The mitochondria-targeted Kaempferol nanoparticle ameliorates severe acute pancreatitis
Abstract Kaempferol (KA), an natural antioxidant of traditional Chinese medicine (TCM), is extensively used as the primary treatment for inflammatory digestive diseases with impaired redox homeostasis. Severe acute pancreatitis (SAP) was exacerbated by mitochondrial dysfunction and abundant ROS, whi...
| Main Authors: | , , , , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2024-04-01
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| Series: | Journal of Nanobiotechnology |
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| Online Access: | https://doi.org/10.1186/s12951-024-02439-y |
| _version_ | 1797219595663179776 |
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| author | E Wen Yi Cao Shiwen He Yuezhou Zhang Lanlan You Tingqiu Wang Zhigang Wang Jun He Yi Feng |
| author_facet | E Wen Yi Cao Shiwen He Yuezhou Zhang Lanlan You Tingqiu Wang Zhigang Wang Jun He Yi Feng |
| author_sort | E Wen |
| collection | DOAJ |
| description | Abstract Kaempferol (KA), an natural antioxidant of traditional Chinese medicine (TCM), is extensively used as the primary treatment for inflammatory digestive diseases with impaired redox homeostasis. Severe acute pancreatitis (SAP) was exacerbated by mitochondrial dysfunction and abundant ROS, which highlights the role of antioxidants in targeting mitochondrial function. However, low bioavailability and high dosage of KA leading to unavoidable side effects limits clinical transformation. The mechanisms of KA with poor bioavailability largely unexplored, hindering development of the efficient strategies to maximizing the medicinal effects of KA. Here, we engineered a novel thioketals (TK)-modified based on DSPE-PEG2000 liposomal codelivery system for improving bioavailability and avoiding side effects (denotes as DSPE-TK-PEG2000-KA, DTM@KA NPs). We demonstrated that the liposome exerts profound impacts on damaging intracellular redox homeostasis by reducing GSH depletion and activating Nrf2, which synergizes with KA to reinforce the inhibition of inadequate fission, excessive mitochondrial fusion and impaired mitophagy resulting in inflammation and apoptosis; and then, the restored mitochondrial homeostasis strengthens ATP supply for PAC renovation and homeostasis. Interestingly, TK bond was proved as the main functional structure to improve the above efficacy of KA compared with the absence of TK bond. Most importantly, DTM@KA NPs obviously suppresses PAC death with negligible side effects in vitro and vivo. Mechanismly, DTM@KA NPs facilitated STAT6-regulated mitochondrial precursor proteins transport via interacting with TOM20 to further promote Drp1-dependent fission and Pink1/Parkin-regulated mitophagy with enhanced lysosomal degradation for removing damaged mitochondria in PAC and then reduce inflammation and apoptosis. Generally, DTM@KA NPs synergistically improved mitochondrial homeostasis, redox homeostasis, energy metabolism and inflammation response via regulating TOM20-STAT6-Drp1 signaling and promoting mitophagy in SAP. Consequently, such a TCM’s active ingredients-based nanomedicine strategy is be expected to be an innovative approach for SAP therapy. Graphical Abstract |
| first_indexed | 2024-04-24T12:36:09Z |
| format | Article |
| id | doaj.art-665537eb56a84ca3b5c73690307eeea5 |
| institution | Directory Open Access Journal |
| issn | 1477-3155 |
| language | English |
| last_indexed | 2024-04-24T12:36:09Z |
| publishDate | 2024-04-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Nanobiotechnology |
