UMI-77 targets MCL-1 to activate mitophagy and ameliorate periodontitis in mice
Objective: To investigate the therapeutic and ameliorative effects of the Myeloid Cell Leukemia 1 protein (MCL-1) inhibitor UMI-77 on experimental murine periodontitis via mitophagy activation, with a focus on comparing administration routes (local/intraperitoneal) and doses (high/low/combined). Met...
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Elsevier
2025-09-01
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| Series: | Immunobiology |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S0171298525002426 |
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| author | Dalei Sun Shu Ouyang Xiaoxuan Xu Jingjing Yan Heqian Wang Chenkai Lan Wubin Ouyang Liangjun Zhong Jun Lin |
| author_facet | Dalei Sun Shu Ouyang Xiaoxuan Xu Jingjing Yan Heqian Wang Chenkai Lan Wubin Ouyang Liangjun Zhong Jun Lin |
| author_sort | Dalei Sun |
| collection | DOAJ |
| description | Objective: To investigate the therapeutic and ameliorative effects of the Myeloid Cell Leukemia 1 protein (MCL-1) inhibitor UMI-77 on experimental murine periodontitis via mitophagy activation, with a focus on comparing administration routes (local/intraperitoneal) and doses (high/low/combined). Methods: A ligature-induced periodontitis model was established in 54 male C57BL/6 J mice, randomized into 9 groups (n = 6 per group): normal control (Group Aa), periodontitis model (Group Ab), positive control (Group Ac, local minocycline), local PBS control (Group Ad), intraperitoneal PBS control (Group Ae), local high-dose UMI-77 (Group Ba, 2 mg/kg), local low-dose UMI-77 (Group Bb, 1 mg/kg), intraperitoneal UMI-77 (Group Ca, 2 mg/kg), and combined intraperitoneal UMI-77 + local minocycline (Group Cb, 2 mg/kg + standard minocycline regimen). Outcomes included periodontal bleeding on probing (BOP), alveolar bone resorption via micro-CT, histopathological analysis (HE/methylene blue staining), MCL-1 expression (Western blot), autolysosome detection (transmission electron microscopy, TEM), and systemic organ safety (HE staining). Results: All UMI-77 treatment groups exhibited significant amelioration of periodontal inflammation and bone resorption compared to the model group (Ab, p < 0.0001). Local high-dose UMI-77 (Group Ba) demonstrated the most potent efficacy, reducing BOP by 76 % (0.67 ± 0.5 vs. Ab: 2.8 ± 0.4, p < 0.001) and cementoenamel junction–alveolar bone crest distance by 48.7 % (0.20 ± 0.04 mm vs. Ab: 0.41 ± 0.05 mm, p < 0.0001), outperforming the positive control (Group Ac, BOP: 2.17 ± 0.4, p < 0.001). Histological analysis showed reduced inflammatory cell infiltration and organized periodontal fibers in Group Ba. Western blot confirmed downregulation of MCL-1 expression to near-normal levels in Group Ba, while TEM detected autolysosomes in both Group Ba and Group Ca, indicating mitophagy activation. Systemic safety assessments revealed only mild grade 1 cardiac septal thickening in Group Ba and transient splenic lymphocyte elevation in Group Ca, with no severe organ toxicity. Conclusion: UMI-77 exerts significant therapeutic and ameliorative effects against periodontitis in mice, with local high-dose administration (Group Ba) demonstrating optimal efficacy. Intraperitoneal UMI-77 combined with local minocycline (Group Cb) achieved comparable outcomes to high-dose local UMI-77, highlighting potential combinatorial strategies. These findings establish UMI-77 as a promising agent for periodontitis treatment via MCL-1-targeted mitophagy activation. Clinical significance: UMI-77, especially with local high-dose administration, offers a new, potentially effective and safe approach for periodontitis treatment, holding great promise for clinical translation. |
| format | Article |
| id | doaj-art-286eb01ec6364df28e4e9b9262b54f23 |
| institution | Kabale University |
| issn | 0171-2985 |
| language | English |
| publishDate | 2025-09-01 |
| publisher | Elsevier |
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| series | Immunobiology |
