FITOTERAPIA
·
2024
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IF 2.5
Yungang Tian,Jingjing Fan,Rongshen Wang,Rui Ding,Chunxue Zhao,Jia Xu,Qingyun Zhang,Tiegui Nan,Xianchan Li,Min Ye
Five previously undescribed protopanaxatriol-type saponins, notoginsenosides Ta-Te ( 1 – 5 ), together with eighteen known triterpenoid saponins ( 6 – 23 ) were isolated from the roots of Panax notoginseng . The structures of new compounds were determined by HRESIMS and NMR spectroscopic analyses and chemical methods. Compounds 1 and 2 were the first examples of ginsenosides featuring a 6-deoxy- β - d -glucose moiety from Panax species. Compounds 1 – 4 , 7 , 10 , 12 , 21 – 22 showed protective effects on L02 cells against the injury of acetaminophen (APAP). Among them, notoginsenoside R1 ( 12 ), ginsenoside Rg1 ( 21 ), and ginsenoside Re ( 22 ) were the most potent ones, with cell viabilities >80%. Moreover, compounds 12 and 22 remarkably alleviated APAP-induced liver injury in mice. These saponins are potential hepatoprotective agents.
研究领域:
药理学
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肝病学
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天然产物化学
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产品关联
DOI
PubMed
高影响因子
Journal of Immunology Research
·
2023
·
IF 4.1
Hui Du,Shiwen Tong,Ge Kuang,Xia Gong,Ningman Jiang,Xian Yang,Hao Liu,Nana Li,Yao Xie,Yang Xiang,Jiashi Guo,Zhenhan Li,Yinglin Yuan,Shengwang Wu,Jingyuan Wan
Acetaminophen (APAP) overdose would lead to liver toxicity and even acute liver failure in severe cases by triggering an inflammatory response and oxidative stress. Sesamin has been reported to possess anti-inflammatory and antioxidant actions in several animal disease models. In the present study, the effects and mechanisms of sesamin on APAP-induced acute liver injury (ALI) were explored. The results showed that pretreatment with sesamin significantly alleviated APAP-induced ALI, as indicated by decreased serum aminotransferase activities, hepatic pathological damages, and hepatic cellular apoptosis. But sesamin has no significant effects on the expression of cytochrome P450 2E1 (CYP2E1), APAP-cysteine adducts (APAP-CYS) production, and glutathione content in the liver of APAP-administered mice. Moreover, APAP-induced liver oxidative stress and inflammatory response also were remarkedly attenuated by sesamin, including reducing hepatic reactive oxygen species levels, promoting antioxidant generation, and inhibiting the expression of TNF-α and IL-1β, as well as decreasing inflammatory cell recruitment. Notably, sesamin inhibited serum high-mobility group box 1 (HMGB1) releases and blocked hepatic activation of Toll-like receptor 4 (TLR4)-interleukin 1 receptor-associated kinase 3-nuclear factor kappa B (NF-κB) signaling pathway in APAP-administered mice. These findings indicated that sesamin could mitigate APAP-induced ALI through suppression of oxidative stress and inflammatory response, which might be mediated by the deactivation of HMGB1/TLR4/NF-κB signaling in mice.
研究领域:
肝病学
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药理学
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免疫学
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产品关联
DOI
PubMed
高影响因子
PHYTOMEDICINE
·
2017
·
IF 3.526
Yi Kuang,Yan Lin,Kai Li,Wei Song,Shuai Ji,Xue Qiao,Qingying Zhang,Min Ye
Background Licorice and its constituents, especially licorice flavonoids have been reported to possess significant hepatoprotective activities. However, previous studies mainly focus on the extract and major compounds, and few reports are available on other licorice compounds. Purpose This work aims to evaluate the in vitro hepatoprotective activities of licorice compounds and screen active compounds, and to establish the structure–activity relationship. Methods A compound library consisting of 180 compounds from three medicinal licorice species, Glycyrrhiza uralensis , G. glabra and G. inflata was established. HepG2 cells were incubated with the compounds, together with the treatment of 0.35% CCl 4 for 6 h and 14 mM APAP for 24 h, respectively. Results A total of 62 compounds at 10 µM showed protective effects against CCl 4 to improve cell viability from 52.5% to >60%, and compounds 5 (licoflavone A), 104 (3,4-didehydroglabridin), 107 (isoliquiritigenin), 108 (3,4,3′,4′-tetrahydroxychalcone), and 111 (licochalcone B) showed the most potent activities, improving cell viability to >80%. And 64 compounds showed protective effects against APAP to improve cell viability from 52.0% to >60%, and compounds 47 (derrone), 76 (xambioona), 77 ((2S)-abyssinone I), 107 (isoliquiritigenin), 118 (licoagrochalcone A), and 144 (2′- O -demethybidwillol B) showed the most potent activities, improving cell viability to >80%. Preliminary structure–activity analysis indicated that free phenolics compounds especially chalcones showed relatively stronger protective activities than other types of compounds. Conclusion Compounds 5, 76, 104, 107, 111, 118 and 144 possess potent activities against both CCl 4 and APAP, and 5, 76 and 118 were reported for the first time. They could be the major active compounds of licorice for the treatment of liver injury.
