7 results on '"Luo, Yinan"'
Search Results
2. MLKL contributes to shikonin-induced glioma cell necroptosis via promotion of chromatinolysis.
- Author
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Ding Y, He C, Lu S, Wang X, Wang C, Wang L, Zhang J, Piao M, Chi G, Luo Y, Sai K, and Ge P
- Subjects
- Animals, Apoptosis Inducing Factor metabolism, Cell Line, Tumor, DNA Fragmentation, DNA, Neoplasm drug effects, Gene Expression Regulation, Neoplastic drug effects, Glioma genetics, Glioma metabolism, Humans, Mice, Mitochondria metabolism, Naphthoquinones pharmacology, Necroptosis, Rats, Reactive Oxygen Species metabolism, Xenograft Model Antitumor Assays, DNA, Neoplasm chemistry, Glioma drug therapy, Naphthoquinones administration & dosage, Protein Kinases metabolism
- Abstract
Chromatinolysis refers to enzymatic degradation of nuclear DNA and is regarded as one of the crucial events leading to cell death. Mixed-lineage kinase domain-like protein (MLKL) has been identified as a key executor of necroptosis, but it remains unclear whether MLKL contributes to necroptosis via regulation of chromatinolysis. In this study, we find that shikonin induces MLKL activation and chromatinolysis in glioma cells in vitro and in vivo, which are accompanied with nuclear translocation of AIF and γ-H2AX formation. In vitro studies reveal that inhibition of MLKL with its specific inhibitor NSA or knockdown of MLKL with siRNA abrogates shikonin-induced glioma cell necroptosis, as well as chromatinolysis. Mechanistically, activated MLKL targets mitochondria and triggers excessive generation of mitochondrial superoxide, which promotes AIF translocation into nucleus via causing mitochondrial depolarization and aggravates γ-H2AX formation via improving intracellular accumulation of ROS. Inhibition of nuclear level of AIF by knockdown of AIF with siRNA or mitigation of γ-H2AX formation by suppressing ROS with antioxidant NAC effectively prevents shikonin-induced chromatinolysis. Then, we found that RIP3 accounts for shikonin-induced activation of MLKL, and activated MLKL reversely up-regulates the protein level of CYLD and promotes the activation of RIP1 and RIP3. Taken together, our data suggest that MLKL contributes to shikonin-induced glioma cell necroptosis via promotion of chromatinolysis, and shikonin induces a positive feedback between MLKL and its upstream signals RIP1 and RIP3., (Copyright © 2019 The Author(s). Published by Elsevier B.V. All rights reserved.)
- Published
- 2019
- Full Text
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3. Pseudolaric acid B triggers ferroptosis in glioma cells via activation of Nox4 and inhibition of xCT.
- Author
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Wang Z, Ding Y, Wang X, Lu S, Wang C, He C, Wang L, Piao M, Chi G, Luo Y, and Ge P
- Subjects
- Amino Acid Transport System y+ metabolism, Animals, Brain Neoplasms pathology, Cell Line, Tumor transplantation, Cyclohexylamines pharmacology, Disease Models, Animal, Diterpenes therapeutic use, Down-Regulation drug effects, Gene Expression Regulation, Neoplastic drug effects, Glioma pathology, Glutathione metabolism, Humans, Hydrogen Peroxide metabolism, Iron metabolism, Mice, Mice, Nude, Mitochondria drug effects, Mitochondria metabolism, NADPH Oxidase 4 metabolism, Phenylenediamines pharmacology, Rats, Reactive Oxygen Species metabolism, Up-Regulation drug effects, Apoptosis drug effects, Brain Neoplasms drug therapy, Diterpenes pharmacology, Glioma drug therapy, Lipid Peroxidation drug effects
- Abstract
Ferroptosis is a form of programmed cell death decided by iron-dependent lipid peroxidation, but its role in glioma cell death remains unclear. In this study, we found Pseudolaric acid B (PAB) inhibited the viabilities of glioma cells in vitro and in vivo, which was accompanied by abnormal increases of intracellular ferrous iron, H
2 O2 and lipid peroxidation, as well as depletion of GSH and cysteine. In vitro studies revealed that the lipid peroxidation and the cell death caused by PAB were both inhibited by iron chelator deferoxamine, but exacerbated by supplement of ferric ammonium citrate. Inhibition of lipid peroxidation with ferrostatin-1 or GSH rescued PAB-induced cell death. Morphologically, the cells treated with PAB presented intact membrane, shrunken mitochondria with increased membrane density, and normal-sized nucleus without chromatin condensation. Mechanistically, PAB improved intracellular iron by upregulation of transferrin receptor. The increased iron activated Nox4, which resulted in overproduction of H2 O2 and lipid peroxides. Moreover, PAB depleted intracellular GSH via p53-mediated xCT pathway, which further exacerbated accumulation of H2 O2 and lipid peroxides. Thus, PAB triggers ferroptosis in glioma cells and is a potential medicine for glioma treatment., (Copyright © 2018 Elsevier B.V. All rights reserved.)- Published
- 2018
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4. RIP1 and RIP3 contribute to shikonin-induced glycolysis suppression in glioma cells via increase of intracellular hydrogen peroxide.
