scholarly journals Blockage of NOX2/MAPK/NF-κB Pathway Protects Photoreceptors against Glucose Deprivation-Induced Cell Death

2017 ◽  
Vol 2017 ◽  
pp. 1-14 ◽  
Author(s):  
Bin Fan ◽  
Bei-Fen Wang ◽  
Lin Che ◽  
Ying-Jian Sun ◽  
Shu-Yan Liu ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Cell Death ◽  
Western Blot ◽  
Glucose Deprivation ◽  
Photoreceptor Cells ◽  
Retinal Neurons ◽  
Dependent Cell ◽  
Ischemic Diseases ◽  
Cell Death Cascade ◽  
Energy Failure

Acute energy failure is one of the critical factors contributing to the pathogenic mechanisms of retinal ischemia. Our previous study demonstrated that glucose deprivation can lead to a caspase-dependent cell death of photoreceptors. The aim of this study was to decipher the upstream signal pathway in glucose deprivation- (GD-) induced cell death. We mimicked acute energy failure by using glucose deprivation in photoreceptor cells (661W cells). GD-induced oxidative stress was evaluated by measuring ROS with the DCFH-DA assay and HO-1 expression by Western blot analysis. The activation of NOX2/MAPK/NF-κB signal was assessed by Western blot and immunohistochemical assays. The roles of these signals in GD-induced cell death were measured by using their specific inhibitors. Inhibition of Rac-1 and NOX2 suppressed GD-induced oxidative stress and protected photoreceptors against GD-induced cell death. NOX2 was an upstream signal in the caspase-dependent cell death cascade, yet the downstream MAPK pathways were activated and blocking MAPK signals rescued 661W cells from GD-induced death. In addition, GD caused the activation of NF-κB signal and inhibiting NF-κB significantly protected 661W cells. These observations may provide insights for treating retinal ischemic diseases and protecting retinal neurons from ischemia-induced cell death.

scholarly journals Overexpression of Transcripts Coding for Renin-b but Not for Renin-a Reduce Oxidative Stress and Increase Cardiomyoblast Survival under Starvation Conditions

Cells ◽  
2021 ◽  
Vol 10 (5) ◽  
pp. 1204
Author(s):  
Heike Wanka ◽  
Philipp Lutze ◽  
Alexander Albers ◽  
Janine Golchert ◽  
Doreen Staar ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Cell Death ◽  
B Cells ◽  
Apoptotic Cell ◽  
Renin Angiotensin System ◽  
Glucose Deprivation ◽  
Protective Effects ◽  
Glucose Depletion ◽  
A Cells ◽  
Apoptosis And Necrosis

A stimulated renin-angiotensin system is known to promote oxidative stress, apoptosis, necrosis and fibrosis. Renin transcripts (renin-b; renin-c) encoding a cytosolic renin isoform have been discovered that may in contrast to the commonly known secretory renin (renin-a) exert protective effects Here, we analyzed the effect of renin-a and renin-b overexpression in H9c2 cardiomyoblasts on apoptosis and necrosis as well as on potential mechanisms involved in cell death processes. To mimic ischemic conditions, cells were exposed to glucose starvation, anoxia or combined oxygen–glucose deprivation (OGD) for 24 h. Under OGD, control cells exhibited markedly increased necrotic and apoptotic cell death accompanied by enhanced ROS accumulation, loss of mitochondrial membrane potential and decreased ATP levels. The effects of OGD on necrosis were exaggerated in renin-a cells, but markedly diminished in renin-b cells. However, with respect to apoptosis, the effects of OGD were almost completely abolished in renin-b cells but interestingly also moderately diminished in renin-a cells. Under glucose depletion we found opposing responses between renin-a and renin-b cells; while the rate of necrosis and apoptosis was aggravated in renin-a cells, it was attenuated in renin-b cells. Based on our results, strategies targeting the regulation of cytosolic renin-b as well as the identification of pathways involved in the protective effects of renin-b may be helpful to improve the treatment of ischemia-relevant diseases.

scholarly journals The role of DJ-1 in the oxidative stress cell death cascade after stroke

2014 ◽  
Vol 9 (15) ◽  
pp. 1430 ◽  
Author(s):  
Naoki Tajiri ◽  
Yuji Kaneko ◽  
Paolina Pantcheva ◽  
Maya Elias ◽  
Kelsey Duncan ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Cell Death ◽  
Cell Death Cascade

scholarly journals ROS Mediate xCT-Dependent Cell Death in Human Breast Cancer Cells under Glucose Deprivation

Cells ◽  
2020 ◽  
Vol 9 (7) ◽  
pp. 1598 ◽  
Author(s):  
Mei-Chun Chen ◽  
Li-Lin Hsu ◽  
Sheng-Fan Wang ◽  
Chih-Yi Hsu ◽  
Hsin-Chen Lee ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cell Death ◽  
Cancer Cells ◽  
Cancer Progression ◽  
Breast Cancer Cells ◽  
Critical Role ◽  
Glucose Deprivation ◽  
Glutathione Biosynthesis ◽  
Dependent Cell ◽  
Amp Activated Protein Kinase