研究领域:
药理学
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细胞生物学
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产品关联
DOI
PubMed
高影响因子
INTERNATIONAL IMMUNOPHARMACOLOGY
·
2025
·
IF 4.7
Lei Sun,Ziming Wu,Zhiwei Huang,Han Li,Pengru Wang,Jiatong Chen,Boyuan Gu,Shenglu Liu,Yu Jiang,Xiaolin Zhong,Yichao Du,Wenguang Fu
Background and Purpose Acetaminophen (APAP) overdose is a major cause of acute liver failure. TBXAS1, driving inflammation via processes like inflammatory cell aggregation, vasoconstriction, and thrombosis, was picked out as a crucial inflammatory regulator that catalyzes thromboxane A2 generation. This study was conducted to explore whether Daidzein (DAI), a bioactive compound, has hepatoprotective effects against APAP-induced liver injury by acting on TBXAS1. Methods and Results In vitro and in vivo experiments revealed that hepatic TBXAS1 levels increased following APAP induction. SiRNA-mediated TBXAS1 knockdown reduced APAP-induced inflammation and cytotoxicity. Network pharmacology and transcriptomic analysis identified TBXAS1 as a potential DAI target. In vivo, DAI pretreatment mitigated APAP-induced liver injury in mice and lowered TBXAS1 levels. In vitro, DAI pretreatment followed by APAP exposure in AML-12 cells resulted in reduced TBXAS1 expression and decreased inflammation, oxidative stress, and apoptosis. Mechanistic analysis showed that DAI regulates TBXAS1 expression both in vitro and in vivo. Specifically, DAI modulates the TLR4/NF-κB pathway by altering TXA2 levels mediated by TBXAS1, thereby protecting against APAP-induced injury. Conclusion TBXAS1 is identified as a novel target of DAI. By modulating TBXAS1, DAI can reduce APAP-induced liver damage, including hepatocyte injury, oxidative stress, apoptosis, and inflammation. This study provides a new therapeutic approach for managing APAP-induced liver damage.
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产品关联
DOI
PubMed
高影响因子
PHYTOMEDICINE
·
2026
·
IF 11.3
Ludong Tan,Xiaodong Bai,Peiyuan Yu,Tinghan Jiang,Zhe Jin
Artemisia capillaris extract alleviates acetaminophen-induced liver injury by inhibiting ferroptosis. • Capillarisin is identified as the primary bioactive constituent responsible for the hepatoprotection. • Capillarisin directly binds to and inhibits Glycogen Synthase Kinase 3β (GSK3β). • Inhibition of GSK3β by Capillarisin activates the Nrf2-mediated anti-ferroptotic pathway. • This study reveals a novel molecular mechanism for a traditional hepatoprotective herb. Background Acetaminophen (APAP) overdose is a leading cause of acute liver failure worldwide, characterized by oxidative stress-driven hepatocyte necrosis. Recent evidence implicates ferroptosis, an iron-dependent cell death, as a critical pathogenic event. Artemisia capillaris Thunb. (ACE) is a traditional hepatoprotective herb; however, its bioactive constituents and molecular targets regulating ferroptosis remain elusive. Purpose This study aimed to identify the bioactive compounds of ACE and elucidate the molecular mechanism underlying its protective effect against APAP-induced hepatotoxicity, with a specific focus on the ferroptosis pathway. Methods We integrated multi-omics, network pharmacology, and rigorous biophysical assays to decipher the protective mechanism. The ethanol extract of A. capillaris was chemically characterized using UPLC-LTQ-Orbitrap MS. An APAP-induced acute liver injury model in C57BL/6 mice and primary mouse hepatocytes were employed. Transcriptomics (RNA-seq) was utilized to identify key signaling pathways. The direct physical interaction between the active compound and its target was validated