Modulation of HMGB1 Release in APAP-Induced Liver Injury: A Possible Strategy of Chikusetsusaponin V Targeting NETs Formation
Acetaminophen (APAP), one of the most common antipyretic analgesics, which is safe at therapeutic dose, cause acute liver injury and even death at overdose. However, the mechanism of APAP-induced inflammation in liver injury is still controversial. Therefore, effective drug intervention is urgently...
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Frontiers Media S.A.
2021-07-01
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| Series: | Frontiers in Pharmacology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fphar.2021.723881/full |
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| author | Jian Liu Jian Liu Jian Liu Min Jiang Min Jiang Min Jiang Quan Jin Quan Jin Quan Jin Yan-Ling Wu Yan-Ling Wu Yan-Ling Wu Zhen-Yu Cui Zhen-Yu Cui Zhen-Yu Cui Ben-Wen Cui Ben-Wen Cui Ben-Wen Cui Yue Shang Yue Shang Yue Shang Zi-Ying Zhan Zi-Ying Zhan Zi-Ying Zhan Yong-Ce Lin Yong-Ce Lin Yong-Ce Lin Jing-Ya Jiao Jing-Ya Jiao Jing-Ya Jiao Mei-Hua Piao Mei-Hua Piao Mei-Hua Piao Zhi-Hong Zhang Zhi-Hong Zhang Zhi-Hong Zhang Rong-Hui Sun Rong-Hui Sun Rong-Hui Sun Ji-Xing Nan Ji-Xing Nan Ji-Xing Nan Ji-Xing Nan Li-Hua Lian Li-Hua Lian Li-Hua Lian |
| author_facet | Jian Liu Jian Liu Jian Liu Min Jiang Min Jiang Min Jiang Quan Jin Quan Jin Quan Jin Yan-Ling Wu Yan-Ling Wu Yan-Ling Wu Zhen-Yu Cui Zhen-Yu Cui Zhen-Yu Cui Ben-Wen Cui Ben-Wen Cui Ben-Wen Cui Yue Shang Yue Shang Yue Shang Zi-Ying Zhan Zi-Ying Zhan Zi-Ying Zhan Yong-Ce Lin Yong-Ce Lin Yong-Ce Lin Jing-Ya Jiao Jing-Ya Jiao Jing-Ya Jiao Mei-Hua Piao Mei-Hua Piao Mei-Hua Piao Zhi-Hong Zhang Zhi-Hong Zhang Zhi-Hong Zhang Rong-Hui Sun Rong-Hui Sun Rong-Hui Sun Ji-Xing Nan Ji-Xing Nan Ji-Xing Nan Ji-Xing Nan Li-Hua Lian Li-Hua Lian Li-Hua Lian |
| author_sort | Jian Liu |
| collection | DOAJ |
| description | Acetaminophen (APAP), one of the most common antipyretic analgesics, which is safe at therapeutic dose, cause acute liver injury and even death at overdose. However, the mechanism of APAP-induced inflammation in liver injury is still controversial. Therefore, effective drug intervention is urgently needed. The aim of this study was to explore the inflammatory exact mechanism of APAP, especially on neutrophils, and to study the intervention effect of Chikusetsusaponin V (CKV) derived from Panax japonicus. Establishment of hepatotoxicity model of APAP in vitro and in vivo. In vitro, HepG2 cells, AML12 cells, primary mouse hepatocytes and neutrophils were used to mimic APAP-affected hepatocytes and neutrophil. In vivo, C57BL/6 mice were administrated overdose of APAP with or without neutrophil depletion or abolishing neutrophil extracellular traps (NETs) formation. In this study, APAP stimulation increased the level of HMGB1, IL-1β and Caspase-1 in mouse liver, especially hepatocytes, which had a synergistic effect with LPS/ATP combination. NETs were formatted at early stage of APAP or HMGB1-stimulated neutrophils’ damage. Conditioned mediums from APAP-treated hepatocytes induced more significant NETs than direct APAP stimulation. Neutrophil depletion or abolishing NETs formation decreased HMGB1 level, eventually blocked hepatocytes necrosis. CKV pretreatment interfered Caspase-1 activation and HMGB1 release in APAP-damaged hepatocytes. CKV also prevented NETs formation. These results indicate that the production of HMGB1 may depend on the activation of Caspase-1 and play a key role in liver inflammation caused by APAP. The cross-dialogue between hepatocytes and neutrophils can be mediated by HMGB1. Therefore, CKV has a positive intervention effect on NETs-related inflammation in APAP-damaged liver, targeting Caspase-1-HMGB1. |
