The chiisanoside derivatives present in the leaves of Acanthopanax sessiliflorus activate autophagy through the LRP6/GSK3β axis and thereafter inhibit oxidative stress, thereby counteracting cisplatin-induced ototoxicity
IntroductionCisplatin is extensively employed in the treatment of multiple solid malignant tumors. Nevertheless, side effects such as cisplatin-induced ototoxicity (CIO) pose obstacles to tumor therapy.The important natural product chiisanoside from Acanthopanax sessiliflorus has abundant activity a...
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Frontiers Media S.A.
2025-01-01
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| author | Wenxin Zhang Wenxin Zhang Hongbo Teng Hongbo Teng Tianyi Zhao Tianyi Zhao Roberts I. Eglitis Xv Wang Xv Wang Zhengxuan Yu Shurong Qu Shurong Qu Haijing Wang Haijing Wang Yaru Zhao Yaru Zhao Bowen Fan Bowen Fan Shuangli Liu Shuangli Liu Yan Zhao Yan Zhao |
| author_facet | Wenxin Zhang Wenxin Zhang Hongbo Teng Hongbo Teng Tianyi Zhao Tianyi Zhao Roberts I. Eglitis Xv Wang Xv Wang Zhengxuan Yu Shurong Qu Shurong Qu Haijing Wang Haijing Wang Yaru Zhao Yaru Zhao Bowen Fan Bowen Fan Shuangli Liu Shuangli Liu Yan Zhao Yan Zhao |
| author_sort | Wenxin Zhang |
| collection | DOAJ |
| description | IntroductionCisplatin is extensively employed in the treatment of multiple solid malignant tumors. Nevertheless, side effects such as cisplatin-induced ototoxicity (CIO) pose obstacles to tumor therapy.The important natural product chiisanoside from Acanthopanax sessiliflorus has abundant activity against CIO.MethodsIn this study, 26 chiisanoside derivatives were screened, and compound 19 demonstrated significant protective activity against CIO damage. A cisplatin—induced HEI—OC1 cell injury model and a mouse ototoxicity model were established. The regulatory effects were revealed through transcriptome sequencing, and the protein expression levels were analyzed by molecular docking, ELISA, Western blotting, and immunofluorescence.ResultsIt was found that compound 19 inhibited cell apoptosis, alleviated abnormal hearing and spiral ganglion damage. Transcriptome sequencing revealed its regulatory effects. Compound 19 treatment increased autophagy levels, thereby alleviating mitochondrial dysfunction and reducing the accumulation of reactive oxygen species (ROS).In-depth studies have found that the autophagy inhibitor 3-methyladenine (3-MA) weakens the regulatory effect of compound 19 on autophagy and inhibits the clearance of damaged cells, resulting in oxidative stress damage, apoptosis and necrosis. By knocking down LRP6, it was found that the protective effect of compound 19 was eliminated, the autophagy level was significantly reduced, oxidative stress and ROS production were induced, and apoptosis after cisplatin exposure was promoted. Finally, the inhibitor LiCl was used to suppress the expression of GSK3β. It was found that inhibiting GSK3β could protect cells from cisplatin-induced damage by activating autophagy.DiscussionThese findings suggest that compound 19 is capable of preventing ototoxicity by activating autophagy via the LRP6/GSK3β axis and consequently inhibiting oxidative stress, offering a new approach for treating CIO and sensorineural hearing loss. |
| format | Article |
| id | doaj-art-f83493c5a4d34cd9bfeeb64aaa2429df |
| institution | Kabale University |
| issn | 1663-9812 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Frontiers Media S.A. |
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| series | Frontiers in Pharmacology |
