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Parthanatos is a form of PARP-1-dependent programmed cell death. The induction of parthanatos is emerging as a new strategy to kill gliomas which are the most common type of primary malignant brain tumor. Oxidative stress is thought to be a critical factor triggering parthanatos, but its underlying mechanism is poorly understood. In this study, we used glioma cell lines and H 2 O 2 to investigate the role of JNK in glioma cell parthanatos induced by oxidative stress. We found that exposure to H 2 O 2 not only induced intracellular accumulation of ROS but also resulted in glioma cell death in a concentration- and incubation time-dependent manner, which was accompanied with cytoplasmic formation of PAR polymer, expressional upregulation of PARP-1, mitochondrial depolarization, and AIF translocation to nucleus. Pharmacological inhibition of PARP-1 with 3AB or genetic knockdown of its level with siRNA rescued glioma cell death, as well as suppressed cytoplasmic accumulation of PAR polymer and nuclear translocation of AIF, which were consistent with the definition of parthanatos. Moreover, the phosphorylated level of JNK increased markedly with the extension of H 2 O 2 exposure time. Either attenuation of intracellular ROS with antioxidant NAC or inhibition of JNK phosphorylation with SP600125 or JNK siRNA could significantly prevent H 2 O 2 -induced parthanatos in glioma cells. Additionally, inhibition of JNK with SP600125 alleviated intracellular accumulation of ROS and attenuated mitochondrial generation of superoxide. Thus, we demonstrated that JNK activation contributes to glioma cell parthanatos caused by oxidative stress via increase of intracellular ROS generation.

Oxidative stress, which is characterized by excessive production of reactive oxygen species (ROS), is a common pathway that results in neuronal injury or death due to various types of pathological stress. Although lycopene has been identified as a potent antioxidant, its effect on hydrogen peroxide (H2O2)‑induced neuronal damage remains unclear. In the present study, pretreatment with lycopene was observed to protect SH‑SY5Y neuroblastoma cells against H2O2‑induced death via inhibition of apoptosis resulting from activation of caspase‑3 and translocation of apoptosis inducing factor (AIF) to the nucleus. Furthermore, the over‑produced ROS, as well as the reduced activities of anti‑oxidative enzymes, superoxide dismutase and catalase, were demonstrated to be alleviated by lycopene. Additionally, lycopene counteracted H2O2‑induced mitochondrial dysfunction, which was evidenced by suppression of mitochondrial permeability transition pore opening, attenuation of the decline of the mitochondrial membrane potential, and inhibition of the increase of Bax and decrease of Bcl‑2 levels within the mitochondria. The release of cytochrome c and AIF from the mitochondria was also reduced. These results indicate that lycopene is a potent neuroprotectant against apoptosis, oxidative stress and mitochondrial dysfunction, and could be administered to prevent neuronal injury or death.

Parthanatos is a new form of programmed cell death that is regulated by hyper-activated PARP-1, and is emerging as a new strategy to kill cancer cells. Deoxypodophyllotoxin (DPT) is a natural chemical that is found to induce cancer cell death, in which the role of parthanatos is unknown. Thus, we investigated this issue in this study by using glioma cell lines and mice model of xenograft glioma. We found that DPT induced glioma cell death in vitro and inhibited the growth of xenograft glioma in vivo, which was accompanied with parthanatos-related biochemical events including expressional upregulation of PARP-1, cytoplasmic accumulation of PAR polymer, and nuclear translocation of AIF. In vitro study revealed that genetic knockdown of PARP-1 with small interfering RNA attenuated DPT-induced elevation in the cytoplasmic PAR-polymer and the nuclear AIF, as well as protected glioma cells against the toxicity of DPT. Further, antioxidant NAC, as well as PARP-1 inhibitor 3AB, not only alleviated the overproduction of ROS caused by DPT, but also reversed the above-mentioned biochemical events, maintained mitochondrial membrane potential and rescued glioma cells death. Therefore, we demonstrated that deoxypodophyllotoxin triggered parthanatos in glioma cells via induction of excessive ROS., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Objective: To investigate the effects of inhalation of hydrogen gas on cognitive impairment induced by transient cerebral ischemia and its potential mechanism., Methods: Two-vessel occlusion rat model was used to produce 10-minute transient global cerebral ischemia. One hundred and twenty male Wistar rats were randomly divided into sham, sham+H(2), ischemia, and ischemia+H(2) groups (n = 30 each group). Inhalation of 2% hydrogen gas was performed immediately at the end of operation and lasted for 3 hours. Cognitive function of rats was evaluated via Morris water maze. Neuronal damage in the CA1 region was quantified according to their morphological changes revealed by hematoxylin-eosin staining. The levels of oxidative stress products malondialdehyde (MDA) and 8-iso-prostaglandin F2alpha, and the activities of anti-oxidative enzymes catalase and superoxide dismutase were measured to investigate the effects of inhalation of hydrogen gas on oxidative stress., Results: Inhalation of hydrogen gas decreased significantly the average latency of the ischemic rats in finding hidden platform and elongated markedly their retention in the target quadrant. The neuronal density 3·3±2·1 cells/mm in CA1 region of the ischemic rats increased to 21·7±2·6 cells/mm after they were treated with hydrogen gas. Moreover, hydrogen gas made higher levels of MDA and 8-iso-PGF2α in the ischemic rats attenuate to 3·2±0·2, 3·5±0·5, 3·4±0·3 and 26·4±2·3, 28·2±2·6, 26·8±2·1 at reperfusion 4, 24, and 72 hours, respectively (P<0·01 versus ischemia group at each indicated time). By contrast, the activities of superoxide dismutase and catalase damaged by ischemia/reperfusion recovered to 129·7±14·8, 100·5±12·2 and 11·4±0·8, 9·6±1·1 at reperfusion 24 and 72 hours, respectively (P<0·01 versus ischemia group at each indicated time)., Conclusion: Inhalation of hydrogen gas could attenuate cognitive impairment in the ischemic rats. This protection is associated with decreased neuronal death in CA1 region and inhibition of oxidative stress.

