脑出血(Intracerebral hemorrhage ,ICH)是一种预后不良的脑血管疾病，约占全球脑卒中的10%至15%，其高致残率、死亡率为患者家庭和社会带来了沉重负担[1,2]。虽然经过多年研究，脑出血患者的急性期管理取得了显著进展，但在脑出血后继发性脑损伤方面的效果仍然有限。脑出血的不良预后主要是由于血肿占位压迫引起的原发性脑损伤以及机械刺激和血肿成分毒性刺激引发的继发性脑损伤[3,4]。原发性损伤和继发性损伤均可导致神经细胞死亡，最终引起神经功能丧失[5]。探寻脑出血后神经细胞死亡相关的内源性蛋白可能为脑出血的基础研究和提供新靶点。 宽带数字电视机顶盒Intracerebral hemorrhage (ICH) is a cerebrovascular disease with poor prognosis, accounting for approximately 10% to 15% of strokes worldwide, and its high disability rate and mortality place a heavy burden on patients' families and society [1,2]. Although significant progress has been made in the acute phase management of patients with Intracerebral hemorrhage after many years of research, the effectiveness of treatment for secondary brain injury after intracerebral hemorrhage remains limited. The poor prognosis of intracerebral hemorrhage is mainly due to primary brain injury caused by hematoma-occ
太阳能淋浴器upied compression and secondary brain injury triggered by mechanical stimulation and toxic stimulation of hematoma components [3, 4]. Both primary and secondary injuries can lead to nerve cell death and eventually lead to loss of nerve function [5]. The exploration of endogenous proteins related to nerve cell death after intracerebral hemorrhage may provide new targets for basic research and treatment of intracerebral hemorrhage.
脑出血后神经细胞的死亡模式主要包含凋亡、焦亡、铁死亡等，焦亡（Pyroptosis）是一种新型的炎症相关性细胞程序性死亡形式[6,35]。经典的细胞焦亡途径主要依赖于半胱天冬酶-1(cysteinyl aspartate specific proteinase 1,Caspase-1)，当细胞受到病原相关或者损伤相关刺激时，由NLRs（NOD-like receptor）、凋亡相关斑点样蛋白（apoptosis-associated speck-like protein, ASC）和Caspase-1构成的炎性小体被激活，最终导致Caspase-1的剪切活化[7,34]。活化的Caspase-1可参与机体固有免疫反应，介导炎症因子的剪切与释放。与此同时，Caspase-1也可以剪切活化细胞焦亡执行蛋白gasdermin D(GSDMD），导致细胞膜穿孔，最终引起细胞焦亡[8,36]。
The death modes of nerve cells after intracerebral hemorrhage mainly include apoptosis, pyroptosis, ferroptosis, etc. Pyroptosis is a novel form of inflammatory related programmed cell death [6, 35]. The classical pyroptosis pathway mainly depends on cysteinyl aspartate specific proteinase 1(Caspase-1). When cells are subjected to etiological or damage-related stimuli, the inflammasome composed of NLRs (NOD-like receptor), apoptosis-associated speck-like protein (ASC) and Caspase-1 is activated, which eventually leads to the shear activation of Caspase-1 [7,34]. Activated Caspase-1 can participate in the innate immune response and mediate the shear and release of inflammatory factors. At the same time, Caspase-1 can also shear and activate the pyroptosis executive protein gasdermin D (GSDMD), leading to cell membrane perforation and ultimately to pyroptosis [8, 36].