| spelling | doaj-art-f83493c5a4d34cd9bfeeb64aaa2429df2025-01-15T06:10:49ZengFrontiers Media S.A.Frontiers in Pharmacology1663-98122025-01-011510.3389/fphar.2024.15188101518810The chiisanoside derivatives present in the leaves of Acanthopanax sessiliflorus activate autophagy through the LRP6/GSK3β axis and thereafter inhibit oxidative stress, thereby counteracting cisplatin-induced ototoxicityWenxin Zhang0Wenxin Zhang1Hongbo Teng2Hongbo Teng3Tianyi Zhao4Tianyi Zhao5Roberts I. Eglitis6Xv Wang7Xv Wang8Zhengxuan Yu9Shurong Qu10Shurong Qu11Haijing Wang12Haijing Wang13Yaru Zhao14Yaru Zhao15Bowen Fan16Bowen Fan17Shuangli Liu18Shuangli Liu19Yan Zhao20Yan Zhao21College of Chinese Medicinal Materials, Jilin Agricultural University, Changchun, Jilin, ChinaInternational Joint Laboratory for Development of Animal and Plant Resources for Food and Medicine, Jilin Agricultural University, Changchun, Jilin, ChinaCollege of Chinese Medicinal Materials, Jilin Agricultural University, Changchun, Jilin, ChinaInternational Joint Laboratory for Development of Animal and Plant Resources for Food and Medicine, Jilin Agricultural University, Changchun, Jilin, ChinaInternational Joint Laboratory for Development of Animal and Plant Resources for Food and Medicine, Jilin Agricultural University, Changchun, Jilin, ChinaInstitute of Changbai Mountain Biology Germplasm Resources, Tonghua Normal University, Tonghua, Jilin, ChinaInstitute of Solid State Physics, University of Latvia, Riga, LatviaCollege of Chinese Medicinal Materials, Jilin Agricultural University, Changchun, Jilin, ChinaInternational Joint Laboratory for Development of Animal and Plant Resources for Food and Medicine, Jilin Agricultural University, Changchun, Jilin, ChinaCollege of Chinese Medicinal Materials, Jilin Agricultural University, Changchun, Jilin, ChinaCollege of Chinese Medicinal Materials, Jilin Agricultural University, Changchun, Jilin, ChinaInternational Joint Laboratory for Development of Animal and Plant Resources for Food and Medicine, Jilin Agricultural University, Changchun, Jilin, ChinaCollege of Chinese Medicinal Materials, Jilin Agricultural University, Changchun, Jilin, ChinaInternational Joint Laboratory for Development of Animal and Plant Resources for Food and Medicine, Jilin Agricultural University, Changchun, Jilin, ChinaCollege of Chinese Medicinal Materials, Jilin Agricultural University, Changchun, Jilin, ChinaInternational Joint Laboratory for Development of Animal and Plant Resources for Food and Medicine, Jilin Agricultural University, Changchun, Jilin, ChinaCollege of Chinese Medicinal Materials, Jilin Agricultural University, Changchun, Jilin, ChinaInternational Joint Laboratory for Development of Animal and Plant Resources for Food and Medicine, Jilin Agricultural University, Changchun, Jilin, ChinaCollege of Chinese Medicinal Materials, Jilin Agricultural University, Changchun, Jilin, ChinaInternational Joint Laboratory for Development of Animal and Plant Resources for Food and Medicine, Jilin Agricultural University, Changchun, Jilin, ChinaCollege of Chinese Medicinal Materials, Jilin Agricultural University, Changchun, Jilin, ChinaInternational Joint Laboratory for Development of Animal and Plant Resources for Food and Medicine, Jilin Agricultural University, Changchun, Jilin, ChinaIntroductionCisplatin is extensively employed in the treatment of multiple solid malignant tumors. Nevertheless, side effects such as cisplatin-induced ototoxicity (CIO) pose obstacles to tumor therapy.The important natural product chiisanoside from Acanthopanax sessiliflorus has abundant activity against CIO.MethodsIn this study, 26 chiisanoside derivatives were screened, and compound 19 demonstrated significant protective activity against CIO damage. A cisplatin—induced HEI—OC1 cell injury model and a mouse ototoxicity model were established. The regulatory effects were revealed through transcriptome sequencing, and the protein expression levels were analyzed by molecular