| first_indexed | 2024-12-18T01:56:07Z |
| format | Article |
| id | doaj.art-f71fc6310cc24e7bb0bcc1e4bf999dd0 |
| institution | Directory Open Access Journal |
| issn | 1663-9812 |
| language | English |
| last_indexed | 2024-12-18T01:56:07Z |
| publishDate | 2021-07-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Pharmacology |
| spelling | doaj.art-f71fc6310cc24e7bb0bcc1e4bf999dd02022-12-21T21:24:54ZengFrontiers Media S.A.Frontiers in Pharmacology1663-98122021-07-011210.3389/fphar.2021.723881723881Modulation of HMGB1 Release in APAP-Induced Liver Injury: A Possible Strategy of Chikusetsusaponin V Targeting NETs FormationJian Liu0Jian Liu1Jian Liu2Min Jiang3Min Jiang4Min Jiang5Quan Jin6Quan Jin7Quan Jin8Yan-Ling Wu9Yan-Ling Wu10Yan-Ling Wu11Zhen-Yu Cui12Zhen-Yu Cui13Zhen-Yu Cui14Ben-Wen Cui15Ben-Wen Cui16Ben-Wen Cui17Yue Shang18Yue Shang19Yue Shang20Zi-Ying Zhan21Zi-Ying Zhan22Zi-Ying Zhan23Yong-Ce Lin24Yong-Ce Lin25Yong-Ce Lin26Jing-Ya Jiao27Jing-Ya Jiao28Jing-Ya Jiao29Mei-Hua Piao30Mei-Hua Piao31Mei-Hua Piao32Zhi-Hong Zhang33Zhi-Hong Zhang34Zhi-Hong Zhang35Rong-Hui Sun36Rong-Hui Sun37Rong-Hui Sun38Ji-Xing Nan39Ji-Xing Nan40Ji-Xing Nan41Ji-Xing Nan42Li-Hua Lian43Li-Hua Lian44Li-Hua Lian45Key Laboratory of Traditional Chinese Korean Medicine Research (Yanbian University), State Ethnic Affairs Commission, Yanji, ChinaKey Laboratory of Natural Medicines of the Changbai Mountain, Ministry of Education, College of Pharmacy, Yanbian University, Yanji, ChinaKey Laboratory for Traditional Chinese Korean Medicine of Jilin Province, College of Pharmacy, Yanbian University, Yanji, ChinaKey Laboratory of Traditional Chinese Korean Medicine Research (Yanbian University), State Ethnic Affairs Commission, Yanji, ChinaKey Laboratory of Natural Medicines of the Changbai Mountain, Ministry of Education, College of Pharmacy, Yanbian University, Yanji, ChinaKey Laboratory for Traditional Chinese Korean Medicine of Jilin Province, College of Pharmacy, Yanbian University, Yanji, ChinaKey Laboratory of Traditional Chinese Korean Medicine Research (Yanbian University), State Ethnic Affairs Commission, Yanji, ChinaKey Laboratory of Natural Medicines of the Changbai Mountain, Ministry of Education, College of Pharmacy, Yanbian University, Yanji, ChinaKey Laboratory for Traditional Chinese Korean Medicine of Jilin Province, College of Pharmacy, Yanbian University, Yanji, ChinaKey Laboratory of Traditional Chinese Korean Medicine Research (Yanbian University), State Ethnic Affairs Commission, Yanji, ChinaKey Laboratory of Natural Medicines of the Changbai Mountain, Ministry of Education, College of Pharmacy, Yanbian University, Yanji, ChinaKey Laboratory for Traditional Chinese Korean Medicine of Jilin Province, College of Pharmacy, Yanbian University, Yanji, ChinaKey Laboratory of Traditional Chinese Korean Medicine Research (Yanbian University), State Ethnic Affairs Commission, Yanji, ChinaKey Laboratory of Natural Medicines of the Changbai Mountain, Ministry of Education, College of Pharmacy, Yanbian University, Yanji, ChinaKey Laboratory for Traditional Chinese Korean Medicine of Jilin Province, College of Pharmacy, Yanbian University, Yanji, ChinaKey Laboratory of Traditional Chinese Korean Medicine Research (Yanbian University), State Ethnic Affairs Commission, Yanji, ChinaKey Laboratory of Natural Medicines of the Changbai Mountain, Ministry of Education, College of Pharmacy, Yanbian University, Yanji, ChinaKey Laboratory for Traditional Chinese Korean Medicine of Jilin Province, College of Pharmacy, Yanbian University, Yanji, ChinaKey Laboratory of Traditional Chinese Korean Medicine Research (Yanbian University), State Ethnic