- Author
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Lu B, Wang Z, Ding Y, Wang X, Lu S, Wang C, He C, Piao M, Chi G, Luo Y, and Ge P
- Subjects
- Animals, Cell Line, Tumor, Cysteine metabolism, Gene Expression Regulation, Neoplastic drug effects, Glioma metabolism, Glutathione metabolism, Humans, Mice, Naphthoquinones pharmacology, Rats, Xenograft Model Antitumor Assays, Glioma drug therapy, Glycolysis drug effects, Hydrogen Peroxide metabolism, Naphthoquinones administration & dosage, Nuclear Pore Complex Proteins metabolism, RNA-Binding Proteins metabolism, Receptor-Interacting Protein Serine-Threonine Kinases metabolism
- Abstract
RIP1 and RIP3 are necroptosis initiators, but their roles in regulation of glycolysis remain elusive. In this study, we found shikonin activated RIP1 and RIP3 in glioma cells in vitro and in vivo, which was accompanied with glycolysis suppression. Further investigation revealed that shikonin-induced decreases of glucose-6-phosphate and pyruvate and downregulation of HK II and PKM2 were significantly prevented when RIP1 or RIP3 was pharmacologically inhibited or genetically knocked down with SiRNA. Moreover, shikonin also triggered accumulation of intracellular H
2 O2 and depletion of GSH and cysteine. Mitigation of intracellular H2 O2 via supplement of GSH reversed shikonin-induced glycolysis suppression. The role of intracellular H2 O2 in regulation of glycolysis suppression was further confirmed in the cells treated with exogenous H2 O2 . Notably, inhibition of RIP1 or RIP3 prevented intracellular H2 O2 accumulation, which was correlated with preventing shikonin-induced downregulation of x-CT and depletion of GSH and cysteine. In addition, supplement of pyruvate effectively inhibited shikonin- or exogenous H2 O2 -induced accumulation of intracellular H2 O2 and glioma cell death. Taken together, we demonstrated in this study that RIP1 and RIP3 contributed to shikonin-induced glycolysis suppression via increasing intracellular H2 O2 ., (Copyright © 2018 Elsevier B.V. All rights reserved.)- Published
- 2018
- Full Text
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5. RIP1 and RIP3 contribute to shikonin-induced DNA double-strand breaks in glioma cells via increase of intracellular reactive oxygen species.
- Author
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Zhou Z, Lu B, Wang C, Wang Z, Luo T, Piao M, Meng F, Chi G, Luo Y, and Ge P
- Subjects
- Animals, Cell Line, Tumor, Disease Models, Animal, Heterografts, Mice, Naphthoquinones pharmacology, Nuclear Pore Complex Proteins genetics, RNA-Binding Proteins genetics, Receptor-Interacting Protein Serine-Threonine Kinases genetics, Up-Regulation, DNA Breaks, Double-Stranded drug effects, Glioma drug therapy, Nuclear Pore Complex Proteins metabolism, RNA-Binding Proteins metabolism, Reactive Oxygen Species, Receptor-Interacting Protein Serine-Threonine Kinases metabolism
- Abstract
Shikonin has been reported to induce glioma cell death via necroptosis, a type of programmed necrosis primarily mediated by RIP1 and RIP3. Although RIP1 and RIP3 are found to regulate some features of necrosis such as energy depletion and cellular membrane disruption, it remains unclear whether RIP1 and RIP3 could modulate DNA double strand breaks (DSBs), which is a crucial event leading to chromatinolysis. In this study, we used glioma cell lines and mice model of xenograft glioma to investigate the roles of RIP1 and RIP3 in shikonin-induced DNA DSBs. We found that shikonin induced upregulation of RIP1 and RIP3, necrosome formation and DNA DSBs in vitro and in vivo. In vitro investigation showed that the DNA DSBs and the reduction of cellular viabilities induced by shikonin were both prevented when RIP1 or RIP3 was pharmacologically inhibited by specific inhibitor or genetically knocked down with siRNA. Then, we proved that suppression of intracellular ROS with antioxidant NAC inhibited DNA DSBs caused by either hydrogen peroxide or shikonin, suggesting that ROS played a crucial role in regulation of DNA DSBs of glioma cells induced by shikonin. Further, we found that RIP1 and RIP3 regulated shikonin-induced overproduction of ROS via causing excessive generation of mitochondrial superoxide and depletion of GSH, indicating that ROS was the downstream signal of RIP1 and RIP3. Taken together, we demonstrated that RIP1 and RIP3 contributed to shikonin-induced DNA DSBs in glioma cells via increase of intracellular ROS levels., (Copyright © 2017 Elsevier B.V. All rights reserved.)