docking, ELISA, Western blotting, and immunofluorescence.ResultsIt was found that compound 19 inhibited cell apoptosis, alleviated abnormal hearing and spiral ganglion damage. Transcriptome sequencing revealed its regulatory effects. Compound 19 treatment increased autophagy levels, thereby alleviating mitochondrial dysfunction and reducing the accumulation of reactive oxygen species (ROS).In-depth studies have found that the autophagy inhibitor 3-methyladenine (3-MA) weakens the regulatory effect of compound 19 on autophagy and inhibits the clearance of damaged cells, resulting in oxidative stress damage, apoptosis and necrosis. By knocking down LRP6, it was found that the protective effect of compound 19 was eliminated, the autophagy level was significantly reduced, oxidative stress and ROS production were induced, and apoptosis after cisplatin exposure was promoted. Finally, the inhibitor LiCl was used to suppress the expression of GSK3β. It was found that inhibiting GSK3β could protect cells from cisplatin-induced damage by activating autophagy.DiscussionThese findings suggest that compound 19 is capable of preventing ototoxicity by activating autophagy via the LRP6/GSK3β axis and consequently inhibiting oxidative stress, offering a new approach for treating CIO and sensorineural hearing loss.https://www.frontiersin.org/articles/10.3389/fphar.2024.1518810/fullcisplatin-induced ototoxicity (CIO)RNA sequencingautophagyoxidative stresschiisanoside derivatives |
| spellingShingle | Wenxin Zhang Wenxin Zhang Hongbo Teng Hongbo Teng Tianyi Zhao Tianyi Zhao Roberts I. Eglitis Xv Wang Xv Wang Zhengxuan Yu Shurong Qu Shurong Qu Haijing Wang Haijing Wang Yaru Zhao Yaru Zhao Bowen Fan Bowen Fan Shuangli Liu Shuangli Liu Yan Zhao Yan Zhao The chiisanoside derivatives present in the leaves of Acanthopanax sessiliflorus activate autophagy through the LRP6/GSK3β axis and thereafter inhibit oxidative stress, thereby counteracting cisplatin-induced ototoxicity Frontiers in Pharmacology cisplatin-induced ototoxicity (CIO) RNA sequencing autophagy oxidative stress chiisanoside derivatives |
| title | The chiisanoside derivatives present in the leaves of Acanthopanax sessiliflorus activate autophagy through the LRP6/GSK3β axis and thereafter inhibit oxidative stress, thereby counteracting cisplatin-induced ototoxicity |
| title_full | The chiisanoside derivatives present in the leaves of Acanthopanax sessiliflorus activate autophagy through the LRP6/GSK3β axis and thereafter inhibit oxidative stress, thereby counteracting cisplatin-induced ototoxicity |
| title_fullStr | The chiisanoside derivatives present in the leaves of Acanthopanax sessiliflorus activate autophagy through the LRP6/GSK3β axis and thereafter inhibit oxidative stress, thereby counteracting cisplatin-induced ototoxicity |
| title_full_unstemmed | The chiisanoside derivatives present in the leaves of Acanthopanax sessiliflorus activate autophagy through the LRP6/GSK3β axis and thereafter inhibit oxidative stress, thereby counteracting cisplatin-induced ototoxicity |
| title_short | The chiisanoside derivatives present in the leaves of Acanthopanax sessiliflorus activate autophagy through the LRP6/GSK3β axis and thereafter inhibit oxidative stress, thereby counteracting cisplatin-induced ototoxicity |
| title_sort | chiisanoside derivatives present in the leaves of acanthopanax sessiliflorus activate autophagy through the lrp6 gsk3β axis and thereafter inhibit oxidative stress thereby counteracting cisplatin induced ototoxicity |
| topic | cisplatin-induced ototoxicity (CIO) RNA sequencing autophagy oxidative stress chiisanoside derivatives |
| url | https://www.frontiersin.org/articles/10.3389/fphar.2024.1518810/full |
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