| spelling | doaj-art-286eb01ec6364df28e4e9b9262b54f232025-08-24T05:11:20ZengElsevierImmunobiology0171-29852025-09-01230515310810.1016/j.imbio.2025.153108UMI-77 targets MCL-1 to activate mitophagy and ameliorate periodontitis in miceDalei Sun0Shu Ouyang1Xiaoxuan Xu2Jingjing Yan3Heqian Wang4Chenkai Lan5Wubin Ouyang6Liangjun Zhong7Jun Lin8Department of Stomatology, Affiliated Hospital of Hangzhou Normal University, 310015, Zhejiang Province, China; Zhejiang University School of Medicine, No. 866 Yuhangtang Road, Hangzhou 310011, ChinaDepartment of Stomatology, Affiliated Hospital of Hangzhou Normal University, 310015, Zhejiang Province, ChinaDepartment of Stomatology, Affiliated Hospital of Hangzhou Normal University, 310015, Zhejiang Province, ChinaDepartment of Stomatology, Affiliated Hospital of Hangzhou Normal University, 310015, Zhejiang Province, ChinaDepartment of Stomatology, Affiliated Hospital of Hangzhou Normal University, 310015, Zhejiang Province, ChinaDepartment of Stomatology, Affiliated Hospital of Hangzhou Normal University, 310015, Zhejiang Province, ChinaDepartment of Stomatology, Affiliated Hospital of Hangzhou Normal University, 310015, Zhejiang Province, ChinaDepartment of Stomatology, Affiliated Hospital of Hangzhou Normal University, 310015, Zhejiang Province, China; Corresponding authors.Department of Stomatology, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China; Corresponding authors.Objective: To investigate the therapeutic and ameliorative effects of the Myeloid Cell Leukemia 1 protein (MCL-1) inhibitor UMI-77 on experimental murine periodontitis via mitophagy activation, with a focus on comparing administration routes (local/intraperitoneal) and doses (high/low/combined). Methods: A ligature-induced periodontitis model was established in 54 male C57BL/6 J mice, randomized into 9 groups (n = 6 per group): normal control (Group Aa), periodontitis model (Group Ab), positive control (Group Ac, local minocycline), local PBS control (Group Ad), intraperitoneal PBS control (Group Ae), local high-dose UMI-77 (Group Ba, 2 mg/kg), local low-dose UMI-77 (Group Bb, 1 mg/kg), intraperitoneal UMI-77 (Group Ca, 2 mg/kg), and combined intraperitoneal UMI-77 + local minocycline (Group Cb, 2 mg/kg + standard minocycline regimen). Outcomes included periodontal bleeding on probing (BOP), alveolar bone resorption via micro-CT, histopathological analysis (HE/methylene blue staining), MCL-1 expression (Western blot), autolysosome detection (transmission electron microscopy, TEM), and systemic organ safety (HE staining). Results: All UMI-77 treatment groups exhibited significant amelioration of periodontal inflammation and bone resorption compared to the model group (Ab, p < 0.0001). Local high-dose UMI-77 (Group Ba) demonstrated the most potent efficacy, reducing BOP by 76 % (0.67 ± 0.5 vs. Ab: 2.8 ± 0.4, p < 0.001) and cementoenamel junction–alveolar bone crest distance by 48.7 % (0.20 ± 0.04 mm vs. Ab: 0.41 ± 0.05 mm, p < 0.0001), outperforming the positive control (Group Ac, BOP: 2.17 ± 0.4, p < 0.001). Histological analysis showed reduced inflammatory cell infiltration and organized periodontal fibers in Group Ba. Western blot confirmed downregulation of MCL-1 expression to near-normal levels in Group Ba, while TEM detected autolysosomes in both Group Ba and Group Ca, indicating mitophagy activation. Systemic safety assessments revealed only mild grade 1 cardiac septal thickening in Group Ba and transient splenic lymphocyte elevation in Group Ca, with no severe organ toxicity. Conclusion: UMI-77 exerts significant therapeutic and ameliorative effects against periodontitis in mice, with local high-dose administration (Group Ba) demonstrating optimal efficacy. Intraperitoneal UMI-77 combined with local minocycline (Group Cb) achieved comparable outcomes to high-dose local UMI-77, highlighting potential combinatorial strategies. These findings establish UMI-77 as a promising agent for periodontitis treatment via MCL-1-targeted mitophagy activation. Clinical significance: UMI-77, especially with local high-dose administration, offers a new, potentially effective and safe approach for periodontitis treatment, holding great promise for clinical translation.http://www.sciencedirect.com/science/article/pii/S0171298525002426PeriodontitisUMI-77MCL-1MitophagyTargeted therapy |
| spellingShingle | Dalei Sun Shu Ouyang Xiaoxuan Xu Jingjing Yan Heqian Wang Chenkai Lan Wubin Ouyang Liangjun Zhong Jun Lin UMI-77 targets MCL-1 to activate mitophagy and ameliorate periodontitis in mice Immunobiology Periodontitis UMI-77 MCL-1 Mitophagy Targeted therapy |
| title | UMI-77 targets MCL-1 to activate mitophagy and ameliorate periodontitis in mice |
| title_full | UMI-77 targets MCL-1 to activate mitophagy and ameliorate periodontitis in mice |
| title_fullStr | UMI-77 targets MCL-1 to activate mitophagy and ameliorate periodontitis in mice |
| title_full_unstemmed | UMI-77 targets MCL-1 to activate mitophagy and ameliorate periodontitis in mice |
| title_short | UMI-77 targets MCL-1 to activate mitophagy and ameliorate periodontitis in mice |
| title_sort | umi 77 targets mcl 1 to activate mitophagy and ameliorate periodontitis in mice |
| topic | Periodontitis UMI-77 MCL-1 Mitophagy Targeted therapy |
| url | http://www.sciencedirect.com/science/article/pii/S0171298525002426 |
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