Inhibition of MST1 ameliorates neuronal apoptosis via GSK3β/β-TrCP/NRF2 pathway in spinal cord injury accompanied by diabetes
Aims: Spinal cord injury (SCI) is a devastating neurological disease that often results in tremendous loss of motor function. Increasing evidence demonstrates that diabetes worsens outcomes for patients with SCI due to the higher levels of neuronal oxidative stress. Mammalian sterile 20-like kinase...
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| Format: | Article |
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Elsevier
2024-05-01
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| Series: | Redox Biology |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2213231724000806 |
| _version_ | 1797235521472167936 |
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| author | Weijun Huang Depeng Wu Chaoyang Cai Hui Yao Zhenming Tian Yang Yang Mao Pang Limin Rong Bin Liu |
| author_facet | Weijun Huang Depeng Wu Chaoyang Cai Hui Yao Zhenming Tian Yang Yang Mao Pang Limin Rong Bin Liu |
| author_sort | Weijun Huang |
| collection | DOAJ |
| description | Aims: Spinal cord injury (SCI) is a devastating neurological disease that often results in tremendous loss of motor function. Increasing evidence demonstrates that diabetes worsens outcomes for patients with SCI due to the higher levels of neuronal oxidative stress. Mammalian sterile 20-like kinase (MST1) is a key mediator of oxidative stress in the central nervous system; however, the mechanism of its action in SCI is still not clear. Here, we investigated the role of MST1 activation in induced neuronal oxidative stress in patients with both SCI and diabetes. Methods: Diabetes was established in mice by diet induction combined with intraperitoneal injection of streptozotocin (STZ). SCI was performed at T10 level through weight dropping. Advanced glycation end products (AGEs) were applied to mimic diabetic conditions in PC12 cell line in vitro. We employed HE, Nissl staining, footprint assessment and Basso mouse scale to evaluate functional recovery after SCI. Moreover, immunoblotting, qPCR, immunofluorescence and protein-protein docking analysis were used to detect the mechanism. Results: Regarding in vivo experiments, diabetes resulted in up-regulation of MST1, excessive neuronal apoptosis and weakened motor function in SCI mice. Furthermore, diabetes impeded NRF2-mediated antioxidant defense of neurons in the damaged spinal cord. Treatment with AAV-siMST1 could restore antioxidant properties of neurons to facilitate reactive oxygen species (ROS) clearance, which subsequently promoted neuronal survival to improve locomotor function recovery. In vitro model found that AGEs worsened mitochondrial dysfunction and increased cellular oxidative stress. While MST1 inhibition through the chemical inhibitor XMU-MP-1 or MST1-shRNA infection restored NRF2 nuclear accumulation and its transcription of downstream antioxidant enzymes, therefore preventing ROS generation. However, these antioxidant effects were reversed by NRF2 knockdown. Our in-depth studies showed that over-activation of MST1 in diabetes directly hindered the neuroprotective AKT1, and subsequently fostered NRF2 ubiquitination and degradation via the GSK3β/β-TrCP pathway. Conclusion: MST1 inhibition significantly restores neurological function in SCI mice with preexisting diabetes, which is largely attributed to the activation of antioxidant properties via the GSK3β(Ser 9)/β-TrCP/NRF2 pathway. MST1 may be a promising pharmacological target for the effective treatment of spinal cord injury patients with diabetes. |
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| institution | Directory Open Access Journal |
| issn | 2213-2317 |
| language | English |
| last_indexed | 2024-04-24T16:49:17Z |
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| spelling | doaj.art-2822e87121cf4db4b6d03e89b102e18a2024-03-29T05:50:14ZengElsevierRedox Biology2213-23172024-05-0171103104Inhibition of MST1 ameliorates neuronal apoptosis via GSK3β/β-TrCP/NRF2 pathway in spinal cord injury accompanied by diabetesWeijun Huang0Depeng Wu1Chaoyang Cai2Hui Yao3Zhenming Tian4Yang Yang5Mao Pang6Limin Rong7Bin Liu8Department of Spine Surgery, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, PR China; Guangdong Provincial Center for Quality Control of Minimally Invasive Spine Surgery, Guangzhou, PR China; Guangdong Provincial Center for Engineering and Technology Research of Minimally Invasive Spine Surgery, Guangzhou, PR ChinaDepartment of Spine Surgery, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, PR China; Guangdong Provincial Center for Quality Control of Minimally Invasive Spine Surgery, Guangzhou, PR China; Guangdong Provincial Center for Engineering and Technology Research of Minimally Invasive Spine Surgery, Guangzhou, PR ChinaDepartment of Spine Surgery, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, PR China; Guangdong Provincial Center for Quality Control of Minimally Invasive Spine Surgery, Guangzhou, PR China; Guangdong Provincial Center for Engineering and Technology Research of Minimally Invasive Spine Surgery, Guangzhou, PR ChinaDepartment of Spine Surgery, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, PR ChinaDepartment of Spine Surgery, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, PR China; Guangdong Provincial Center for Quality Control of Minimally Invasive Spine Surgery, Guangzhou, PR China; Guangdong Provincial Center for Engineering and Technology Research of Minimally Invasive Spine Surgery, Guangzhou, PR ChinaDepartment of Spine Surgery, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, PR China; Guangdong Provincial