Department of Orthopedics, The First Hospical of China Medical University, Shenyang, Liaoning Province, 110001, China; Third People's Hospital of Dalian, Dalian, Liaoning Province, 116091, China.
Third People's Hospital of Dalian, Dalian, Liaoning Province, 116091, China.
Biomed Pharmacother. 2018 Jul;103:127-134. doi: 10.1016/j.biopha.2018.03.117. Epub 2018 Apr 24.
HIPK2 is considered to be a tumor suppressor. It also has been implicated in several functions such as apoptosis and inflammation that are linked to spinal cord injury (SCI). However, whether HIPK2 ameliorates the neurological pain of SCI remains unclear. Here, we investigated the effects of HIPK2 on neurological function, oxidative stress, levels of inflammatory cytokines and expression of Bcl-2/Bax in an SCI model. Firstly, we evaluated the therapeutic effects of HIPK2 on neurological pain in the SCI rat using the Basso, Beattie and Bresnahan scores and H & E staining. Overexpression of HIPK2 significantly elevated the levels of brain-derived neurotrophic factor (BDNF) and glial cell line-derived neurotrophic factor (GDNF), and reduced the mRNA expression of Nogo-A and RhoA in SCI rats. Furthermore, terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) assays showed that overexpression of HIPK2 significantly reduced the number of apoptotic cells. Overexpression of HIPK2 also decreased expression of Bax and Caspase-3 and elevated expression of Bcl-2 in the SCI model, indicating that HIPK2 exhibited its protective activity by inhibiting SCI-induced apoptosis. Then, we measured the serum concentrations of malondialdehyde (MDA), superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GSH-PX). We also determined the mRNA and protein levels of nuclear factor-κB p65 unit, tumor necrosis factor-α (TNF-α), and interleukin (IL)-1β. HIPK2 overexpression reduced oxidative stress and the levels of inflammatory cytokines compared with SCI control animals. Additionally, acetylation of HIPK2 was reduced in SCI rats. Overexpression of HIPK2 could enhance autophagy by elevating the expression of Beclin-1 and LC3-II while autophagy is regarded as a beneficial regulator to improve spinal cord injury. Together, overexpression of HIPK2 improved contusive SCI induced pain by modulating oxidative stress, Bcl‑2 and Bax signaling, and inflammation, and also regulating autophagy.
HIPK2 被认为是一种肿瘤抑制因子。它还与几种功能有关，如凋亡和炎症，这些功能与脊髓损伤 (SCI) 有关。然而，HIPK2 是否能改善 SCI 的神经痛尚不清楚。在这里，我们研究了 HIPK2 在 SCI 模型中对神经功能、氧化应激、炎症细胞因子水平和 Bcl-2/Bax 表达的影响。首先，我们使用 Basso、Beattie 和 Bresnahan 评分和 H&E 染色评估了 HIPK2 对 SCI 大鼠神经痛的治疗作用。HIPK2 的过表达显著提高了脑源性神经营养因子 (BDNF) 和胶质细胞源性神经营养因子 (GDNF) 的水平，并降低了 SCI 大鼠中 Nogo-A 和 RhoA 的 mRNA 表达。此外，末端脱氧核苷酸转移酶介导的 dUTP 缺口末端标记 (TUNEL) 检测显示，HIPK2 的过表达显著减少了凋亡细胞的数量。HIPK2 的过表达还降低了 SCI 模型中 Bax 和 Caspase-3 的表达，同时增加了 Bcl-2 的表达，表明 HIPK2 通过抑制 SCI 诱导的细胞凋亡发挥其保护作用。然后，我们测量了血清中丙二醛 (MDA)、超氧化物歧化酶 (SOD)、过氧化氢酶 (CAT) 和谷胱甘肽过氧化物酶 (GSH-PX) 的浓度。我们还测定了核因子-κB p65 单位、肿瘤坏死因子-α (TNF-α) 和白细胞介素 (IL)-1β 的 mRNA 和蛋白水平。与 SCI 对照组相比，HIPK2 的过表达降低了氧化应激和炎症细胞因子的水平。此外，SCI 大鼠中 HIPK2 的乙酰化减少。HIPK2 的过表达通过提高 Beclin-1 和 LC3-II 的表达来增强自噬，而自噬被认为是一种有益的调节剂，可改善脊髓损伤。总之，HIPK2 通过调节氧化应激、Bcl-2 和 Bax 信号以及炎症，以及调节自噬，改善了压迫性 SCI 诱导的疼痛。
