitis (AP) is a severe and potentially fatal disease caused predominantly by alcohol excess and gallstones, which lacks a specific therapy. The role of Receptor-Interacting Protein Kinase 1 (RIPK1), a key component of programmed necrosis (Necroptosis), is unclear in AP. We assessed the effects of RIPK1 inhibitor Necrostatin-1 (Nec-1) and RIPK1 modification (RIPK1K45A: kinase dead) in bile acid (TLCS-AP), alcoholic (FAEE-AP) and caerulein hyperstimulation (CER-AP) mouse models. Involvement of collateral Nec-1 target indoleamine 2,3-dioxygenase (IDO) was probed with the inhibitor Epacadostat (EPA). Effects of Nec-1 and RIPK1K45A were also compared on pancreatic acinar cell (PAC) fate in vitro and underlying mechanisms explored. Nec-1 markedly ameliorated histological and biochemical changes in all models. However, these were only partially reduced or unchanged in RIPK1K45A mice. Inhibition of IDO with EPA was protective in TLCS-AP. Both Nec-1 and RIPK1K45A modification inhibited TLCS- and FAEE-induced PAC necrosis in vitro. Nec-1 did not affect TLCS-induced Ca2+ entry in PACs, however, it inhibited an associated ROS elevation. The results demonstrate protective actions of Nec-1 in multiple models. However, RIPK1-dependent necroptosis only partially contributed to beneficial effects, and actions on targets such as IDO are likely to be important.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2021 |
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| Erschienen: |
2021 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:10 |
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| Enthalten in: |
Cells - 10(2021), 5 vom: 27. Apr. |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Ouyang, Yulin [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 22.10.2021 Date Revised 26.02.2024 published: Electronic Citation Status MEDLINE |
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| doi: |
10.3390/cells10051035 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM324789785 |
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| 100 | 1 | |a Ouyang, Yulin |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Protective Effects of Necrostatin-1 in Acute Pancreatitis |b Partial Involvement of Receptor Interacting Protein Kinase 1 |
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| 500 | |a Date Revised 26.02.2024 | ||
| 500 | |a published: Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Acute pancreatitis (AP) is a severe and potentially fatal disease caused predominantly by alcohol excess and gallstones, which lacks a specific therapy. The role of Receptor-Interacting Protein Kinase 1 (RIPK1), a key component of programmed necrosis (Necroptosis), is unclear in AP. We assessed the effects of RIPK1 inhibitor Necrostatin-1 (Nec-1) and RIPK1 modification (RIPK1K45A: kinase dead) in bile acid (TLCS-AP), alcoholic (FAEE-AP) and caerulein hyperstimulation (CER-AP) mouse models. Involvement of collateral Nec-1 target indoleamine 2,3-dioxygenase (IDO) was probed with the inhibitor Epacadostat (EPA). Effects of Nec-1 and RIPK1K45A were also compared on pancreatic acinar cell (PAC) fate in vitro and underlying mechanisms explored. Nec-1 markedly ameliorated histological and biochemical changes in all models. However, these were only partially reduced or unchanged in RIPK1K45A mice. Inhibition of IDO with EPA was protective in TLCS-AP. Both Nec-1 and RIPK1K45A modification inhibited TLCS- and FAEE-induced PAC necrosis in vitro. Nec-1 did not affect TLCS-induced Ca2+ entry in PACs, however, it inhibited an associated ROS elevation. The results demonstrate protective actions of Nec-1 in multiple models. However, RIPK1-dependent necroptosis only partially contributed to beneficial effects, and actions on targets such as IDO are likely to be important | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 4 | |a RIPK1 | |
| 650 | 4 | |a acute pancreatitis | |
| 650 | 4 | |a cell death | |
| 650 | 4 | |a epacadostat | |
| 650 | 4 | |a indoleamine 2,3-dioxygenase | |
| 650 | 4 | |a necroptosis | |
| 650 | 4 | |a necrostatin-1 | |
| 650 | 4 | |a receptor-interacting protein kinase 1 | |
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| 650 | 7 | |a Bile Acids and Salts |2 NLM | |
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| 650 | 7 | |a Indoleamine-Pyrrole 2,3,-Dioxygenase |2 NLM | |
| 650 | 7 | |a Indoles |2 NLM | |
| 650 | 7 | |a Protective Agents |2 NLM | |
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| 700 | 1 | |a Wen, Li |e verfasserin |4 aut | |
| 700 | 1 | |a Armstrong, Jane A |e verfasserin |4 aut | |
| 700 | 1 | |a Chvanov, Michael |e verfasserin |4 aut | |
| 700 | 1 | |a Latawiec, Diane |e verfasserin |4 aut | |
| 700 | 1 | |a Cai, Wenhao |e verfasserin |4 aut | |
| 700 | 1 | |a Awais, Mohammad |e verfasserin |4 aut | |
| 700 | 1 | |a Mukherjee, Rajarshi |e verfasserin |4 aut | |
| 700 | 1 | |a Huang, Wei |e verfasserin |4 aut | |
| 700 | 1 | |a Gough, Peter J |e verfasserin |4 aut | |
| 700 | 1 | |a Bertin, John |e verfasserin |4 aut | |
| 700 | 1 | |a Tepikin, Alexei V |e verfasserin |4 aut | |
| 700 | 1 | |a Sutton, Robert |e verfasserin |4 aut | |
| 700 | 1 | |a Criddle, David N |e verfasserin |4 aut | |
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