Ursolic acid drug-drug nanocrystals ameliorate cholestatic liver injury via inhibiting oxidative stress and regulating bile acid metabolism
IntroductionCholestatic liver injury (CLI) is a liver dysfunction closely associated with oxidative stress and bile acid (BA) metabolic disorders, but effective therapies are lacking.The use of ursolic acid (UA) and α-Tocopherol succinate (VES) together for treating CLI is promising due to their res...
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Frontiers Media S.A.
2025-05-01
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| author | Manhang Hu Xiaolu Hua Xiaolu Hua Wei Xiong Enhui Zheng Xingyue Yang Yu Lu Bing He Xiaolin Zhong Zongzhe Jiang Qingbi Zhang Qingbi Zhang Yan Liu |
| author_facet | Manhang Hu Xiaolu Hua Xiaolu Hua Wei Xiong Enhui Zheng Xingyue Yang Yu Lu Bing He Xiaolin Zhong Zongzhe Jiang Qingbi Zhang Qingbi Zhang Yan Liu |
| author_sort | Manhang Hu |
| collection | DOAJ |
| description | IntroductionCholestatic liver injury (CLI) is a liver dysfunction closely associated with oxidative stress and bile acid (BA) metabolic disorders, but effective therapies are lacking.The use of ursolic acid (UA) and α-Tocopherol succinate (VES) together for treating CLI is promising due to their respective effects on regulating bile acid metabolism and providing antioxidant activity.MethodsIn this study, we synthesized drug-drug nanocrystals (UA-NSps) composed of UA and VES to treat CLI and evaluated their synergistic therapeutic effects by regulating bile acid metabolism and inhibiting oxidative stress in ANIT-induced CLI mice.Results and discussionOur investigation demonstrated that UA-NSps exhibited high drug-loading capacity, spherical morphology, and improved dissolution and oral bioavailability. In the ANIT model, UA-NSps effectively restored liver function, as evidenced by histopathological and biochemical improvements. Mechanistically, UA-NSps enhanced Nrf2 nuclear translocation, upregulated Nrf2 and HO-1, reduced pro-inflammatory cytokines, and ameliorated mitochondrial damage. Moreover, UA-NSps alleviated the bile acid metabolism disorders by upregulating the transcriptional activity of UGT2B1, BSEP, and MRP2, as well as the protein expression of nuclear receptors and metabolic enzymes PXR,CYP3A4, and UGT1A1. Our study presents a novel drug-drug nanocrystal strategy that enhances the therapeutic efficacy against CLI by inhibiting oxidative stress and regulating bile acid metabolism. |
| format | Article |
| id | doaj-art-d1316bdc304b444e8ac7bf6594c5d4e5 |
| institution | DOAJ |
| issn | 1663-9812 |
| language | English |
| publishDate | 2025-05-01 |
| publisher | Frontiers Media S.A. |
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| series | Frontiers in Pharmacology |
| spelling | doaj-art-d1316bdc304b444e8ac7bf6594c5d4e52025-08-20T03:21:47ZengFrontiers Media S.A.Frontiers in Pharmacology1663-98122025-05-011610.3389/fphar.2025.15861411586141Ursolic acid drug-drug nanocrystals ameliorate cholestatic liver injury via inhibiting oxidative stress and regulating bile acid metabolismManhang Hu0Xiaolu Hua1Xiaolu Hua2Wei Xiong3Enhui Zheng4Xingyue Yang5Yu Lu6Bing He7Xiaolin Zhong8Zongzhe Jiang9Qingbi Zhang10Qingbi Zhang11Yan Liu12Basic Medicine Research Innovation Center for Cardiometabolic Diseases, Ministry of Education, Luzhou Municipal Key Laboratory of Thrombosis and Vascular Biology, Metabolic Vascular Diseases Key Laboratory of Sichuan Province, School of Pharmacy, School of Public Health, Southwest Medical University, Luzhou, ChinaBasic Medicine Research Innovation Center for Cardiometabolic Diseases, Ministry of Education, Luzhou Municipal Key Laboratory of Thrombosis and Vascular Biology, Metabolic Vascular Diseases Key Laboratory of Sichuan Province, School of Pharmacy, School of Public Health, Southwest Medical University, Luzhou, ChinaEnvironmental Health Effects and Risk Assessment Key Laboratory of Luzhou, Southwest Medical University, Luzhou, ChinaDepartment of Science and Technology, Southwest Medical University, Luzhou, ChinaBasic Medicine Research Innovation Center for Cardiometabolic Diseases, Ministry of Education, Luzhou Municipal Key Laboratory of Thrombosis and Vascular Biology, Metabolic Vascular Diseases Key Laboratory of Sichuan Province, School of Pharmacy, School of Public Health, Southwest Medical University, Luzhou, ChinaBasic Medicine Research Innovation Center for Cardiometabolic Diseases, Ministry of Education, Luzhou Municipal Key Laboratory of Thrombosis and Vascular Biology, Metabolic Vascular Diseases Key Laboratory of Sichuan Province, School of Pharmacy, School of Public Health, Southwest Medical University, Luzhou, ChinaBasic Medicine Research Innovation Center for Cardiometabolic Diseases, Ministry of Education, Luzhou