using Microscale Thermophoresis (MST), Cellular Thermal Shift Assay (CETSA), Drug Affinity Responsive Target Stability (DARTS), and molecular dynamics (MD) simulations. Functional validation was performed using gene overexpression and specific inhibitors. Results ACE pretreatment significantly attenuated APAP-induced liver injury, inflammation, and oxidative stress in mice. Transcriptomic profiling identified ferroptosis as a primary target pathway. Through chemical screening, we identified Capillarisin as the key bioactive coumarin responsible for this effect. Capillarisin treatment effectively suppressed lipid peroxidation, iron overload, and the expression of ferroptotic markers (COX2, ACSL4) while restoring GPX4 levels both in vivo and in vitro . Mechanistically, we demonstrated that Capillarisin acts as a direct inhibitor of Glycogen Synthase Kinase 3β (GSK3β). Capillarisin binds stably to the ATP-binding pocket of GSK3β ( K d = 0.87 µM), thereby inhibiting its kinase activity. This inhibition blocks the phosphorylation-dependent degradation of Nrf2, promoting its nuclear translocation and the subsequent transcriptional activation of anti-ferroptotic genes ( Gpx4, Slc7a11 ). Overexpression of GSK3β or pharmacological inhibition of Nrf2 abolished the protective effects of Capillarisin. Conclusion Our study reveals a novel mechanism whereby Capillarisin alleviates APAP-induced hepatotoxicity by directly targeting GSK3β to activate the Nrf2-mediated anti-ferroptosis defense. These findings provide a rigorous scientific basis for the ethnopharmacological use of Artemisia capillaris and highlight Capillarisin as a promising lead candidate for targeting GSK3β in the treatment of drug-induced liver injury. Download: Download high-res image (228KB) Download: Download full-size image
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产品关联
DOI
PubMed
高影响因子
SPECTROCHIMICA ACTA PART A-MOLECULAR AND BIOMOLECULAR SPECTROSCOPY
·
2024
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IF 4.3
Tianfeng Ma,Yanyan Jia,Lin Shi,Xiaohua Xu,Kun Zheng,Zijia Fu,Huan Wang,Yongchang Lu
Acetaminophen, also known as paracetamol (APAP), is a commonly used over-the-counter medication that is often used to treat headaches, toothaches, joint pain, muscle pain, and to lower body temperature. However, overdose can lead to liver damage, gastrointestinal distress, kidney damage, and cardiovascular disease. Therefore, it is very important to establish a method to quickly detect APAP. A novel “ON-OFF-ON” colorimetric and fluorescence dual-signal sensing system was constructed for the quantitative detection of APAP based on 5,10,15,20-tetrakis(4-sulphonatophenyl) porphyrin (TSPP) dual-signal probe. The absorbance and fluorescence intensity of TSPP respectively were quenched when Fe 3+ was introduced into TSPP solution. At this point, the color of the corresponding solution changed from red to green. The absorbance and fluorescence intensity of TSPP respectively were restored when APAP was added to the TSPP-Fe 3+ system. At this time, the color of the solution changed from green to colorless. Therefore, an “ON-OFF-ON” dual-signal sensing study of APAP were constructed using TSPP as the colorimetric and fluorescent probe. The proposed colorimetric sensing system had a wide linear range in the 13.12 mM ∼ 23.20 mM with 0.11 mM of limit of detection (LOD, S/N = 3). And the proposed fluorescence sensing system had a wide linear range in the 3.45 mM ∼ 12.50 mM and 41.67 mM ∼ 65.22 mM with 0.83 mM of limit of detection (LOD, S/N = 3). The dual-signal sensing system were applied to the APAP detection of real samples.
