Ethyl Acetate Extract of <i>Cichorium glandulosum</i> Activates the P21/Nrf2/HO-1 Pathway to Alleviate Oxidative Stress in a Mouse Model of Alcoholic Liver Disease
Background: Alcoholic liver disease (ALD) is a significant global health concern, primarily resulting from chronic alcohol consumption, with oxidative stress as a key driver. The ethyl acetate extract of <i>Cichorium glandulosum</i> (CGE) exhibits antioxidant and hepatoprotective propert...
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| author | Shuwen Qi Chunzi Zhang Junlin Yan Xiaoyan Ma Yewei Zhong Wenhui Hou Juan Zhang Tuxia Pang Xiaoli Ma |
| author_facet | Shuwen Qi Chunzi Zhang Junlin Yan Xiaoyan Ma Yewei Zhong Wenhui Hou Juan Zhang Tuxia Pang Xiaoli Ma |
| author_sort | Shuwen Qi |
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| description | Background: Alcoholic liver disease (ALD) is a significant global health concern, primarily resulting from chronic alcohol consumption, with oxidative stress as a key driver. The ethyl acetate extract of <i>Cichorium glandulosum</i> (CGE) exhibits antioxidant and hepatoprotective properties, but its detailed mechanism of action against ALD remains unclear. This study investigates the effects and mechanisms of CGE in alleviating alcohol-induced oxidative stress and liver injury. Methods: Ultra-Performance Liquid Chromatography coupled with Quadrupole-Orbitrap Mass Spectrometry (UPLC-Q-Orbitrap-MS) was used to identify CGE components. A C57BL/6J mouse model of ALD was established via daily oral ethanol (56%) for six weeks, with CGE treatment at low (100 mg/kg) and high doses (200 mg/kg). Silibinin (100 mg/kg) served as a positive control. Liver function markers, oxidative stress indicators, and inflammatory markers were assessed. Transcriptomic and network pharmacology analyses identified key genes and pathways, validated by reverse transcription quantitative polymerase chain reaction (RT-qPCR) and Western blotting. Results: UPLC-Q-Orbitrap-MS identified 81 CGE compounds, mainly including terpenoids, flavonoids, and phenylpropanoids. CGE significantly ameliorated liver injury by reducing alanine aminotransferase (ALT), aspartate aminotransferase (AST), and alkaline phosphatase (ALP) levels and enhancing antioxidative markers such as total antioxidant capacity (T-AOC) and total superoxide dismutase (T-SOD) while lowering hepatic malondialdehyde (MDA) levels. Inflammation was mitigated through reduced levels of Tumor Necrosis Factor Alpha (TNF-α), Interleukin-1 Beta (IL-1β), and C-X-C Motif Chemokine Ligand 10 (CXCL-10). Transcriptomic and network pharmacology analysis revealed seven key antioxidant-related genes, including <i>HMOX1</i>, <i>RSAD2</i>, <i>BCL6</i>, <i>CDKN1A</i>, <i>THBD</i>, <i>SLC2A4</i>, and <i>TGFβ3</i>, validated by RT-qPCR. CGE activated the P21/Nuclear Factor Erythroid 2-Related Factor 2 (Nrf2)/Heme Oxygenase-1 (HO-1) signaling axis, increasing P21, Nrf2, and HO-1 protein levels while suppressing Kelch-like ECH-associated Protein 1 (Keap1) expression. Conclusions: CGE mitigates oxidative stress and liver injury by activating the P21/Nrf2/HO-1 pathway and regulating antioxidant genes. Its hepatoprotective effects and multi-target mechanisms highlight CGE’s potential as a promising therapeutic candidate for ALD treatment. |
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| spelling | doaj-art-ed2b1481a6c847449c562c26024889112025-01-24T13:41:16ZengMDPI AGMetabolites2218-19892025-01-011514110.3390/metabo15010041Ethyl Acetate Extract of <i>Cichorium glandulosum</i> Activates the P21/Nrf2/HO-1 Pathway to Alleviate Oxidative Stress in a Mouse Model of Alcoholic Liver DiseaseShuwen Qi0Chunzi Zhang1Junlin Yan2Xiaoyan Ma3Yewei Zhong4Wenhui Hou5Juan Zhang6Tuxia Pang7Xiaoli Ma8College of Pharmacy, Xinjiang Medical University, Urumqi 830011, ChinaCollege of Pharmacy, Xinjiang Medical University, Urumqi 830011, ChinaCollege of Pharmacy, Xinjiang Medical University, Urumqi 830011, ChinaCollege of Pharmacy, Xinjiang Medical University, Urumqi 830011, ChinaCollege of Pharmacy, Xinjiang Medical University, Urumqi 830011, ChinaCollege of Pharmacy, Xinjiang Medical University, Urumqi 830011, ChinaCollege of Pharmacy, Xinjiang Medical University, Urumqi 830011, ChinaCollege of Pharmacy, Xinjiang Medical University, Urumqi 830011, ChinaCollege of Pharmacy, Xinjiang Medical