Cerebral ischemia-reperfusion injury (CIRI) is the second leading cause of death worldwide, posing a huge risk to human life and health. Therefore, investigating the pathogenesis underlying CIRI and developing effective treatments are essential. Ferroptosis is an iron-dependent mode of cell death, which is caused by disorders in iron metabolism and lipid peroxidation. Previous studies demonstrated that ferroptosis is also a form of autophagic cell death, and nuclear receptor coactivator 4(NCOA4) mediated ferritinophagy was found to regulate ferroptosis by interfering with iron metabolism. Ferritinophagy and ferroptosis are important pathogenic mechanisms in CIRI. This review mainly summarizes the link and regulation between ferritinophagy and ferroptosis and further discusses their mechanisms in CIRI. In addition, the potential treatment methods targeting ferritinophagy and ferroptosis for CIRI are presented, providing new ideas for the prevention and treatment of clinical CIRI in the future.

ObjectiveTo explore the mechanisms of acupuncture against cerebral ischemia/reperfusion injury （CIRI） through observing the expression of circular RNA HDAC2 （circHDAC2） in the hippocampus of rats.MethodsSD rats were randomly divided into sham-operation， model and acupuncture groups， with 13 rats in each group. The rat model of CIRI was established by middle cerebral artery occlusion. In the acupuncture group， acupuncture was delivvered at “Dazhui” （GV14）， “Shuigou” （GV26） and “Baihui” （GV20）， and the needles were retained for 30 min each time and acupuncture was conducted once every 12 h for a total of 7 sessions. Before and after intervention， using modified Garcia scale， the neurological function of the rats were evaluated， and TTC staining was employed to determine the cerebral infarct area. Gene chip technology was used to screen the circRNAs with differential expressions in the ischemic hippocampus， and the circRNAs with co-differential expression （co-DE circRNAs） in the model group/sham-operation group， and the acupuncture group/model group separately. Among those circRNAs， the core circRNAs were screened according to P value， fold change （FC） and gene ontology （GO） analysis； and their expressions in the ischemic hippocampus were determined using quantitative real-time PCR （qPCR）. Based on the verification results， a competing endogenous RNA （ceRNA） prediction network was constructed. The expression levels of microRNA （miRNA） and mRNA with high node centrality in the prediction network were validated by qPCR.ResultsBefore intervention， compared with the sham-operation group， the modified Garcia score of each modeling group decreased （P<0.01）. After intervention， the modified Garcia score was reduced and the cerebral infarct area ratio increased （P<0.01） in the model group when compared with the sham-operation group. In the acupuncture group， the modified Garcia score was higher and the cerebral infarct area ratio lower （P<0.01） than those of the model group. The microarray results of gene chip showed that 16 co-DE circRNAs were down-regulated in the model group and up-regulated in the acupuncture group， and 7 co-DE circRNAs up-regulated in the model group and down-regulated in the acupuncture group. The core circHDAC2 and circNTRK2 were screened according to P value， FC and the enrichment number of GO entries. QPCR results showed that， compared with the sham-operation group， the expression of circHDAC2 and circNTRK2 of the ischemic hippocampal tissue was down-regulated in the model group （P<0.01）； and that of circHDAC2 and circNTRK2 up-regulated in the acupuncture group when compared with the model group （P<0.01）. The relevant ceRNA regulatory network was constructed for circHDAC2 and the prediction results showed that the regulatory networks contained 12 miRNAs and 31 mRNAs. Results of verifying miRNA with high network node centrality and mRNA relevant with nerve regulation showed that， when compared with the sham-operation group， the expression levels of miR-29a， miR-29b and the solute carrier family 30 member 3 （SLC30A3） mRNA in the ischemic hippocampus were down-regulated （P<0.01）； and those of miR-3065 and mercaptopyruvate sulfurtransferase （MPST） up-regulated （P<0.01） in the model group. Compared with the model group， the expressions of miR-29a， miR-29b and SLC30A3 mRNA in the ischemic hippocampus were up-regulated （P<0.01，P<0.05）， while that of miR-3065 down-regulated （P<0.05） in the acupuncture group.ConclusionAcupuncture significantly improves the neurological function and reduces the cerebral infarct area in CIRI rats， which may be related to the regulation of hippocampal circHDAC2/miR-3065/SLC30A3 axis.