研究领域:
分析化学
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药物分析
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生物医学
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产品关联
DOI
PubMed
高影响因子
CHEMICO-BIOLOGICAL INTERACTIONS
·
2025
·
IF 5.4
Lin-Song Teng,Zhen-Dong Ying,Xiao-Han Sun,Hao-Cheng Hou,Shi-Dong Qiu,Peng Liu,Ke-Jing Li,Lei Zhang,Xie-Huang Sheng
Ferroptosis is an iron-dependent form of regulated cell death characterized by lethal lipid peroxidation and implicated in various human diseases. Despite intensive research, clinically applicable ferroptosis inhibitors remain unavailable. In this study, we identify formoterol, a β 2 -adrenergic agonist widely used to treat asthma and COPD, as a potent and selective ferroptosis inhibitor through scaffold-based screening of FDA-approved drugs. Formoterol confers robust protection against ferroptotic cell death induced by diverse triggers across multiple human and rodent cell lines, functioning independently of classical pathways such as GPX4, FSP1, or iron chelation. Mechanistic studies reveal that formoterol suppresses ferroptosis by directly scavenging lipid peroxyl radicals, mediated by its unique ortho -amino phenol moiety. In vivo, formoterol significantly alleviates acetaminophen-induced acute liver injury, reducing hepatic lipid peroxidation and preserving tissue integrity. These findings establish formoterol as a clinically approved agent with previously unrecognized anti-ferroptotic activity, offering a compelling example of drug repurposing to accelerate the development of ferroptosis-targeted therapies.
研究领域:
药理学
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细胞生物学
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肝脏病学
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药物化学
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药物研发
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产品关联
DOI
PubMed
高影响因子
EXPERIMENTAL BIOLOGY AND MEDICINE
·
2023
·
IF 3.2
Jinhong Tian,Shuaishuai Zhang,Lu Li,Xueman Lin,Yongmei Li,Kunlu Zhao,Fengxin Zheng,Yongjun Chen,Yang Yang,Ting Wu,Jianxin Pang
Excessive acetaminophen (APAP) application is a major cause of drug-induced liver injury (DILI). Febuxostat (Feb), a drug for reducing uric acid (UA) levels, was demonstrated to relieve hepatic inflammation and reverse organ functions. However, the effect of Feb on APAP-induced DILI and its mechanisms have not been fully explored. In this study, Feb (10 mg/kg) was given to mice by gavage 1 h after APAP (300 mg/kg, i.g.) induction. Serum and liver samples were collected 12 or 3 h after APAP challenge. Feb treatment was found to remarkably improve APAP-induced DILI, as evidenced by reduced serum ALT, AST and UA levels, pathomorphology, inflammatory, and oxidative responses. Consistently, treatment with Feb also reduced the cell injury induced by APAP in LO2 cells. Mechanistically, Feb induced GPX4 expression, activated the Keap1/Nrf2 pathway, and inhibited the TLR4/NF-κB p65 pathway. Feb also inhibited glutathione (GSH) depletion and Jun N-terminal kinase (JNK) activation in the early injury phase. Notably, pretreatment with Feb for 3 days also revealed preventive effects against APAP-induced DILI in mice. Overall, our data revealed a potential health impact of Feb on APAP-mediated DILI in vivo and in vitro, suggesting that Feb might be a potential candidate for treating DILI.
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DOI
PubMed
高影响因子
ANALYTICAL CHEMISTRY
·
2026
·
IF 7.3
Zizhe An,Lexin Chen,Changkai Bu,Deling Shi,Bin Zhang,Lan Jin,Lianli Chi
Heparan sulfate (HS), one of the mostly negatively charged biomacromolecules anchored on the membrane surface of nearly all mammal cells, plays critical regulatory roles through interacting with a variety of proteins. However, there is still no method capable to directly sequence the domain alterations of HS in pathological states. In the current study, the pathological alterations of HS were elucidated for the first time in APAP-induced acute liver injury by a deep learning-driven chemical derivatization-tandem mass spectrometry strategy, and the sequence changes up to octasaccharides within the bioactive domain “GlcA-GlcNS6S” were successfully decoded. GAG-Explorer, a software incorporated with a comprehensive deep learning model capable of predicting the fragmentation patterns of HS oligomers under actual MS/MS condition was developed to facilitate large-scale sequencing of natural HS structures. The HS alterations in the sequence aspect were elucidated thoroughly in APAP-induced acute liver injury, rather than their compositional changes, which is of great significance for the applications of HS-based therapeutic agents in the biomedical field.