| spelling | doaj.art-665537eb56a84ca3b5c73690307eeea52024-04-07T11:29:15ZengBMCJournal of Nanobiotechnology1477-31552024-04-0122111510.1186/s12951-024-02439-yThe mitochondria-targeted Kaempferol nanoparticle ameliorates severe acute pancreatitisE Wen0Yi Cao1Shiwen He2Yuezhou Zhang3Lanlan You4Tingqiu Wang5Zhigang Wang6Jun He7Yi Feng8Department of Ultrasound, The Second Affiliated Hospital of Chongqing Medical UniversityDepartment of Ultrasound, The Second Affiliated Hospital of Chongqing Medical UniversityDepartment of Ultrasound, The Second Affiliated Hospital of Chongqing Medical UniversityDepartment of Hepatobiliary Surgery, The Second Affiliated Hospital of Chongqing Medical UniversityDepartment of Ultrasound, The Second Affiliated Hospital of Chongqing Medical UniversityDepartment of Ultrasound, The Second Affiliated Hospital of Chongqing Medical UniversityDepartment of Ultrasound, The Second Affiliated Hospital of Chongqing Medical UniversityThe First Affiliated Hospital of Chengdu Medical CollegeInstitute of Burn Research, State Key Lab of Trauma, Burn and Combined Injury, Chongqing Key Laboratory for Disease Proteomics, Southwest Hospital, Third Military Medical University (Army Medical University)Abstract Kaempferol (KA), an natural antioxidant of traditional Chinese medicine (TCM), is extensively used as the primary treatment for inflammatory digestive diseases with impaired redox homeostasis. Severe acute pancreatitis (SAP) was exacerbated by mitochondrial dysfunction and abundant ROS, which highlights the role of antioxidants in targeting mitochondrial function. However, low bioavailability and high dosage of KA leading to unavoidable side effects limits clinical transformation. The mechanisms of KA with poor bioavailability largely unexplored, hindering development of the efficient strategies to maximizing the medicinal effects of KA. Here, we engineered a novel thioketals (TK)-modified based on DSPE-PEG2000 liposomal codelivery system for improving bioavailability and avoiding side effects (denotes as DSPE-TK-PEG2000-KA, DTM@KA NPs). We demonstrated that the liposome exerts profound impacts on damaging intracellular redox homeostasis by reducing GSH depletion and activating Nrf2, which synergizes with KA to reinforce the inhibition of inadequate fission, excessive mitochondrial fusion and impaired mitophagy resulting in inflammation and apoptosis; and then, the restored mitochondrial homeostasis strengthens ATP supply for PAC renovation and homeostasis. Interestingly, TK bond was proved as the main functional structure to improve the above efficacy of KA compared with the absence of TK bond. Most importantly, DTM@KA NPs obviously suppresses PAC death with negligible side effects in vitro and vivo. Mechanismly, DTM@KA NPs facilitated STAT6-regulated mitochondrial precursor proteins transport via interacting with TOM20 to further promote Drp1-dependent fission and Pink1/Parkin-regulated mitophagy with enhanced lysosomal degradation for removing damaged mitochondria in PAC and then reduce inflammation and apoptosis. Generally, DTM@KA NPs synergistically improved mitochondrial homeostasis, redox homeostasis, energy metabolism and inflammation response via regulating TOM20-STAT6-Drp1 signaling and promoting mitophagy in SAP. Consequently, such a TCM’s active ingredients-based nanomedicine strategy is be expected to be an innovative approach for SAP therapy. Graphical Abstracthttps://doi.org/10.1186/s12951-024-02439-yKaempferolTK bondNanosystemMitochondrial homeostasisSevere acute pancreatitis |
| spellingShingle | E Wen Yi Cao Shiwen He Yuezhou Zhang Lanlan You Tingqiu Wang Zhigang Wang Jun He Yi Feng The mitochondria-targeted Kaempferol nanoparticle ameliorates severe acute pancreatitis Journal of Nanobiotechnology Kaempferol TK bond Nanosystem Mitochondrial homeostasis Severe acute pancreatitis |
| title | The mitochondria-targeted Kaempferol nanoparticle ameliorates severe acute pancreatitis |
| title_full | The mitochondria-targeted Kaempferol nanoparticle ameliorates severe acute pancreatitis |
| title_fullStr | The mitochondria-targeted Kaempferol nanoparticle ameliorates severe acute pancreatitis |
| title_full_unstemmed | The mitochondria-targeted Kaempferol nanoparticle ameliorates severe acute pancreatitis |
| title_short | The mitochondria-targeted Kaempferol nanoparticle ameliorates severe acute pancreatitis |
| title_sort | mitochondria targeted kaempferol nanoparticle ameliorates severe acute pancreatitis |
| topic | Kaempferol TK bond Nanosystem Mitochondrial homeostasis Severe acute pancreatitis |
| url | https://doi.org/10.1186/s12951-024-02439-y |
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