Cyclic helix B peptide alleviates proinflammatory cell death and improves functional recovery after traumatic spinal cord injury
Yu Xu,
Yibo Geng,
Hui Wang,
Haojie Zhang,
Jianjun Qi,
Feida Li,
Xinli Hu,
Yituo Chen,
Haipeng Si,
Yao Li,
Xiangyang Wang,
Huazi Xu,
Jianzhong Kong,
Yuepiao Cai,
Aimin Wu,
Wenfei Ni,
Jian Xiao,
Kailiang Zhou
Affiliations
Yu Xu
Department of Orthopaedics, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, 325027, China; Zhejiang Provincial Key Laboratory of Orthopaedics, Wenzhou, 325027, China; Department of Orthopedics, Qilu Hospital of Shandong University, Jinan, 250012, China
Yibo Geng
Department of Orthopaedics, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, 325027, China; Zhejiang Provincial Key Laboratory of Orthopaedics, Wenzhou, 325027, China
Hui Wang
Department of Orthopaedics, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, 325027, China; Zhejiang Provincial Key Laboratory of Orthopaedics, Wenzhou, 325027, China
Haojie Zhang
Department of Orthopaedics, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, 325027, China; Zhejiang Provincial Key Laboratory of Orthopaedics, Wenzhou, 325027, China
Jianjun Qi
Department of Clinical Laboratory, The First Affiliated Hospital of Wannan Medical College (Yi jishan Hospital of Wannan Medical College), Wuhu, 241001, China
Feida Li
Department of Orthopaedics, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, 325027, China; Zhejiang Provincial Key Laboratory of Orthopaedics, Wenzhou, 325027, China
Xinli Hu
Department of Orthopaedics, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, 325027, China; Zhejiang Provincial Key Laboratory of Orthopaedics, Wenzhou, 325027, China
Yituo Chen
Department of Orthopaedics, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, 325027, China; Zhejiang Provincial Key Laboratory of Orthopaedics, Wenzhou, 325027, China
Haipeng Si
Department of Orthopedics, Qilu Hospital of Shandong University, Jinan, 250012, China
Yao Li
Department of Orthopaedics, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, 325027, China; Zhejiang Provincial Key Laboratory of Orthopaedics, Wenzhou, 325027, China
Xiangyang Wang
Department of Orthopaedics, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, 325027, China; Zhejiang Provincial Key Laboratory of Orthopaedics, Wenzhou, 325027, China
Huazi Xu
Department of Orthopaedics, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, 325027, China; Zhejiang Provincial Key Laboratory of Orthopaedics, Wenzhou, 325027, China
Jianzhong Kong
Department of Orthopaedics, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, 325027, China; Zhejiang Provincial Key Laboratory of Orthopaedics, Wenzhou, 325027, China
Yuepiao Cai
Molecular Pharmacology Research Center, School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, 325000, China
Aimin Wu
Department of Orthopaedics, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, 325027, China; Zhejiang Provincial Key Laboratory of Orthopaedics, Wenzhou, 325027, China
Wenfei Ni
Department of Orthopaedics, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, 325027, China; Zhejiang Provincial Key Laboratory of Orthopaedics, Wenzhou, 325027, China; Corresponding author. Department of Orthopaedics, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, 325027, China.
Jian Xiao
Molecular Pharmacology Research Center, School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, 325000, China; Corresponding author. Molecular Pharmacology Research Center, School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, 325000, China.
Kailiang Zhou
Department of Orthopaedics, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, 325027, China; Zhejiang Provincial Key Laboratory of Orthopaedics, Wenzhou, 325027, China; Corresponding author. Department of Orthopaedics, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, 325027, China.
Background: Necroptosis and pyroptosis, two types of proinflammatory programmed cell death, were recently found to play important roles in spinal cord injury (SCI). Moreover, cyclic helix B peptide (CHBP) was designed to maintain erythropoietin (EPO) activity and protect tissue against the adverse effects of EPO. However, the protective mechanism of CHBP following SCI is still unknown. This research explored the necroptosis- and pyroptosis-related mechanism underlying the neuroprotective effect of CHBP after SCI. Methods: Gene Expression Omnibus (GEO) datasets and RNA sequencing were used to identify the molecular mechanisms of CHBP for SCI. A mouse model of contusion SCI was constructed, and HE staining, Nissl staining, Masson staining, footprint analysis and the Basso Mouse Scale (BMS) were applied for histological and behavioural analyses. qPCR, Western blot analysis, immunoprecipitation and immunofluorescence were utilized to analyse the levels of necroptosis, pyroptosis, autophagy and molecules associated with the AMPK signalling pathway. Results: The results revealed that CHBP significantly improved functional restoration, elevated autophagy, suppressed pyroptosis, and mitigated necroptosis after SCI. 3-Methyladenine (3-MA), an autophagy inhibitor, attenuated these beneficial effects of CHBP. Furthermore, CHBP-triggered elevation of autophagy was mediated by the dephosphorylation and nuclear translocation of TFEB, and this effect was due to stimulation of the AMPK-FOXO3a-SPK2-CARM1 and AMPK-mTOR signalling pathways. Conclusion: CHBP acts as a powerful regulator of autophagy that improves functional recovery by alleviating proinflammatory cell death after SCI and thus might be a prospective therapeutic agent for clinical application.
