2′-Hydroxycinnamaldehyde mitigates acetaminophen-induced acute liver injury by inhibiting the Warburg effect-mediated pyroptosis via the PKM2-NLRP3 axis
Acetaminophen (APAP) overdose is the leading cause of drug-induced acute liver injury. However, the underlying mechanisms appear to be multifaceted and there are few effective treatments. In this study, we used the 2′-Hydroxycinnamaldehyde (HCA), an active ingredient extracted from cinnamon stem bar...
| Main Authors: | , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2023-11-01
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| Series: | Journal of Functional Foods |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S1756464623004723 |
| _version_ | 1827766439352729600 |
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| author | Luying Zhao Jun Xu Xiangting Zhang Qian Xu Kanglei Ying Weimin Cai Yinrong Ding Huiya Ying Xian Song Zhuoyan Chen Liuwei Zeng Xiao Wu Ruoru Zhou Yuan Zeng Fujun Yu |
| author_facet | Luying Zhao Jun Xu Xiangting Zhang Qian Xu Kanglei Ying Weimin Cai Yinrong Ding Huiya Ying Xian Song Zhuoyan Chen Liuwei Zeng Xiao Wu Ruoru Zhou Yuan Zeng Fujun Yu |
| author_sort | Luying Zhao |
| collection | DOAJ |
| description | Acetaminophen (APAP) overdose is the leading cause of drug-induced acute liver injury. However, the underlying mechanisms appear to be multifaceted and there are few effective treatments. In this study, we used the 2′-Hydroxycinnamaldehyde (HCA), an active ingredient extracted from cinnamon stem bark to evaluate the therapeutic effect against APAP-induced ALI. The results indicated that pyruvate kinase M2 (PKM2)-mediated aerobic glycolysis may activate NLRP3 inflammasome in APAP-induced ALI, However, this process was prevented by HCA. Additionally, overexpression of PKM2 by adeno-associated virus (AAV9-PKM2) in vivo and plasmid (PKM2-OE) in vitro reversed the inhibition of NLRP3 inflammasome by HCA. Intriguingly, the HCA-triggered repressive pyroptosis was mediated through dephosphorylation and nuclear translocation of PKM2. Furthermore, the therapeutic effect of HCA on APAP-induced ALI was achieved by partially stimulating the Akt-mTOR signaling pathway, thus inhibiting the PKM2-NLRP3 axis. These findings elucidate that a potential drug to the clinical treatment of APAP overdose by HCA. |
| first_indexed | 2024-03-11T11:42:00Z |
| format | Article |
| id | doaj.art-ea69a974e1564d5e83a1c2d00d3b8e9c |
| institution | Directory Open Access Journal |
| issn | 1756-4646 |
| language | English |
| last_indexed | 2024-03-11T11:42:00Z |
| publishDate | 2023-11-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Journal of Functional Foods |
| spelling | doaj.art-ea69a974e1564d5e83a1c2d00d3b8e9c2023-11-10T04:16:16ZengElsevierJournal of Functional Foods1756-46462023-11-011101058722′-Hydroxycinnamaldehyde mitigates acetaminophen-induced acute liver injury by inhibiting the Warburg effect-mediated pyroptosis via the PKM2-NLRP3 axisLuying Zhao0Jun Xu1Xiangting Zhang2Qian Xu3Kanglei Ying4Weimin Cai5Yinrong Ding6Huiya Ying7Xian Song8Zhuoyan Chen9Liuwei Zeng10Xiao Wu11Ruoru Zhou12Yuan Zeng13Fujun Yu14Department of Gastroenterology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, ChinaDepartment of Gastroenterology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, ChinaDepartment of Gastroenterology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, ChinaDepartment of Gastroenterology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, ChinaDepartment of Gastroenterology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, ChinaDepartment of Gastroenterology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, ChinaDepartment of Gastroenterology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, ChinaDepartment of