Parthanatos is a type of programmed cell death dependent on hyper-activation of poly (ADP-ribose) polymerase 1 (PARP-1). SIRT1 is a highly conserved nuclear deacetylase and often acts as an inhibitor of parthanatos by deacetylation of PARP1. Our previous study showed that deoxypodophyllotoxin (DPT), a natural compound isolated from the traditional herb Anthriscus sylvestris, triggered glioma cell death via parthanatos. In this study, we investigated the role of SIRT1 in DPT-induced human glioma cell parthanatos. We showed that DPT (450 nmol/L) activated both PARP1 and SIRT1, and induced parthanatos in U87 and U251 glioma cells. Activation of SIRT1 with SRT2183 (10 μmol/L) enhanced, while inhibition of SIRT1 with EX527 (200 μmol/L) or knockdown of SIRT1 attenuated DPT-induced PARP1 activation and glioma cell death. We demonstrated that DPT (450 nmol/L) significantly decreased intracellular NAD+ levels in U87 and U251 cells. Further decrease of NAD+ levels with FK866 (100 μmol/L) aggravated, but supplement of NAD+ (0.5, 2 mmol/L) attenuated DPT-induced PARP1 activation. We found that NAD+ depletion enhanced PARP1 activation via two ways: one was aggravating ROS-dependent DNA DSBs by upregulation of NADPH oxidase 2 (NOX2); the other was reinforcing PARP1 acetylation via increase of N-acetyltransferase 10 (NAT10) expression. We found that SIRT1 activity was improved when being phosphorylated by JNK at Ser27, the activated SIRT1 in reverse aggravated JNK activation via upregulating ROS-related ASK1 signaling, thus forming a positive feedback between JNK and SIRT1. Taken together, SIRT1 activated by JNK contributed to DPT-induced human glioma cell parthanatos via initiation of NAD+ depletion-dependent upregulation of NOX2 and NAT10.

Parthanatos is a type of programmed cell death initiated by over-activated poly (ADP-ribose) polymerase 1 (PARP1). Nuclear translocation of apoptosis inducing factor (AIF) is a prominent feature of parthanatos. But it remains unclear how activated nuclear PARP1 induces mitochondrial AIF translocation into nuclei. Evidence has shown that deoxypodophyllotoxin (DPT) induces parthanatos in glioma cells via induction of excessive ROS. In this study we explored the downstream signal of activated PARP1 to induce nuclear translocation of AIF in DPT-triggered glioma cell parthanatos. We showed that treatment with DPT (450 nM) induced PARP1 over-activation and Tax1 binding protein 1 (TAX1BP1) distribution to mitochondria in human U87, U251 and U118 glioma cells. PARP1 activation promoted TAX1BP1 distribution to mitochondria by depleting nicotinamide adenine dinucleotide (NAD+). Knockdown of TAX1BP1 with siRNA not only inhibited TAX1BP1 accumulation in mitochondria, but also alleviated nuclear translocation of AIF and glioma cell death. We demonstrated that TAX1BP1 enhanced the activity of respiratory chain complex I not only by upregulating the expression of ND1, ND2, NDUFS2 and NDUFS4, but also promoting their assemblies into complex I. The activated respiratory complex I generated more superoxide to cause mitochondrial depolarization and nuclear translocation of AIF, while the increased mitochondrial superoxide reversely reinforced PARP1 activation by inducing ROS-dependent DNA double strand breaks. In mice bearing human U87 tumor xenograft, administration of DPT (10 mg· kg−1 ·d−1, i.p., for 8 days) markedly inhibited the tumor growth accompanied by NAD+ depletion, TAX1BP1 distribution to mitochondria, AIF distribution to nuclei as well as DNA DSBs and PARP1 activation in tumor tissues. Taken together, these data suggest that TAX1BP1 acts as a downstream signal of activated PARP1 to trigger nuclear translocation of AIF by activation of mitochondrial respiratory chain complex I.

BNIP3 is found to eliminate cancer cells via causing mitochondrial damage and endoplasmic reticulum stress, but it remains elusive of its role in regulating DNA double strand breaks (DSBs). In this study, we find that silibinin triggers DNA DSBs, ROS accumulation and expressional upregulation of BNIP3 in glioma cells. Mitigation of ROS with antioxidant GSH significantly inhibits silibinin-induced DNA DSBs and glioma cell death. Then, we find knockdown of BNIP3 with SiRNA obviously prevents silibinin-induced DNA DSBs and ROS accumulation. Mechanistically, BNIP3 knockdown not only reverses silibinin-triggered depletion of cysteine and GSH via maintaining xCT level, but also abrogates catalase decrease. Notably, silibinin-induced dephosphorylation of mTOR is also prevented when BNIP3 is knocked down. Given that activated mTOR could promote xCT expression and inhibit autophagic degradation of catalase, our data suggest that BNIP3 contributes to silibinin-induced DNA DSBs via improving intracellular ROS by inhibition of mTOR.

