The therapeutic potential of PX-478 in a murine model of pelvic organ prolapse
Background Pelvic organ prolapse (POP), characterised by the downward displacement of pelvic organs, is a prevalent disorder that affects adult women. This study explored the therapeutic potential of PX-478, a selective hypoxia-inducible factor-1α (HIF-1α) inhibitor, in a murine POP model.Methods A...
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| Format: | Article |
| Language: | English |
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Taylor & Francis Group
2024-12-01
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| Series: | Journal of Obstetrics and Gynaecology |
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| Online Access: | https://www.tandfonline.com/doi/10.1080/01443615.2024.2415669 |
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| author | Wei-Min Fan Yu-Qi Yang Li-Wen Zhang Xiao-Hui Mei Ke Sun Duan-Qing Wu Ying Yang Chun-Fang Duan Jun Ye Ru-Jun Chen |
| author_facet | Wei-Min Fan Yu-Qi Yang Li-Wen Zhang Xiao-Hui Mei Ke Sun Duan-Qing Wu Ying Yang Chun-Fang Duan Jun Ye Ru-Jun Chen |
| author_sort | Wei-Min Fan |
| collection | DOAJ |
| description | Background Pelvic organ prolapse (POP), characterised by the downward displacement of pelvic organs, is a prevalent disorder that affects adult women. This study explored the therapeutic potential of PX-478, a selective hypoxia-inducible factor-1α (HIF-1α) inhibitor, in a murine POP model.Methods A murine POP model was established through ovariectomy, mimicking oestrogen deprivation. Fifteen C57BL/6J mice were randomly assigned to control, POP, and PX-478 groups. PX-478, targeting HIF-1α, was administered intravaginally. The analysis of fibroblasts, macrophage and inflammation was performed through Masson staining, immunofluorescence, and ELISA. Collagen distribution was assessed using Sirius Red staining. Expression levels of matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMP-1) were determined through immunohistochemistry and western blot. Fibroblast proliferation and apoptosis were evaluated by CCK-8 assay and flow cytometry.Results PX-478 treatment significantly reduced vaginal length, indicating a therapeutic effect on POP severity. Masson staining revealed reduced fibrotic changes and collagen disruption in PX-478-treated mice. Immunofluorescence showed increased fibroblast markers (Vimentin, α-SMA) and collagen fibres by PX-478. Sirius Red staining indicated PX-478 mitigated damage to Type I and Type III collagen fibres. PX-478 significantly reduced MMP-2 and MMP-9 expression while increased TIMP-1. In macrophages, PX-478 decreased M1 and M2 markers (CD80, CD206) and IL-18 secretion. Fibroblasts exhibited increased proliferation, reduced apoptosis, and altered MMP/TIMP expression under PX-478 influence.Conclusion PX-478 demonstrates a therapeutic potential in the mice POP model. It reduces vaginal length, attenuates fibrosis, and modulates collagen synthesis. Its immunomodulation is evident through reduced M1 and M2 macrophages and suppressed IL-18 secretion. |
| format | Article |
| id | doaj-art-1d5942c6d6e04a54915e7b19494cf5f4 |
| institution | Kabale University |
| issn | 0144-3615 1364-6893 |
| language | English |
| publishDate | 2024-12-01 |
| publisher | Taylor & Francis Group |
| record_format | Article |
| series | Journal of Obstetrics and Gynaecology |