Center for Quality Control of Minimally Invasive Spine Surgery, Guangzhou, PR China; Guangdong Provincial Center for Engineering and Technology Research of Minimally Invasive Spine Surgery, Guangzhou, PR ChinaDepartment of Spine Surgery, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, PR China; Guangdong Provincial Center for Quality Control of Minimally Invasive Spine Surgery, Guangzhou, PR China; Guangdong Provincial Center for Engineering and Technology Research of Minimally Invasive Spine Surgery, Guangzhou, PR ChinaDepartment of Spine Surgery, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, PR China; Guangdong Provincial Center for Quality Control of Minimally Invasive Spine Surgery, Guangzhou, PR China; Guangdong Provincial Center for Engineering and Technology Research of Minimally Invasive Spine Surgery, Guangzhou, PR China; Corresponding author. Department of Spine Surgery, The Third Affiliated Hospital of Sun, Yat-Sen University, Guangzhou, 510630, PR China.Department of Spine Surgery, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, PR China; Guangdong Provincial Center for Quality Control of Minimally Invasive Spine Surgery, Guangzhou, PR China; Guangdong Provincial Center for Engineering and Technology Research of Minimally Invasive Spine Surgery, Guangzhou, PR China; Corresponding author. Department of Spine Surgery, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, 510630, PR China.Aims: Spinal cord injury (SCI) is a devastating neurological disease that often results in tremendous loss of motor function. Increasing evidence demonstrates that diabetes worsens outcomes for patients with SCI due to the higher levels of neuronal oxidative stress. Mammalian sterile 20-like kinase (MST1) is a key mediator of oxidative stress in the central nervous system; however, the mechanism of its action in SCI is still not clear. Here, we investigated the role of MST1 activation in induced neuronal oxidative stress in patients with both SCI and diabetes. Methods: Diabetes was established in mice by diet induction combined with intraperitoneal injection of streptozotocin (STZ). SCI was performed at T10 level through weight dropping. Advanced glycation end products (AGEs) were applied to mimic diabetic conditions in PC12 cell line in vitro. We employed HE, Nissl staining, footprint assessment and Basso mouse scale to evaluate functional recovery after SCI. Moreover, immunoblotting, qPCR, immunofluorescence and protein-protein docking analysis were used to detect the mechanism. Results: Regarding in vivo experiments, diabetes resulted in up-regulation of MST1, excessive neuronal apoptosis and weakened motor function in SCI mice. Furthermore, diabetes impeded NRF2-mediated antioxidant defense of neurons in the damaged spinal cord. Treatment with AAV-siMST1 could restore antioxidant properties of neurons to facilitate reactive oxygen species (ROS) clearance, which subsequently promoted neuronal survival to improve locomotor function recovery. In vitro model found that AGEs worsened mitochondrial dysfunction and increased cellular oxidative stress. While MST1 inhibition through the chemical inhibitor XMU-MP-1 or MST1-shRNA infection restored NRF2 nuclear accumulation and its transcription of downstream antioxidant enzymes, therefore preventing ROS generation. However, these antioxidant effects were reversed by NRF2 knockdown. Our in-depth studies showed that over-activation of MST1 in diabetes directly hindered the neuroprotective AKT1, and subsequently fostered NRF2 ubiquitination and degradation via the GSK3β/β-TrCP pathway. Conclusion: MST1 inhibition significantly restores neurological function in SCI mice with preexisting diabetes, which is largely attributed to the activation of antioxidant properties via the GSK3β(Ser 9)/β-TrCP/NRF2 pathway. MST1 may be a promising pharmacological target for the effective treatment of spinal cord injury patients with diabetes.http://www.sciencedirect.com/science/article/pii/S2213231724000806Spinal cord injury (SCI)DiabetesMammalian sterile20-like kinase (MST1)Oxidative stressNuclear factor erythroid 2-related factor 2 (NRF2) |
| spellingShingle | Weijun Huang Depeng Wu Chaoyang Cai Hui Yao Zhenming Tian Yang Yang Mao Pang Limin Rong Bin Liu Inhibition of MST1 ameliorates neuronal apoptosis via GSK3β/β-TrCP/NRF2 pathway in spinal cord injury accompanied by diabetes Redox Biology Spinal cord injury (SCI) Diabetes Mammalian sterile20-like kinase (MST1) Oxidative stress Nuclear factor erythroid 2-related factor 2 (NRF2) |
| title | Inhibition of MST1 ameliorates neuronal apoptosis via GSK3β/β-TrCP/NRF2 pathway in spinal cord injury accompanied by diabetes |
| title_full | Inhibition of MST1 ameliorates neuronal apoptosis via GSK3β/β-TrCP/NRF2 pathway in spinal cord injury accompanied by diabetes |
| title_fullStr | Inhibition of MST1 ameliorates neuronal apoptosis via GSK3β/β-TrCP/NRF2 pathway in spinal cord injury accompanied by diabetes |
| title_full_unstemmed | Inhibition of MST1 ameliorates neuronal apoptosis via GSK3β/β-TrCP/NRF2 pathway in spinal cord injury accompanied by diabetes |
| title_short | Inhibition of MST1 ameliorates neuronal apoptosis via GSK3β/β-TrCP/NRF2 pathway in spinal cord injury accompanied by diabetes |
| title_sort | inhibition of mst1 ameliorates neuronal apoptosis via gsk3β β trcp nrf2 pathway in spinal cord injury accompanied by diabetes |
| topic | Spinal cord injury (SCI) Diabetes Mammalian sterile20-like kinase (MST1) Oxidative stress Nuclear factor erythroid 2-related factor 2 (NRF2) |
| url | http://www.sciencedirect.com/science/article/pii/S2213231724000806 |
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