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DOI
PubMed
高影响因子
Cell Death & Disease
·
2018
·Vol. 9
·期 5
·1-12
·
IF 5.638
Sun Jiahong,Wen Yajie,Zhou Yanying,Jiang Yiming,Chen Yixin,Zhang Huizheng,Guan Lihuan,Yao Xinpeng,Huang Min,Bi Huichang
Acetaminophen (APAP) overdose is the most frequent cause of drug-induced acute liver failure. Inhibition of APAP metabolic activation and promotion in APAP disposition are important to protect against APAP-induced liver injury. Tumor suppressor p53 is traditionally recognized as a surveillance molecule to preserve genome integrity. Recent studies have emerged on discovering its functions in metabolic regulation. Our previous study reported that p53 promoted bile acid disposition and alleviated cholestastic syndrome. Here, we examined the effect of doxorubicin (Dox)-mediated p53 activation on APAP-induced hepatotoxicity in mice and revealed a novel role of p53 in regulating APAP metabolism and disposition. Histopathological and biochemical assessments demonstrated that administration of Dox (10 mg/kg/d) before APAP treatment (400 mg/kg) significantly alleviated APAP-induced hepatotoxicity. Dox treatment prevented APAP-induced GSH depletion and lipid peroxidation. p53-null mice were more susceptible to APAP-induced liver injury. Further, we found that the expression of drug-metabolizing enzymes and transporters CYPs, SULTs and MRPs was regulated by p53. Dox treatment also promoted Nrf2 activation and increased the expression of Nrf2 target genes including GSTα/μ and NQO1, which contribute to APAP detoxification. Overall, this study is the first to demonstrate the protective role of p53 in regulating APAP metabolism and disposition, which provides a potential new therapeutic target for APAP-induced liver injury.
研究领域:
药理学
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毒理学
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分子生物学
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肝病学
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DOI
PubMed
高影响因子
EUROPEAN JOURNAL OF PHARMACOLOGY
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2026
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IF 5.7
Pingting Wu,Weilai Chen,Jie Li,Jiayi Xing,Haote Wu,Jingyang Tong,Ping Chen,Haibin Tong,Yongping Chen,Chenwei Pan
Acetaminophen (APAP) overdose causes acute liver injury (ALI) by triggering regulated hepatocyte death. While Imperata cylindrica (Imperatae Rhizoma) (IR) is used in traditional medicine for its hepatoprotective effects, its active compounds and their capacity to modulate this pyroptotic switch remain unknown. In the present study, friedelin (FRI) and 6-methoxyflavone (6-METH) were identified as the principal active compounds of IR, and their protective effects against APAP-induced ALI were evaluated in vivo and in vitro. The results showed that both FRI and 6-METH significantly ameliorated APAP-induced liver injury and reduced hepatocyte death. Mechanistically, their hepatoprotective effects were associated with AKT1-dependent activation of the PI3K/AKT pathway, accompanied by suppression of Caspase-3/ Gasdermin E (GSDME) signaling and attenuation of apoptosis and pyroptosis. Moreover, pharmacological inhibition or genetic silencing of AKT1 markedly weakened these protective effects. Taken together, these findings suggest that FRI and 6-METH are major hepatoprotective constituents of IR and that modulation of the AKT1-mediated Caspase-3/GSDME pathway may contribute to their protective actions against APAP-induced ALI. These findings validate its active compounds as promising therapeutic leads for ALI.
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DOI
PubMed
高影响因子
JOURNAL OF FOOD BIOCHEMISTRY
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2020
·Vol. 44
·期 10
·e13420
·
IF 1.662
Cheng Hu,Ying Chen,Yiyuan Cao,Yiqun Jia,Jiaqi Zhang
We investigated the protective effect of Hyperoside (HPS) on liver injury induced by acetaminophen (APAP) in C57 mice. HPS was administered orally for 7 days and APAP was administered orally on the 7th day. Serum and liver samples were then collected for biochemical analyses, histopathology assessments, and metabolomics studies. Metabolites were assessed using a UHPLC-MS system. Principal component analysis (PCA) and orthogonal partial least squares discriminant analysis (OPLS-DA) were used to process the data. Pathway analyses were performed using Metaboanalyst 4.0. Western blot and qRT-PCR were used to determine the protein and mRNA levels, respectively. HPS interacted with active sites in CYP2E1 and caused protein degradation. In conclusion, our results suggested that HPS prevented the oxidative stress-induced liver injury caused by APAP. Practical applications Hyperoside was shown to have potential protective and therapeutic effects against liver diseases. Male C57 mice were used to perform pharmacodynamic, pharmacology, and metabolomics evaluations. At a dose of 60 mg/kg, HPS prevented oxidative stress-induced liver injury caused by APAP by regulating the glutathione-related metabolites and enzymes through the inhibition of CYP2E1.
研究领域:
药理学
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代谢组学
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毒理学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
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