Ferroptosis triggered by hemin is regarded as a primary factor accounting for neuronal death secondary to intracerebral hemorrhage. Thus, compounds with inhibitory effect on hemin-induced ferroptosis might be potential medicines to prevent neuronal death caused by intracerebral hemorrhage. Herein, we investigate whether maltol could alleviate hemin-induced SH-SY5Y cell ferroptosis and its potential mechanisms. It is found that maltol effectively prevents hemin-induced SH-SY5Y cell ferroptosis via three pathways. The first one is inhibiting intracellular iron increase via preventing upregulation of transferrin receptor, the second one is alleviating lipid peroxidation via attenuating H2O2 generation by NOX4 and promoting H2O2 clearance by catalase, and the third one is to reduce peroxidized lipids via maintaining GPX4/GSH pathway. Therefore, maltol is a novel agent preventing hemin-induced SH-SY5Y cell ferroptosis.

FOXO3a (forkhead box transcription factor 3a) is involved in regulating multiple biological processes in cancer cells. BNIP3 (Bcl-2/adenovirus E1B 19-kDa-interacting protein 3) is a receptor accounting for priming damaged mitochondria for autophagic removal. In this study we investigated the role of FOXO3a in regulating the sensitivity of glioma cells to temozolomide (TMZ) and its relationship with BNIP3-mediated mitophagy. We showed that TMZ dosage-dependently inhibited the viability of human U87, U251, T98G, LN18 and rat C6 glioma cells with IC 50 values of 135.75, 128.26, 142.65, 155.73 and 111.60 μM, respectively. In U87 and U251 cells, TMZ (200 μM) induced DNA double strand breaks (DSBs) and nuclear translocation of apoptosis inducing factor (AIF), which was accompanied by BNIP3-mediated mitophagy and FOXO3a accumulation in nucleus. TMZ treatment induced intracellular ROS accumulation in U87 and U251 cells via enhancing mitochondrial superoxide, which not only contributed to DNA DSBs and exacerbated mitochondrial dysfunction, but also upregulated FOXO3a expression. Knockdown of FOXO3a aggravated TMZ-induced DNA DSBs and mitochondrial damage, as well as glioma cell death. TMZ treatment not only upregulated BNIP3 and activated autophagy, but also triggered mitophagy by prompting BNIP3 translocation to mitochondria and reinforcing BNIP3 interaction with LC3BII. Inhibition of mitophagy by knocking down BNIP3 with SiRNA or blocking autophagy with 3MA or bafilomycin A1 exacerbated mitochondrial superoxide and intracellular ROS accumulation. Moreover, FOXO3a knockdown inhibited TMZ-induced BNIP3 upregulation and autophagy activation. In addition, we showed that treatment with TMZ (100 mg·kg −1 ·d −1 , ip) for 12 days in C6 cell xenograft mice markedly inhibited tumor growth accompanied by inducing FOXO3a upregulation, oxidative stress and BNIP3-mediated mitophagy in tumor tissues. These results demonstrate that FOXO3a attenuates temozolomide-induced DNA double strand breaks in human glioma cells via promoting BNIP3-mediated mitophagy.

Ferroptotic cell death is characterized by iron-dependent lipid peroxidation that is initiated by ferrous iron and H 2 O 2 via Fenton reaction, in which the role of activating transcription factor 3 (ATF3) remains elusive. Brucine is a weak alkaline indole alkaloid extracted from the seeds of Strychnos nux-vomica , which has shown potent antitumor activity against various tumors, including glioma. In this study, we showed that brucine inhibited glioma cell growth in vitro and in vivo, which was paralleled by nuclear translocation of ATF3, lipid peroxidation, and increases of iron and H 2 O 2 . Furthermore, brucine-induced lipid peroxidation was inhibited or exacerbated when intracellular iron was chelated by deferoxamine (500 μM) or improved by ferric ammonium citrate (500 μM). Suppression of lipid peroxidation with lipophilic antioxidants ferrostatin-1 (50 μM) or liproxstatin-1 (30 μM) rescued brucine-induced glioma cell death. Moreover, knockdown of ATF3 prevented brucine-induced accumulation of iron and H 2 O 2 and glioma cell death. We revealed that brucine induced ATF3 upregulation and translocation into nuclei via activation of ER stress. ATF3 promoted brucine-induced H 2 O 2 accumulation via upregulating NOX4 and SOD1 to generate H 2 O 2 on one hand, and downregulating catalase and xCT to prevent H 2 O 2 degradation on the other hand. H 2 O 2 then contributed to brucine-triggered iron increase and transferrin receptor upregulation, as well as lipid peroxidation. This was further verified by treating glioma cells with exogenous H 2 O 2 alone. Moreover, H 2 O 2 reversely exacerbated brucine-induced ER stress. Taken together, ATF3 contributes to brucine-induced glioma cell ferroptosis via increasing H 2 O 2 and iron.