- Published
- 2017
- Full Text
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6. Pristimerin triggers AIF-dependent programmed necrosis in glioma cells via activation of JNK.
- Author
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Zhao H, Wang C, Lu B, Zhou Z, Jin Y, Wang Z, Zheng L, Liu K, Luo T, Zhu D, Chi G, Luo Y, and Ge P
- Subjects
- Animals, Cell Growth Processes drug effects, Cell Line, Tumor, Enzyme Activation drug effects, Glioma metabolism, Glioma pathology, Humans, Mice, Inbred BALB C, Mice, Nude, Necrosis, Pentacyclic Triterpenes, Rats, Xenograft Model Antitumor Assays, Antineoplastic Agents pharmacology, Apoptosis Inducing Factor metabolism, Glioma drug therapy, MAP Kinase Kinase 4 metabolism, Triterpenes pharmacology
- Abstract
Programmed necrosis is established as a new form of programmed cell death and is emerging as a new strategy of treatment for cancers. Pristimerin is a natural chemical with anti-tumor effect despite the fact that its mechanism remains poorly understood. In this study, we used glioma cell lines and mice model of xenograft glioma to investigate the effect of pristimerin on glioma and its underlying mechanism. We found that pristimerin inhibited the viabilities of glioma cells in vitro and the growth of xenograft gliomas in vivo, which was accompanied by upregulation of JNK and phosphor-JNK, nuclear accumulation of AIF, and elevation in the ratio of Bax/Bcl-2. In vitro studies showed that pristimerin induced necrosis in glioma cells, as well as mitochondrial depolarization, overproduction of ROS and reduction of GSH. Ablation of AIF level with SiRNA mitigated pristimerin-induced nuclear accumulation of AIF and prevented necrosis in glioma cells. Moreover, pharmacological inhibition of JNK with SP600125 or knockdown of its level with SiRNA reversed mitochondrial depolarization attenuated the elevation of Bax/Bcl-2 and suppressed nuclear accumulation of AIF. Further, inhibition of ROS with NAC not only rescued glioma cell necrosis but also suppressed JNK activation, mitigated Bax/Bcl-2 ratio, maintained mitochondrial membrane potential, and inhibited AIF translocation into nucleus. Therefore, we demonstrated first in this study that pristimerin triggered AIF-dependent necroptosis in glioma cells via induction of mitochondrial dysfunction by activation of JNK through overproduction of ROS. These results suggest that pristimerin has potential therapeutic effects on glioma., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)
- Published
- 2016
- Full Text
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7. Deoxypodophyllotoxin triggers parthanatos in glioma cells via induction of excessive ROS.
- Author
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Ma D, Lu B, Feng C, Wang C, Wang Y, Luo T, Feng J, Jia H, Chi G, Luo Y, and Ge P
- Subjects
- Active Transport, Cell Nucleus, Animals, Antioxidants pharmacology, Apoptosis Inducing Factor metabolism, Brain Neoplasms genetics, Brain Neoplasms metabolism, Brain Neoplasms pathology, Cell Death drug effects, Cell Line, Tumor, Dose-Response Relationship, Drug, Drugs, Chinese Herbal, Glioma genetics, Glioma metabolism, Glioma pathology, Humans, Membrane Potential, Mitochondrial drug effects, Mice, Inbred BALB C, Mice, Nude, Podophyllotoxin pharmacology, Poly (ADP-Ribose) Polymerase-1, Poly(ADP-ribose) Polymerase Inhibitors pharmacology, Poly(ADP-ribose) Polymerases genetics, Poly(ADP-ribose) Polymerases metabolism, RNA Interference, Rats, Signal Transduction drug effects, Time Factors, Transfection, Tumor Burden drug effects, Xenograft Model Antitumor Assays, Antineoplastic Agents pharmacology, Brain Neoplasms drug therapy, Glioma drug therapy, Oxidative Stress drug effects, Podophyllotoxin analogs & derivatives, Reactive Oxygen Species metabolism
- Abstract
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.)
- Published
- 2016
- Full Text
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