Isomaculosidine facilitates NLRP3 inflammasome activation by promoting mitochondrial reactive oxygen species production and causes idiosyncratic liver injury
Copyright © 2023 Elsevier B.V. All rights reserved..
ETHNOPHARMACOLOGICAL RELEVANCE: Dictamnus dasycarpus Turcz. (Dictamni Cortex, DC), a Chinese herbal medicine, is commonly used for treating chronic dermatosis and rheumatism, but can also cause herb-induced liver injury (HILI). Our study has demonstrated that DC can induce idiosyncratic HILI, but the mechanism remains unknown. The NLRP3 inflammasome has become a major target for addressing many diseases. The activation of NLRP3 inflammasome is responsible for many liver-related inflammatory diseases, including idiosyncratic HILI.
AIM OF THE STUDY: The objective of our study was to demonstrate the mechanism underlying the idiosyncratic HILI induced by DC and clarify the susceptible component in DC.
MATERIALS AND METHODS: Bone marrow-derived macrophages (BMDMs) and THP1 cells were selected to assess the effect of isomaculosidine (IMD) on NLRP3 inflammasome activation in vitro. Western blot, ELISA and Caspase-Glo® 1 Inflammasome Assay, flow cytometry and Immunofluorescence were employed to detect the mechanism of IMD on NLRP3 inflammasome activation. To assess the efficacy of IMD in vivo, mice were intravenously administrated with LPS and then IMD were injected intraperitoneally for 6 h.
RESULTS: The results of our in vitro studies demonstrate that IMD, the major constituent of DC, specifically promoted ATP- and nigericin-induced activation of NLRP3 inflammasome, but not NLRC4 and AIM2 inflammasomes. Additionally, IMD promoted nigericin-induced ASC oligomerization. Notably, synergistic induction of mtROS played a key role on the activation of NLRP3 inflammasome. IMD increased the mtROS production in the activation of NLRP3 inflammasome induced by nigericin. In addition, the results of our in vivo study showed that the combination of nonhepatotoxic doses of LPS and IMD can increase the levels of ALT, AST, and DBIL, leading to liver injury.
CONCLUSIONS: IMD specifically facilitated the activation of NLRP3 inflammasome induced by nigericin and ATP, which is responsible for DC-induced idiosyncratic HILI.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2024 2023 |
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| Erschienen: |
2024 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:319 |
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| Enthalten in: |
Journal of ethnopharmacology - 319(2023), Pt 1 vom: 30. Jan., Seite 117063 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Shi, Wei [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 22.11.2023 Date Revised 22.11.2023 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1016/j.jep.2023.117063 |
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| Förderinstitution / Projekttitel: |
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NLM360975313 |
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| 245 | 1 | 0 | |a Isomaculosidine facilitates NLRP3 inflammasome activation by promoting mitochondrial reactive oxygen species production and causes idiosyncratic liver injury |
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| 500 | |a Date Completed 22.11.2023 | ||
| 500 | |a Date Revised 22.11.2023 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Copyright © 2023 Elsevier B.V. All rights reserved. | ||
| 520 | |a ETHNOPHARMACOLOGICAL RELEVANCE: Dictamnus dasycarpus Turcz. (Dictamni Cortex, DC), a Chinese herbal medicine, is commonly used for treating chronic dermatosis and rheumatism, but can also cause herb-induced liver injury (HILI). Our study has demonstrated that DC can induce idiosyncratic HILI, but the mechanism remains unknown. The NLRP3 inflammasome has become a major target for addressing many diseases. The activation of NLRP3 inflammasome is responsible for many liver-related inflammatory diseases, including idiosyncratic HILI | ||
| 520 | |a AIM OF THE STUDY: The objective of our study was to demonstrate the mechanism underlying the idiosyncratic HILI induced by DC and clarify the susceptible component in DC | ||
| 520 | |a MATERIALS AND METHODS: Bone marrow-derived macrophages (BMDMs) and THP1 cells were selected to assess the effect of isomaculosidine (IMD) on NLRP3 inflammasome activation in vitro. Western blot, ELISA and Caspase-Glo® 1 Inflammasome Assay, flow cytometry and Immunofluorescence were employed to detect the mechanism of IMD on NLRP3 inflammasome activation. To assess the efficacy of IMD in vivo, mice were intravenously administrated with LPS and then IMD were injected intraperitoneally for 6 h | ||
| 520 | |a RESULTS: The results of our in vitro studies demonstrate that IMD, the major constituent of DC, specifically promoted ATP- and nigericin-induced activation of NLRP3 inflammasome, but not NLRC4 and AIM2 inflammasomes. Additionally, IMD promoted nigericin-induced ASC oligomerization. Notably, synergistic induction of mtROS played a key role on the activation of NLRP3 inflammasome. IMD increased the mtROS production in the activation of NLRP3 inflammasome induced by nigericin. In addition, the results of our in vivo study showed that the combination of nonhepatotoxic doses of LPS and IMD can increase the levels of ALT, AST, and DBIL, leading to liver injury | ||
| 520 | |a CONCLUSIONS: IMD specifically facilitated the activation of NLRP3 inflammasome induced by nigericin and ATP, which is responsible for DC-induced idiosyncratic HILI | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Dictamni cortex | |
| 650 | 4 | |a Idiosyncratic HILI | |
| 650 | 4 | |a Isomaculosidine | |
| 650 | 4 | |a Mitochondrial reactive oxygen species | |
| 650 | 4 | |a NLRP3 inflammasome | |
| 650 | 7 | |a Inflammasomes |2 NLM | |
| 650 | 7 | |a NLR Family, Pyrin Domain-Containing 3 Protein |2 NLM | |
| 650 | 7 | |a Reactive Oxygen Species |2 NLM | |
| 650 | 7 | |a Nigericin |2 NLM | |
| 650 | 7 | |a RRU6GY95IS |2 NLM | |
| 650 | 7 | |a Lipopolysaccharides |2 NLM | |
| 650 | 7 | |a Adenosine Triphosphate |2 NLM | |
| 650 | 7 | |a 8L70Q75FXE |2 NLM | |
| 700 | 1 | |a Liu, Tingting |e verfasserin |4 aut | |
| 700 | 1 | |a Yang, Huijie |e verfasserin |4 aut | |
| 700 | 1 | |a Zhao, Jia |e verfasserin |4 aut | |
| 700 | 1 | |a Wei, Ziying |e verfasserin |4 aut | |
| 700 | 1 | |a Huang, Yujiao |e verfasserin |4 aut | |
| 700 | 1 | |a Li, Zhiyong |e verfasserin |4 aut | |
| 700 | 1 | |a Li, Hui |e verfasserin |4 aut | |
| 700 | 1 | |a Liang, Longxin |e verfasserin |4 aut | |
| 700 | 1 | |a Hou, Xiaorong |e verfasserin |4 aut | |
| 700 | 1 | |a Chen, Yuanyuan |e verfasserin |4 aut | |
| 700 | 1 | |a Gao, Yuan |e verfasserin |4 aut | |
| 700 | 1 | |a Bai, Zhaofang |e verfasserin |4 aut | |
| 700 | 1 | |a Xiao, Xiaohe |e verfasserin |4 aut | |
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