Induction of lethal autophagy has become a strategy to eliminate glioma cells, but it remains elusive whether autophagy contributes to cell death via causing mitochondria damage and nuclear translocation of apoptosis inducing factor (AIF). In this study, we find that silibinin induces AIF translocation from mitochondria to nuclei in glioma cells in vitro and in vivo, which is accompanied with autophagy activation. In vitro studies reveal that blocking autophagy with 3MA, bafilomycin A1 or by knocking down ATG5 with SiRNA inhibits silibinin-induced mitochondrial accumulation of superoxide, AIF translocation from mitochondria to nuclei and glioma cell death. Mechanistically, silibinin activates autophagy through depleting ATP by suppressing glycolysis. Then, autophagy improves intracellular H2O2 via promoting p53-mediated depletion of GSH and cysteine and downregulation of xCT. The increased H2O2 promotes silibinin-induced BNIP3 upregulation and translocation to mitochondria. Knockdown of BNIP3 with SiRNA inhibits silibinin-induced mitochondrial depolarization, accumulation of mitochondrial superoxide, and AIF translocation from mitochondria to nuclei, as well as prevents glioma cell death. Furthermore, we find that the improved H2O2 reinforces silibinin-induced glycolysis dysfunction. Collectively, autophagy contributes to silibinin-induced glioma cell death via promotion of oxidative stress-mediated BNIP3-dependent nuclear translocation of AIF.

脑出血有较高的病死率及致残率,而血肿增大则严重影响病人预后.因此,早期评估血肿增大风险并予以针对性治疗有助于改善病人预后.近年来,血肿增大预测因素的研究很多.本文详细总结了血肿增大的相关预测因素,从病人性别、血压、实验室检查、影像学检查等方面作一综述,从而更具针对性的预测血肿增大风险. 1 性别 有多变量分析认为男性脑出血病人的血肿增大风险及早晚期病死率高于女性脑出血病人,其机制有待进一步研究[1].其原因可能为:不同性别病人脑损伤的生物学途径存在差异,导致血肿增大的可能性不同;生活方式等不同所致的病人动脉粥样硬化及心脑血管疾病发病率差异.但有关此方面的研究较少,故需更多研究来明确性别与血肿增大之间的关系.

Objective To summarize experience in treating the ruptured anterior circulation aneurysms by the microsurgery via lateral supraorbital (LSO) approach. Methods The clinical data of 70 patients with 74 ruptured anterior circulation aneurysms (Hunt-Hess grade Ⅰ to Ⅲ), who underwent microsurgery via from March, 2014 to July, 2017 were analyzed retrospectively. The therapeutic outcomes were assessed by GOS score 3~6 months after the surgery. Results A total of 73 aneurysms were successfully occluded and 1 aneurysm successfully wrapped in 70 patients. The mean operation duration was (152.5 ± 15.6) min. The length of operative cut was(9.3±0.9)cm and average hospital stay was(12.1±3.7)days.CTA or DSA showed that all the aneurysms were totally occluded on discharge from hospital. No aneurysms recurred in all the patients during the following up from 3 to 6 months. Of 70 patients,66 were recovered well,3 moderately disabled and 1 severely disabled according to GOS score 3~6 months after the surgery. Conclusions The microsurgery via LSO approach is suitable for treatment of patients with ruptured anterior circulation aneurysms and is worth spreading at present stage because it may provide sufficient surgical exposure and was relatively minimally invasive.

正>颅内动脉瘤破裂所致蛛网膜下腔出血的发生率在脑卒中排名第三,仅次于脑梗死及高血压脑出血。而脑积水是其主要并发症之一,常需二次手术治疗。有学者研究指出动脉瘤夹闭术中行终板造瘘可以降低脑积水的发生率,也有学者持相反观点。本文结合国内外文献就终板造瘘对动脉瘤破裂所致蛛网膜下腔出血后脑积水影响的研究进展进行综述。脑积水是动脉瘤性蛛网膜下腔出血（aneurysmal subarachnoid hemorrhage,aSAH）后主要并发

目的 探讨眶上外侧入路与翼点入路显微手术治疗急性期前循环破裂动脉瘤的疗效.方法 2014年3月至2015年9月采用显微手术治疗Hunt-Hess分级Ⅰ～Ⅲ级急性期前循环破裂动脉瘤81例,经眶上外侧入路夹闭43例(观察组),翼点入路夹闭38例(对照组).结果 观察组手术时间[(152.7±19.1)min]、手术切口长度[(9.1±0.9)cm]、住院时间[(12.3±3.6)d]较对照组[分别为(182.4±26.6) min、(15.1±1.1)cm、(15.3±2.8)d]均明显减少(P＜0.01).两组术后3个月GOS评分无统计学差异(P＞0.05).结论 眶上外侧入路创伤小、手术时间短、术后恢复快,治疗Hunt-Hess分级低级别急性期前循环破裂动脉瘤手术效果良好.