Affairs Commission, Yanji, ChinaKey Laboratory of Natural Medicines of the Changbai Mountain, Ministry of Education, College of Pharmacy, Yanbian University, Yanji, ChinaKey Laboratory for Traditional Chinese Korean Medicine of Jilin Province, College of Pharmacy, Yanbian University, Yanji, ChinaKey Laboratory of Traditional Chinese Korean Medicine Research (Yanbian University), State Ethnic Affairs Commission, Yanji, ChinaKey Laboratory of Natural Medicines of the Changbai Mountain, Ministry of Education, College of Pharmacy, Yanbian University, Yanji, ChinaKey Laboratory for Traditional Chinese Korean Medicine of Jilin Province, College of Pharmacy, Yanbian University, Yanji, ChinaKey Laboratory of Traditional Chinese Korean Medicine Research (Yanbian University), State Ethnic Affairs Commission, Yanji, ChinaKey Laboratory of Natural Medicines of the Changbai Mountain, Ministry of Education, College of Pharmacy, Yanbian University, Yanji, ChinaKey Laboratory for Traditional Chinese Korean Medicine of Jilin Province, College of Pharmacy, Yanbian University, Yanji, ChinaKey Laboratory of Traditional Chinese Korean Medicine Research (Yanbian University), State Ethnic Affairs Commission, Yanji, ChinaKey Laboratory of Natural Medicines of the Changbai Mountain, Ministry of Education, College of Pharmacy, Yanbian University, Yanji, ChinaKey Laboratory for Traditional Chinese Korean Medicine of Jilin Province, College of Pharmacy, Yanbian University, Yanji, ChinaKey Laboratory of Traditional Chinese Korean Medicine Research (Yanbian University), State Ethnic Affairs Commission, Yanji, ChinaKey Laboratory of Natural Medicines of the Changbai Mountain, Ministry of Education, College of Pharmacy, Yanbian University, Yanji, ChinaKey Laboratory for Traditional Chinese Korean Medicine of Jilin Province, College of Pharmacy, Yanbian University, Yanji, ChinaKey Laboratory of Traditional Chinese Korean Medicine Research (Yanbian University), State Ethnic Affairs Commission, Yanji, ChinaKey Laboratory of Natural Medicines of the Changbai Mountain, Ministry of Education, College of Pharmacy, Yanbian University, Yanji, ChinaKey Laboratory for Traditional Chinese Korean Medicine of Jilin Province, College of Pharmacy, Yanbian University, Yanji, ChinaKey Laboratory of Traditional Chinese Korean Medicine Research (Yanbian University), State Ethnic Affairs Commission, Yanji, ChinaKey Laboratory of Natural Medicines of the Changbai Mountain, Ministry of Education, College of Pharmacy, Yanbian University, Yanji, ChinaKey Laboratory for Traditional Chinese Korean Medicine of Jilin Province, College of Pharmacy, Yanbian University, Yanji, ChinaKey Laboratory of Traditional Chinese Korean Medicine Research (Yanbian University), State Ethnic Affairs Commission, Yanji, ChinaKey Laboratory of Natural Medicines of the Changbai Mountain, Ministry of Education, College of Pharmacy, Yanbian University, Yanji, ChinaKey Laboratory for Traditional Chinese Korean Medicine of Jilin Province, College of Pharmacy, Yanbian University, Yanji, ChinaClinical Research Centre, Yanbian University Hospital, Yanji, ChinaKey Laboratory of Traditional Chinese Korean Medicine Research (Yanbian University), State Ethnic Affairs Commission, Yanji, ChinaKey Laboratory of Natural Medicines of the Changbai Mountain, Ministry of Education, College of Pharmacy, Yanbian University, Yanji, ChinaKey Laboratory for Traditional Chinese Korean Medicine of Jilin Province, College of Pharmacy, Yanbian University, Yanji, ChinaAcetaminophen (APAP), one of the most common antipyretic analgesics, which is safe at therapeutic dose, cause acute liver injury and even death at overdose. However, the mechanism of APAP-induced inflammation