"或针结,针着大肠泄水穴"指以病邪凝结经络,气血运行受阻为主要病机之结病,可针刺大肠俞和二间两个穴位.经络腧穴理论中,大肠俞属足太阳膀胱经,是大肠之经气转输、聚结体表所在,有疏调肠胃、宣导气血之功,二间为大肠经的水穴,可针泻用以治疗大肠经的各种实证.标本气街理论中,大肠俞属于背俞穴,位于标部,二间穴属于五输穴,位于本部,本部与标部穴位相配可流转十二经气,利于气血运行.气街与标本关系密切,大肠俞位于背部,可治疗相应脏腑疾病.气血津液与脏腑学说中,针刺二间穴可以使大肠传化糟粕,调节津液代谢的功能恢复正常.针刺大肠俞可宣泄水液,调节膀胱的津液代谢.基于以上理论探讨"或针结,针着大肠泄水穴"中选穴及配穴方法切实可行,可为临床治疗结病提供参考.

目的 探讨针刺对脑缺血再灌注损伤(CIRI)大鼠脑保护作用与海马组织差异表达核心基因、转录网中信使RNAs(mRNAs)功能之间的联系,为针刺调控环状RNAs(circRNAs)抗CIRI后神经损伤研究提供参考.方法 将54只SD大鼠随机分为假手术组、模型组和针刺组,每组18只,后两组采用改良Longa线栓法制备大脑中动脉阻塞再灌注模型,假手术组仅剥离血管,不插线栓.干预期内针刺组捆绑于鼠板并针刺"大椎""水沟""百会"穴,均匀捻转刺激1 min,频率为90次/min,15 min后行针1次,共留针30 min,每12 h干预1次,共7次.假手术组、模型组捆绑于鼠板不针刺.改良加西亚(Garcia)评分法检测大鼠神经功能状况,2,3,5-氯化三苯基四氮唑(TTC)染色法观察脑梗死面积;通过基因芯片技术筛选缺血侧海马组织差异表达基因,整理出模型组/假手术组、针刺组/模型组共同差异表达的环状RNAs(co-DE circRNAs),根据P值、差异倍数(FC)、基因本体(GO)数据库条目富集数量筛选出高表达的核心co-DE circRNAs,分析核心co-DE circRNAs来源基因的GO功能;统计缺血侧海马CA1区尼氏染色阳性细胞数;通过实时荧光定量逆转录聚合酶链式反应(RT-qPCR)法验证核心co-DE circRNAs表达量,选取表达趋势与芯片结果一致的circRNAs进行竞争性内源RNA(ceRNA)网络预测,对预测网络中的mRNAs进行GO功能富集分析.结果 干预前,与假手术组比较,各造模组改良Garcia 神经功能评分显著降低(P<0.05);干预后,与假手术组比较,模型组脑梗死面积比显著升高,改良 Garcia 神经功能评分和CA1区尼氏染色阳性细胞数显著降低(P<0.05);与模型组比较,针刺组脑梗死面积比显著降低,改良Garcia 神经功能评分和CA1区尼氏染色阳性细胞数显著升高(P<0.05);组内干预前后比较,针刺组改良Garcia 神经功能评分显著升高(P<0.05).芯片结果显示,模型组下调/针刺组上调、模型组上调/针刺组下调的co-DE circRNAs为23个,根据FC>1.25和GO数据库条目富集数量筛选出核心基因为环状RNA组蛋白去乙酰化酶2基因(circHDAC2)、环状RNA神经营养受体酪氨酸激酶2基因(circNTRK2);GO数据库分析显示,二者富集于神经元的产生、神经系统发育、神经元分化等条目.验证其表达量发现,与假手术组比较,模型组大鼠缺血侧海马组织circHDAC2、circNTRK2 表达量均显著下调(P<0.05);与模型组比较,针刺组大鼠缺血侧海马组织circHDAC2、circNTRK2表达量均显著上调(P<0.05).circHDAC2表达趋势与芯片结果一致,由此对circHDAC2 构建相关 ceRNA调控网络,调控网络中mRNAs的GO分析主要富集在神经元的产生、神经元分化的调控、轴突引导、神经系统发育、神经元死亡的调节等条目.结论 针刺可改善CIRI大鼠改良 Garcia神经功能评分与脑梗死面积比,降低缺血侧海马组织的神经元损伤,其作用可能与调控缺血侧海马组织circHDAC2表达以及激发调控网络中mRNA的神经元产生、神经元分化、神经元细胞体功能等有关.