Protein aggregation has been proved to be a pathological basis accounting for neuronal death caused by either transient global ischemia or oxygen glucose deprivation (OGD), and inhibition of protein aggregation is emerging as a potential strategy of preventing brain damage. Trehalose was found to inhibit protein aggregation caused by neurodegenerative diseases via induction of autophagy, whereas its effect is still elusive on ischemia-induced protein aggregation. In this study, we investigated this issue by using rat model of transient global ischemia and SH-SY5Y model of OGD. We found that pretreatment with trehalose inhibited transient global ischemia-induced neuronal death in the hippocampus CA1 neurons and OGD-induced death in SH-SY5Y cells, which was associated with inhibition of the formation of ubiquitin-labeled protein aggregates and preservation of proteasome activity. In vitro study showed that the protection of trehalose against OGD-induced cell death and protein aggregation in SH-SY5Y cells was reversed when proteasome activity was inhibited by MG-132. Further studies revealed that trehalose prevented OGD-induced reduction of proteasome activity via suppression of both oxidative stress and endoplasmic reticulum stress. Particularly, our results showed that trehalose inhibited OGD-induced autophagy. Therefore, we demonstrated that proteasome dysfunction contributed to protein aggregation caused by ischemic insults and trehalose prevented protein aggregation via preservation of proteasome activity, not via induction of autophagy. [ABSTRACT FROM AUTHOR]

Background and Purpose: Shikonin was reported to induce necroptosis in leukemia cells, but apoptosis in glioma cell lines. Thus, it is needed to clarify whether shikonin could cause necroptosis in glioma cells and investigate its underlying mechanisms. Methods: Shikonin and rat C6 glioma cell line and Human U87 glioma cell line were used in this study. The cellular viability was assayed by MTT. Flow cytometry with annexin V-FITC and PI double staining was used to analyze cellular death modes. Morphological alterations in C6 glioma cells treated with shikoinin were evaluated by electronic transmission microscopy and fluorescence microscopy with Hoechst 33342 and PI double staining. The level of reactive oxygen species was assessed by using redox-sensitive dye DCFH-DA. The expressional level of necroptosis associated protein RIP-1 was analyzed by western blotting. Results: Shikonin induced cell death in C6 and U87 glioma cells in a dose and time dependent manner. The cell death in C6 and U87 glioma cells could be inhibited by necroptosis inhibitor necrotatin-1, not by pan-caspase inhibitor z-VAD-fmk. Shikonin treated C6 glioma cells presented electron-lucent cytoplasm, loss of plasma membrane integrity and intact nuclear membrane in morphology. The increased ROS level caused by shikonin was attenuated by necrostatin-1 and blocking ROS by anti-oxidant NAC rescued shikonin-induced cell death in both C6 and U87 glioma cells. Moreover, the expressional level of RIP-1 was up-regulated by shikonin in a dose and time dependent manner as well, but NAC suppressed RIP-1 expression. Conclusions: We demonstrated that the cell death caused by shikonin in C6 and U87 glioma cells was mainly via necroptosis. Moreover, not only RIP-1 pathway, but also oxidative stress participated in the activation of shikonin induced necroptosis. [ABSTRACT FROM AUTHOR]