in liver injury is still controversial. Therefore, effective drug intervention is urgently needed. The aim of this study was to explore the inflammatory exact mechanism of APAP, especially on neutrophils, and to study the intervention effect of Chikusetsusaponin V (CKV) derived from Panax japonicus. Establishment of hepatotoxicity model of APAP in vitro and in vivo. In vitro, HepG2 cells, AML12 cells, primary mouse hepatocytes and neutrophils were used to mimic APAP-affected hepatocytes and neutrophil. In vivo, C57BL/6 mice were administrated overdose of APAP with or without neutrophil depletion or abolishing neutrophil extracellular traps (NETs) formation. In this study, APAP stimulation increased the level of HMGB1, IL-1β and Caspase-1 in mouse liver, especially hepatocytes, which had a synergistic effect with LPS/ATP combination. NETs were formatted at early stage of APAP or HMGB1-stimulated neutrophils’ damage. Conditioned mediums from APAP-treated hepatocytes induced more significant NETs than direct APAP stimulation. Neutrophil depletion or abolishing NETs formation decreased HMGB1 level, eventually blocked hepatocytes necrosis. CKV pretreatment interfered Caspase-1 activation and HMGB1 release in APAP-damaged hepatocytes. CKV also prevented NETs formation. These results indicate that the production of HMGB1 may depend on the activation of Caspase-1 and play a key role in liver inflammation caused by APAP. The cross-dialogue between hepatocytes and neutrophils can be mediated by HMGB1. Therefore, CKV has a positive intervention effect on NETs-related inflammation in APAP-damaged liver, targeting Caspase-1-HMGB1.https://www.frontiersin.org/articles/10.3389/fphar.2021.723881/fullacetaminophendrug-induced liver injuryHMGB1neutrophil extracellular trapschikusetsusaponin V |
| spellingShingle | Jian Liu Jian Liu Jian Liu Min Jiang Min Jiang Min Jiang Quan Jin Quan Jin Quan Jin Yan-Ling Wu Yan-Ling Wu Yan-Ling Wu Zhen-Yu Cui Zhen-Yu Cui Zhen-Yu Cui Ben-Wen Cui Ben-Wen Cui Ben-Wen Cui Yue Shang Yue Shang Yue Shang Zi-Ying Zhan Zi-Ying Zhan Zi-Ying Zhan Yong-Ce Lin Yong-Ce Lin Yong-Ce Lin Jing-Ya Jiao Jing-Ya Jiao Jing-Ya Jiao Mei-Hua Piao Mei-Hua Piao Mei-Hua Piao Zhi-Hong Zhang Zhi-Hong Zhang Zhi-Hong Zhang Rong-Hui Sun Rong-Hui Sun Rong-Hui Sun Ji-Xing Nan Ji-Xing Nan Ji-Xing Nan Ji-Xing Nan Li-Hua Lian Li-Hua Lian Li-Hua Lian Modulation of HMGB1 Release in APAP-Induced Liver Injury: A Possible Strategy of Chikusetsusaponin V Targeting NETs Formation Frontiers in Pharmacology acetaminophen drug-induced liver injury HMGB1 neutrophil extracellular traps chikusetsusaponin V |
| title | Modulation of HMGB1 Release in APAP-Induced Liver Injury: A Possible Strategy of Chikusetsusaponin V Targeting NETs Formation |
| title_full | Modulation of HMGB1 Release in APAP-Induced Liver Injury: A Possible Strategy of Chikusetsusaponin V Targeting NETs Formation |
| title_fullStr | Modulation of HMGB1 Release in APAP-Induced Liver Injury: A Possible Strategy of Chikusetsusaponin V Targeting NETs Formation |
| title_full_unstemmed | Modulation of HMGB1 Release in APAP-Induced Liver Injury: A Possible Strategy of Chikusetsusaponin V Targeting NETs Formation |
| title_short | Modulation of HMGB1 Release in APAP-Induced Liver Injury: A Possible Strategy of Chikusetsusaponin V Targeting NETs Formation |
| title_sort | modulation of hmgb1 release in apap induced liver injury a possible strategy of chikusetsusaponin v targeting nets formation |
| topic | acetaminophen drug-induced liver injury HMGB1 neutrophil extracellular traps chikusetsusaponin V |
| url | https://www.frontiersin.org/articles/10.3389/fphar.2021.723881/full |
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