Municipal Key Laboratory of Thrombosis and Vascular Biology, Metabolic Vascular Diseases Key Laboratory of Sichuan Province, School of Pharmacy, School of Public Health, Southwest Medical University, Luzhou, ChinaThe Public Platform of Advanced Detecting Instruments, Public Center of Experimental Technology, Southwest Medical University, Luzhou, ChinaDepartment of Gastroenterology, The Affiliated Hospital of Southwest Medical University, Luzhou, ChinaBasic Medicine Research Innovation Center for Cardiometabolic Diseases, Ministry of Education, Luzhou Municipal Key Laboratory of Thrombosis and Vascular Biology, Metabolic Vascular Diseases Key Laboratory of Sichuan Province, School of Pharmacy, School of Public Health, Southwest Medical University, Luzhou, ChinaBasic Medicine Research Innovation Center for Cardiometabolic Diseases, Ministry of Education, Luzhou Municipal Key Laboratory of Thrombosis and Vascular Biology, Metabolic Vascular Diseases Key Laboratory of Sichuan Province, School of Pharmacy, School of Public Health, Southwest Medical University, Luzhou, ChinaEnvironmental Health Effects and Risk Assessment Key Laboratory of Luzhou, Southwest Medical University, Luzhou, ChinaBasic Medicine Research Innovation Center for Cardiometabolic Diseases, Ministry of Education, Luzhou Municipal Key Laboratory of Thrombosis and Vascular Biology, Metabolic Vascular Diseases Key Laboratory of Sichuan Province, School of Pharmacy, School of Public Health, Southwest Medical University, Luzhou, ChinaIntroductionCholestatic liver injury (CLI) is a liver dysfunction closely associated with oxidative stress and bile acid (BA) metabolic disorders, but effective therapies are lacking.The use of ursolic acid (UA) and α-Tocopherol succinate (VES) together for treating CLI is promising due to their respective effects on regulating bile acid metabolism and providing antioxidant activity.MethodsIn this study, we synthesized drug-drug nanocrystals (UA-NSps) composed of UA and VES to treat CLI and evaluated their synergistic therapeutic effects by regulating bile acid metabolism and inhibiting oxidative stress in ANIT-induced CLI mice.Results and discussionOur investigation demonstrated that UA-NSps exhibited high drug-loading capacity, spherical morphology, and improved dissolution and oral bioavailability. In the ANIT model, UA-NSps effectively restored liver function, as evidenced by histopathological and biochemical improvements. Mechanistically, UA-NSps enhanced Nrf2 nuclear translocation, upregulated Nrf2 and HO-1, reduced pro-inflammatory cytokines, and ameliorated mitochondrial damage. Moreover, UA-NSps alleviated the bile acid metabolism disorders by upregulating the transcriptional activity of UGT2B1, BSEP, and MRP2, as well as the protein expression of nuclear receptors and metabolic enzymes PXR,CYP3A4, and UGT1A1. Our study presents a novel drug-drug nanocrystal strategy that enhances the therapeutic efficacy against CLI by inhibiting oxidative stress and regulating bile acid metabolism.https://www.frontiersin.org/articles/10.3389/fphar.2025.1586141/fullursolic acidnanocrystalscholestatic liver injuryVESoxidative stressPXR/CYP3A4/UGT1A1 |
| spellingShingle | Manhang Hu Xiaolu Hua Xiaolu Hua Wei Xiong Enhui Zheng Xingyue Yang Yu Lu Bing He Xiaolin Zhong Zongzhe Jiang Qingbi Zhang Qingbi Zhang Yan Liu Ursolic acid drug-drug nanocrystals ameliorate cholestatic liver injury via inhibiting oxidative stress and regulating bile acid metabolism Frontiers in Pharmacology ursolic acid nanocrystals cholestatic liver injury VES oxidative stress PXR/CYP3A4/UGT1A1 |
| title | Ursolic acid drug-drug nanocrystals ameliorate cholestatic liver injury via inhibiting oxidative stress and regulating bile acid metabolism |
| title_full | Ursolic acid drug-drug nanocrystals ameliorate cholestatic liver injury via inhibiting oxidative stress and regulating bile acid metabolism |
| title_fullStr | Ursolic acid drug-drug nanocrystals ameliorate cholestatic liver injury via inhibiting oxidative stress and regulating bile acid metabolism |
| title_full_unstemmed | Ursolic acid drug-drug nanocrystals ameliorate cholestatic liver injury via inhibiting oxidative stress and regulating bile acid metabolism |
| title_short | Ursolic acid drug-drug nanocrystals ameliorate cholestatic liver injury via inhibiting oxidative stress and regulating bile acid metabolism |
| title_sort | ursolic acid drug drug nanocrystals ameliorate cholestatic liver injury via inhibiting oxidative stress and regulating bile acid metabolism |
| topic | ursolic acid nanocrystals cholestatic liver injury VES oxidative stress PXR/CYP3A4/UGT1A1 |
| url | https://www.frontiersin.org/articles/10.3389/fphar.2025.1586141/full |
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