Gastroenterology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, ChinaDepartment of Gastroenterology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, ChinaDepartment of Gastroenterology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, ChinaDepartment of Gastroenterology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, ChinaDepartment of Gastroenterology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, ChinaDepartment of Gastroenterology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, ChinaCorresponding authors.; Department of Gastroenterology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, ChinaCorresponding authors.; Department of Gastroenterology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, ChinaAcetaminophen (APAP) overdose is the leading cause of drug-induced acute liver injury. However, the underlying mechanisms appear to be multifaceted and there are few effective treatments. In this study, we used the 2′-Hydroxycinnamaldehyde (HCA), an active ingredient extracted from cinnamon stem bark to evaluate the therapeutic effect against APAP-induced ALI. The results indicated that pyruvate kinase M2 (PKM2)-mediated aerobic glycolysis may activate NLRP3 inflammasome in APAP-induced ALI, However, this process was prevented by HCA. Additionally, overexpression of PKM2 by adeno-associated virus (AAV9-PKM2) in vivo and plasmid (PKM2-OE) in vitro reversed the inhibition of NLRP3 inflammasome by HCA. Intriguingly, the HCA-triggered repressive pyroptosis was mediated through dephosphorylation and nuclear translocation of PKM2. Furthermore, the therapeutic effect of HCA on APAP-induced ALI was achieved by partially stimulating the Akt-mTOR signaling pathway, thus inhibiting the PKM2-NLRP3 axis. These findings elucidate that a potential drug to the clinical treatment of APAP overdose by HCA.http://www.sciencedirect.com/science/article/pii/S1756464623004723Acute liver injuryPyroptosisAerobic glycolysis2′-HydroxycinnamaldehydePyruvate kinase M2NLRP3 inflammasome |
| spellingShingle | Luying Zhao Jun Xu Xiangting Zhang Qian Xu Kanglei Ying Weimin Cai Yinrong Ding Huiya Ying Xian Song Zhuoyan Chen Liuwei Zeng Xiao Wu Ruoru Zhou Yuan Zeng Fujun Yu 2′-Hydroxycinnamaldehyde mitigates acetaminophen-induced acute liver injury by inhibiting the Warburg effect-mediated pyroptosis via the PKM2-NLRP3 axis Journal of Functional Foods Acute liver injury Pyroptosis Aerobic glycolysis 2′-Hydroxycinnamaldehyde Pyruvate kinase M2 NLRP3 inflammasome |
| title | 2′-Hydroxycinnamaldehyde mitigates acetaminophen-induced acute liver injury by inhibiting the Warburg effect-mediated pyroptosis via the PKM2-NLRP3 axis |
| title_full | 2′-Hydroxycinnamaldehyde mitigates acetaminophen-induced acute liver injury by inhibiting the Warburg effect-mediated pyroptosis via the PKM2-NLRP3 axis |
| title_fullStr | 2′-Hydroxycinnamaldehyde mitigates acetaminophen-induced acute liver injury by inhibiting the Warburg effect-mediated pyroptosis via the PKM2-NLRP3 axis |
| title_full_unstemmed | 2′-Hydroxycinnamaldehyde mitigates acetaminophen-induced acute liver injury by inhibiting the Warburg effect-mediated pyroptosis via the PKM2-NLRP3 axis |
| title_short | 2′-Hydroxycinnamaldehyde mitigates acetaminophen-induced acute liver injury by inhibiting the Warburg effect-mediated pyroptosis via the PKM2-NLRP3 axis |
| title_sort | 2 hydroxycinnamaldehyde mitigates acetaminophen induced acute liver injury by inhibiting the warburg effect mediated pyroptosis via the pkm2 nlrp3 axis |
| topic | Acute liver injury Pyroptosis Aerobic glycolysis 2′-Hydroxycinnamaldehyde Pyruvate kinase M2 NLRP3 inflammasome |
| url | http://www.sciencedirect.com/science/article/pii/S1756464623004723 |
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