| spelling | doaj-art-1d5942c6d6e04a54915e7b19494cf5f42025-01-09T12:13:17ZengTaylor & Francis GroupJournal of Obstetrics and Gynaecology0144-36151364-68932024-12-0144110.1080/01443615.2024.2415669The therapeutic potential of PX-478 in a murine model of pelvic organ prolapseWei-Min Fan0Yu-Qi Yang1Li-Wen Zhang2Xiao-Hui Mei3Ke Sun4Duan-Qing Wu5Ying Yang6Chun-Fang Duan7Jun Ye8Ru-Jun Chen9Department of Gynecology, Shanghai Fifth People’s Hospital, Fudan University, Shanghai, ChinaDepartment of Gynecology, Shanghai Fifth People’s Hospital, Fudan University, Shanghai, ChinaDepartment of Gynecology, Shanghai Fifth People’s Hospital, Fudan University, Shanghai, ChinaDepartment of Gynecology, Shanghai Fifth People’s Hospital, Fudan University, Shanghai, ChinaDepartment of Gynecology, Shanghai Fifth People’s Hospital, Fudan University, Shanghai, ChinaDepartment of Gynecology, Shanghai Fifth People’s Hospital, Fudan University, Shanghai, ChinaDepartment of Gynecology, Shanghai Fifth People’s Hospital, Fudan University, Shanghai, ChinaDepartment of Gynecology, Longling People’s Hospital, YunNan, LongLing County, ChinaDepartment of Gynecology, Shanghai Fifth People’s Hospital, Fudan University, Shanghai, ChinaDepartment of Gynecology, Shanghai Fifth People’s Hospital, Fudan University, Shanghai, ChinaBackground Pelvic organ prolapse (POP), characterised by the downward displacement of pelvic organs, is a prevalent disorder that affects adult women. This study explored the therapeutic potential of PX-478, a selective hypoxia-inducible factor-1α (HIF-1α) inhibitor, in a murine POP model.Methods A murine POP model was established through ovariectomy, mimicking oestrogen deprivation. Fifteen C57BL/6J mice were randomly assigned to control, POP, and PX-478 groups. PX-478, targeting HIF-1α, was administered intravaginally. The analysis of fibroblasts, macrophage and inflammation was performed through Masson staining, immunofluorescence, and ELISA. Collagen distribution was assessed using Sirius Red staining. Expression levels of matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMP-1) were determined through immunohistochemistry and western blot. Fibroblast proliferation and apoptosis were evaluated by CCK-8 assay and flow cytometry.Results PX-478 treatment significantly reduced vaginal length, indicating a therapeutic effect on POP severity. Masson staining revealed reduced fibrotic changes and collagen disruption in PX-478-treated mice. Immunofluorescence showed increased fibroblast markers (Vimentin, α-SMA) and collagen fibres by PX-478. Sirius Red staining indicated PX-478 mitigated damage to Type I and Type III collagen fibres. PX-478 significantly reduced MMP-2 and MMP-9 expression while increased TIMP-1. In macrophages, PX-478 decreased M1 and M2 markers (CD80, CD206) and IL-18 secretion. Fibroblasts exhibited increased proliferation, reduced apoptosis, and altered MMP/TIMP expression under PX-478 influence.Conclusion PX-478 demonstrates a therapeutic potential in the mice POP model. It reduces vaginal length, attenuates fibrosis, and modulates collagen synthesis. Its immunomodulation is evident through reduced M1 and M2 macrophages and suppressed IL-18 secretion.https://www.tandfonline.com/doi/10.1080/01443615.2024.2415669Pelvic organ prolapse (POP)fibroblastshypoxia-inducible factor-1α (HIF-1α)PX-478macrophagesinflammation |
| spellingShingle | Wei-Min Fan Yu-Qi Yang Li-Wen Zhang Xiao-Hui Mei Ke Sun Duan-Qing Wu Ying Yang Chun-Fang Duan Jun Ye Ru-Jun Chen The therapeutic potential of PX-478 in a murine model of pelvic organ prolapse Journal of Obstetrics and Gynaecology Pelvic organ prolapse (POP) fibroblasts hypoxia-inducible factor-1α (HIF-1α) PX-478 macrophages inflammation |
| title | The therapeutic potential of PX-478 in a murine model of pelvic organ prolapse |
| title_full | The therapeutic potential of PX-478 in a murine model of pelvic organ prolapse |
| title_fullStr | The therapeutic potential of PX-478 in a murine model of pelvic organ prolapse |
| title_full_unstemmed | The therapeutic potential of PX-478 in a murine model of pelvic organ prolapse |
| title_short | The therapeutic potential of PX-478 in a murine model of pelvic organ prolapse |
| title_sort | therapeutic potential of px 478 in a murine model of pelvic organ prolapse |
| topic | Pelvic organ prolapse (POP) fibroblasts hypoxia-inducible factor-1α (HIF-1α) PX-478 macrophages inflammation |
| url | https://www.tandfonline.com/doi/10.1080/01443615.2024.2415669 |
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