University, Urumqi 830011, ChinaBackground: Alcoholic liver disease (ALD) is a significant global health concern, primarily resulting from chronic alcohol consumption, with oxidative stress as a key driver. The ethyl acetate extract of <i>Cichorium glandulosum</i> (CGE) exhibits antioxidant and hepatoprotective properties, but its detailed mechanism of action against ALD remains unclear. This study investigates the effects and mechanisms of CGE in alleviating alcohol-induced oxidative stress and liver injury. Methods: Ultra-Performance Liquid Chromatography coupled with Quadrupole-Orbitrap Mass Spectrometry (UPLC-Q-Orbitrap-MS) was used to identify CGE components. A C57BL/6J mouse model of ALD was established via daily oral ethanol (56%) for six weeks, with CGE treatment at low (100 mg/kg) and high doses (200 mg/kg). Silibinin (100 mg/kg) served as a positive control. Liver function markers, oxidative stress indicators, and inflammatory markers were assessed. Transcriptomic and network pharmacology analyses identified key genes and pathways, validated by reverse transcription quantitative polymerase chain reaction (RT-qPCR) and Western blotting. Results: UPLC-Q-Orbitrap-MS identified 81 CGE compounds, mainly including terpenoids, flavonoids, and phenylpropanoids. CGE significantly ameliorated liver injury by reducing alanine aminotransferase (ALT), aspartate aminotransferase (AST), and alkaline phosphatase (ALP) levels and enhancing antioxidative markers such as total antioxidant capacity (T-AOC) and total superoxide dismutase (T-SOD) while lowering hepatic malondialdehyde (MDA) levels. Inflammation was mitigated through reduced levels of Tumor Necrosis Factor Alpha (TNF-α), Interleukin-1 Beta (IL-1β), and C-X-C Motif Chemokine Ligand 10 (CXCL-10). Transcriptomic and network pharmacology analysis revealed seven key antioxidant-related genes, including <i>HMOX1</i>, <i>RSAD2</i>, <i>BCL6</i>, <i>CDKN1A</i>, <i>THBD</i>, <i>SLC2A4</i>, and <i>TGFβ3</i>, validated by RT-qPCR. CGE activated the P21/Nuclear Factor Erythroid 2-Related Factor 2 (Nrf2)/Heme Oxygenase-1 (HO-1) signaling axis, increasing P21, Nrf2, and HO-1 protein levels while suppressing Kelch-like ECH-associated Protein 1 (Keap1) expression. Conclusions: CGE mitigates oxidative stress and liver injury by activating the P21/Nrf2/HO-1 pathway and regulating antioxidant genes. Its hepatoprotective effects and multi-target mechanisms highlight CGE’s potential as a promising therapeutic candidate for ALD treatment.https://www.mdpi.com/2218-1989/15/1/41<i>Cichorium glandulosum</i>alcoholic liver diseaseoxidative stresstranscriptomicsnetwork pharmacology |
| spellingShingle | Shuwen Qi Chunzi Zhang Junlin Yan Xiaoyan Ma Yewei Zhong Wenhui Hou Juan Zhang Tuxia Pang Xiaoli Ma Ethyl Acetate Extract of <i>Cichorium glandulosum</i> Activates the P21/Nrf2/HO-1 Pathway to Alleviate Oxidative Stress in a Mouse Model of Alcoholic Liver Disease Metabolites <i>Cichorium glandulosum</i> alcoholic liver disease oxidative stress transcriptomics network pharmacology |
| title | Ethyl Acetate Extract of <i>Cichorium glandulosum</i> Activates the P21/Nrf2/HO-1 Pathway to Alleviate Oxidative Stress in a Mouse Model of Alcoholic Liver Disease |
| title_full | Ethyl Acetate Extract of <i>Cichorium glandulosum</i> Activates the P21/Nrf2/HO-1 Pathway to Alleviate Oxidative Stress in a Mouse Model of Alcoholic Liver Disease |
| title_fullStr | Ethyl Acetate Extract of <i>Cichorium glandulosum</i> Activates the P21/Nrf2/HO-1 Pathway to Alleviate Oxidative Stress in a Mouse Model of Alcoholic Liver Disease |
| title_full_unstemmed | Ethyl Acetate Extract of <i>Cichorium glandulosum</i> Activates the P21/Nrf2/HO-1 Pathway to Alleviate Oxidative Stress in a Mouse Model of Alcoholic Liver Disease |
| title_short | Ethyl Acetate Extract of <i>Cichorium glandulosum</i> Activates the P21/Nrf2/HO-1 Pathway to Alleviate Oxidative Stress in a Mouse Model of Alcoholic Liver Disease |
| title_sort | ethyl acetate extract of i cichorium glandulosum i activates the p21 nrf2 ho 1 pathway to alleviate oxidative stress in a mouse model of alcoholic liver disease |
| topic | <i>Cichorium glandulosum</i> alcoholic liver disease oxidative stress transcriptomics network pharmacology |
| url | https://www.mdpi.com/2218-1989/15/1/41 |
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