神经元Per-Arnt-Sim结构域蛋白4(Neuronal Per-Arnt-Sim domain protein 4，NPAS4) ，是碱性螺旋-环-螺旋(BHLH)-PAS蛋白家族中的一员，是在神经系统中高度特异性表达的一种转录因子[9,10]。BHLH-PAS蛋白是bHLH转录因子超家族的成员，它们通常包含两个结构
保守的PAS结构域[11]。研究表明，bHLH-PAS蛋白参与许多生物学过程，如中枢神经系统的发育和缺氧后的生理反应等[12,37,38]。越来越多的研究表明NPAS4在神经系统疾病中起到重要作用，据报道，NPAS4在多种脑损伤中表达上调，包括局灶性和全局性缺血性中风[9,13-16]。并且，有研究表明，NPAS4在缺血性脑卒中、自闭症、抑郁症和认知障碍等神经系统疾病中发挥重要作用[17-19]。然而，NPAS4对脑出血后继发性脑损伤的作用仍然未知。
Neuronal Per-Arnt-Sim domain protein 4(NPAS4), a member of the basic helix-loop-helix (BHLH)-PAS protein family, is a transcription factor highly specifically expressed in the nervous system [9, 10]. BHLH-PAS protein is a member of the bHLH transcription factor superfamily, which typically contain two structurally conserved PAS domains [11]. Studies have shown that bHLH-PAS protein is involved in many biological processes, such as the development of central nervous system and physiological response after hypoxia 棉絮加工[12, 37, 38]. More and more studies have shown that NPAS4 plays an important role in neurological diseases, and it has been reported that NPAS4 shows up-regulation in a vari速闭阀
ety of brain injuries, including focal and global ischemic strokes [9, 13-16]. Moreover, studies have shown that NPAS4 plays an important role in neurological diseases such as ischemic stroke, autism, depression, cognitive disorders, etc [17-19]. However, the role of NPAS4 in secondary brain injury after intracerebral hemorrhage remains unknown.
为进一步探索NPAS4在脑出血后脑损伤中发挥作用的具体机制，我们通过生物信息学分析，预测出NPAS4与NLR家族热蛋白结构域蛋白6(NOD-like receptor pyrin domain containing 6，Nlrp6)基因启动子区域存在结合位点。NLRP6是已报道的人类NLR蛋白家族的新成员，它可以在宿主炎症和微生物防御中发挥作用[7,20]。NLRP6同其他NLRs家族成员一样，可在机体免疫反应中组成炎性小体，调节Caspase-1的活化[21]。我们课题组前期研究发现，敲低NLRP6的表达，可减轻脑出血后的脑损伤，提示NLRP6炎性小体的活化可以加重脑出血后脑损伤[22]。
In order to further explore the specific mechanism of NPAS4's role in brain injury after intracerebral hemorrhage, we predicted, through bioinformatics analysis, that there is a binding site in the promoter region between the NPAS4 and NLR family pyrin domain prot
ein 6 (NOD-like receptor pyrin domain containing 6, Nlrp6) gene. NLRP6 is a new member of the human NLR protein family reported to play a role in host inflammation and microbial defense [7, 20]. NLRP6, like other NLRs family members, can form inflammasome and regulate the activation of Caspase-1 in the body's immune response [21]古籍扫描仪. Our research group's previous study found that knocking down the expression of NLRP6 can reduce brain injury after intracerebral hemorrhage, suggesting that the activation of NLRP6 inflammasome can aggravate brain injury after intracerebral hemorrhage [22].
基于以上研究背景，我们推测NPAS4可能通过转录调控NLRP6的表达，调节NLRP6下游因子Caspase-1的活化，参与ICH后神经细胞焦亡损伤，这将补充脑出血后继发性脑损伤的基础研究。本研究将探讨NPAS4在脑出血中的作用及其可能机制。
Based on the above research background, we speculate that NPAS4 may regulate the expression of NLRP6 through transcription, regulate the activation of NLRP6 downstream factor Caspase-1, and participate in the pyroptosis injury of nerve cells after ICH, which w
ill supplement the basic research on secondary brain injury after intracerebral hemorrhage. This study will investigate the role of NPAS4 in intracerebral hemorrhage and its possible mechanism
细胞焦亡是细胞病理性死亡的主要形式之一，其特征为甘汞电极细胞膜孔道形成和破裂、核DNA断裂、染质浓缩等，其中主要由Caspase-1依赖途径导致的细胞膜破坏将焦亡与传统凋亡区别开来[25]。在脑血管疾病中，缺血性脑卒中模型和脑出血模型均显示抑制Caspase-1介导的神经细胞焦亡可以起到明显的神经保护作用[26-28]。抑制焦亡可能为脑出血后脑损伤提供潜在的策略。焦亡相关蛋白Caspase-1和N-GSDMD的表达升高，干扰NPAS4可降低Caspase-1和N-GSDMD的表达，减轻细胞焦亡。
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