S‐allyl‐L‐cysteine protects hepatocytes from indomethacin‐induced apoptosis by attenuating endoplasmic reticulum stress
Drug‐induced liver injury (DILI) can lead to acute liver failure, a lethal condition which may require liver transplantation. Hepatotoxicity associated with nonsteroidal anti‐inflammatory drugs (NSAIDs) accounts for ~ 10% of all DILI. In the current study, we determined whether indomethacin, one of...
| Main Authors: | , , , , , , |
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| Format: | Article |
| Language: | English |
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Wiley
2020-09-01
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| Series: | FEBS Open Bio |
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| Online Access: | https://doi.org/10.1002/2211-5463.12945 |
| _version_ | 1797821934878064640 |
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| author | Peng Chen Chen Chen Mingdao Hu Rui Cui Feng Liu Henghai Yu Yuling Ren |
| author_facet | Peng Chen Chen Chen Mingdao Hu Rui Cui Feng Liu Henghai Yu Yuling Ren |
| author_sort | Peng Chen |
| collection | DOAJ |
| description | Drug‐induced liver injury (DILI) can lead to acute liver failure, a lethal condition which may require liver transplantation. Hepatotoxicity associated with nonsteroidal anti‐inflammatory drugs (NSAIDs) accounts for ~ 10% of all DILI. In the current study, we determined whether indomethacin, one of the most commonly used NSAIDS, induced apoptosis in hepatocytes and investigated the underlying mechanism. Meanwhile, we investigated the protective effect of S‐allyl‐L‐cysteine (SAC), an active garlic derivative, on indomethacin‐induced hepatocyte apoptosis, and its implication on endoplasmic reticulum (ER) stress. We found that indomethacin triggered ER stress, as indicated by the elevated expression of phosphorylated eukaryotic translation initiation factor 2α (eIF2α), C/EBP homologous protein (CHOP) and spliced XBP1 in a rat liver BRL‐3A cell line. Following indomethacin treatment, caspase 3 activation and hepatocyte apoptosis were also observed. Inhibition of ER stress by chemical chaperone 4‐phenyl butyric acid alleviated cell apoptosis caused by indomethacin, indicating that ER stress is involved in indomethacin‐induced hepatocyte apoptosis. Moreover, SAC abated indomethacin‐induced eIF2α phosphorylation, inhibited CHOP upregulation and its nuclear translocation, abrogated the activation of caspase 3 and finally, protected hepatocytes from apoptosis. In conclusion, SAC protects indomethacin‐induced hepatocyte apoptosis through mitigating ER stress and may be suitable for development into a potential new therapeutic agent for the treatment of DILI. |
| first_indexed | 2024-03-13T10:00:01Z |
| format | Article |
| id | doaj.art-acd0eb46dead49fb974c60d82bf8f5ca |
| institution | Directory Open Access Journal |
| issn | 2211-5463 |
| language | English |
| last_indexed | 2024-03-13T10:00:01Z |
| publishDate | 2020-09-01 |
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| series | FEBS Open Bio |
| spelling | doaj.art-acd0eb46dead49fb974c60d82bf8f5ca2023-05-23T06:46:11ZengWileyFEBS Open Bio2211-54632020-09-011091900191110.1002/2211-5463.12945S‐allyl‐L‐cysteine protects hepatocytes from indomethacin‐induced apoptosis by attenuating endoplasmic reticulum stressPeng Chen0Chen Chen1Mingdao Hu2Rui Cui3Feng Liu4Henghai Yu5Yuling Ren6Department of Hepatopancreatobiliary Surgery The Second Affiliated Hospital of Kunming Medical University Kunming ChinaDepartment of Ophthalmology The Second People's Hospital of Yunnan Province Kunming ChinaDepartment of Hepatopancreatobiliary Surgery The Second Affiliated Hospital of Kunming Medical University Kunming ChinaDepartment of Hepatopancreatobiliary Surgery The Second Affiliated Hospital of Kunming Medical University Kunming ChinaDepartment of Hepatopancreatobiliary Surgery The Second Affiliated Hospital of Kunming Medical University Kunming ChinaDepartment of Hepatopancreatobiliary Surgery The Second Affiliated Hospital of Kunming Medical University Kunming ChinaDepartment of Ophthalmology The Second People's Hospital of Yunnan Province Kunming ChinaDrug‐induced liver injury (DILI) can lead to acute liver failure, a lethal condition which may require liver transplantation. Hepatotoxicity associated with nonsteroidal anti‐inflammatory drugs (NSAIDs) accounts for ~ 10% of all DILI. In the current study, we determined whether indomethacin, one of the most commonly used NSAIDS, induced apoptosis in hepatocytes and investigated the underlying mechanism. Meanwhile, we investigated the protective effect of S‐allyl‐L‐cysteine (SAC), an active garlic derivative, on indomethacin‐induced hepatocyte apoptosis, and its implication on endoplasmic reticulum (ER) stress. We found that indomethacin triggered ER stress, as indicated by the elevated expression of phosphorylated eukaryotic translation initiation factor 2α (eIF2α), C/EBP homologous protein (CHOP) and spliced XBP1 in a rat liver BRL‐3A cell line. Following indomethacin treatment, caspase 3 activation and hepatocyte apoptosis were also observed. Inhibition of ER stress by chemical chaperone 4‐phenyl butyric acid alleviated cell apoptosis caused by indomethacin, indicating that ER stress is involved in indomethacin‐induced hepatocyte apoptosis. Moreover, SAC abated indomethacin‐induced eIF2α phosphorylation, inhibited CHOP upregulation and its nuclear translocation, abrogated the activation of caspase 3 and finally, protected hepatocytes from apoptosis. In conclusion, SAC protects indomethacin‐induced hepatocyte apoptosis through mitigating ER stress and may be suitable for development into a potential new therapeutic agent for the treatment of DILI.https://doi.org/10.1002/2211-5463.12945apoptosisendoplasmic reticulum stresshepatocyteindomethacinS‐allyl‐l‐cysteine |
| spellingShingle | Peng Chen Chen Chen Mingdao Hu Rui Cui Feng Liu Henghai Yu Yuling Ren S‐allyl‐L‐cysteine protects hepatocytes from indomethacin‐induced apoptosis by attenuating endoplasmic reticulum stress FEBS Open Bio apoptosis endoplasmic reticulum stress hepatocyte indomethacin S‐allyl‐l‐cysteine |
| title | S‐allyl‐L‐cysteine protects hepatocytes from indomethacin‐induced apoptosis by attenuating endoplasmic reticulum stress |
| title_full | S‐allyl‐L‐cysteine protects hepatocytes from indomethacin‐induced apoptosis by attenuating endoplasmic reticulum stress |
| title_fullStr | S‐allyl‐L‐cysteine protects hepatocytes from indomethacin‐induced apoptosis by attenuating endoplasmic reticulum stress |
| title_full_unstemmed | S‐allyl‐L‐cysteine protects hepatocytes from indomethacin‐induced apoptosis by attenuating endoplasmic reticulum stress |
| title_short | S‐allyl‐L‐cysteine protects hepatocytes from indomethacin‐induced apoptosis by attenuating endoplasmic reticulum stress |
| title_sort | s allyl l cysteine protects hepatocytes from indomethacin induced apoptosis by attenuating endoplasmic reticulum stress |
| topic | apoptosis endoplasmic reticulum stress hepatocyte indomethacin S‐allyl‐l‐cysteine |
| url | https://doi.org/10.1002/2211-5463.12945 |
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