xCT, also known as solute carrier family 7 member 11 (SLC7A11), the light chain of the cystine/glutamate antiporter, is positively correlated with cancer progression due to antioxidant function. During glucose deprivation, the overexpression of xCT does not protect cancer cells but instead promotes cell death. Further understanding the mechanism of glucose deprivation-induced cell death is important for developing anticancer treatments targeting the glucose metabolism. In this study, we found that breast cancer cells with a high expression of xCT demonstrated increased levels of reactive oxygen species (ROS) and were more sensitive to glucose deprivation than the cells with a low expression of xCT. However, AMP-activated protein kinase (AMPK) did not significantly affect glucose-deprivation-induced cell death. The antioxidant N-acetyl-cysteine prevented glucose-deprivation-induced cell death, and the glutathione biosynthesis inhibitor L-buthionine-S, R-sulfoximine enhanced glucose-deprivation-induced cell death. The inhibition of xCT by sulfasalazine or a knockdown of xCT reduced the glucose-deprivation-increased ROS levels and glucose-deprivation-induced cell death. Glucose deprivation reduced the intracellular glutamate, and supplementation with α-ketoglutarate prevented the glucose-deprivation-increased ROS levels and rescued cell death. The knockdown of sirtuin-3 (SIRT3) further enhanced the ROS levels, and promoted xCT-related cell death after glucose deprivation. In conclusion, our results suggested that ROS play a critical role in xCT-dependent cell death in breast cancer cells under glucose deprivation.

scholarly journals Screening for Lung Cancer with Low Dose Computed Tomography (LDCT)

2021 ◽  
pp. 794-832
Author(s):  
Elena Locci ◽  
Silvia Raymond
Keyword(s):  
Oxidative Stress ◽  
Cell Death ◽  
Research Team ◽  
Low Dose ◽  
Small Cell ◽  
Small Cell Lung ◽  
Tumor Cell Death ◽  
Dependent Cell ◽  
Keywords Cancer ◽  
Low Dose Computed Tomography

Using samples of small cell lung tumors, a research team led by biologist Dr. Raymond discovered two new ways to induce tumor cell death. By activating ferroptosis, one of two subtypes of tumor cells can be targeted: first, iron-dependent cell death due to oxidative stress, and second, oxidative stress. Therefore, cell death can also be induced in a different way. Both types of cell death must be caused by drugs at the same time to eliminate the majority of the tumor mass. Keywords: Cancer; Cells; Tissues, Tumors; Prevention, Prognosis; Diagnosis; Imaging; Screening; Treatment; Management

scholarly journals Role of CNC1 gene in TDP-43 aggregation-induced oxidative stress-mediated cell death in S. cerevisiae model of ALS

2020 ◽  
Author(s):  
Vidhya Bharathi ◽  
Amandeep Girdhar ◽  
Basant K Patel
Keyword(s):  
Oxidative Stress ◽  
Cell Death ◽  
Stress Response ◽  
Molecular Mechanisms ◽  
Motor Neuron Diseases ◽  
C Protein ◽  
Cell Death Pathway ◽  
Cyclin C ◽  
Dependent Cell ◽  
Anti Oxidant

ABSTRACTTDP-43 is a multi-functional ribonucleoprotein that is also found deposited as hyper-phosphorylated and ubiquitinated TDP-43 inclusions in the brain and spinal cord of the patients of the motor neuron diseases, amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). Till date, how the cell death ensues is not fully deciphered although several molecular mechanisms of the TDP-43 toxicity such as impairments of endocytosis and chromatin remodelling, mis-regulations of autophagy and proteasome function, mis-localization to the mitochondria and generation of oxidative stress etc., have been proposed. A predominantly nuclear protein, Cyclin C, can regulate the oxidative stress response by affecting the transcription of stress response genes and also by translocation to the cytoplasm for the activation of the mitochondrial fragmentation-dependent cell death pathway. Using the well-established yeast model of TDP-43 aggregation and toxicity, we examined here whether upon TDP-43 aggregation, the cell survival depends on the presence of the CNC1 gene that encodes Cyclin C protein or other genes that encode proteins that function in conjunction with Cyclin C, such as the DNM1, FIS1 and MED13 genes. We found that the TDP-43 toxicity is significantly reduced in the yeast deleted for the CNC1 or DNM1 genes. Importantly, the rescue of TDP-43 toxicity in these yeast deletion backgrounds required the presence of functional mitochondria. Also, the deletion of YBH3 gene, which encodes for a protein involved in the mitochondria-dependent apoptosis, also reduced the TDP-43 toxicity. Furthermore, Cyclin C-YFP was observed to localize from the nucleus to the cytoplasm in response to the TDP-43 co-expression. Also, this cytoplasmic localization of Cyclin C was prevented by the addition of an anti-oxidant molecule, N-acetyl-cysteine. Taken together, our data suggest that Cyclin C, Dnm1 and Ybh3 proteins are important in mediating the TDP-43-induced oxidative stress-mediated cell death in the S. cerevisiae model.

scholarly journals Loss of protein targeting to glycogen sensitizes human hepatocellular carcinoma cells towards glucose deprivation mediated oxidative stress and cell death

2015 ◽  
Vol 35 (3) ◽  
Author(s):  
Rongqiang Yang ◽  
Mei Zhang ◽  
Amber Renee Gustafson ◽  
Eugenia Wang ◽  
Marsha Paulette Cole ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Hepatocellular Carcinoma ◽  
Cell Death ◽  
Protein Targeting ◽  
Glucose Deprivation ◽  
Carcinoma Cells ◽  
Glycogen Accumulation ◽  
Liver Cancer Cells ◽  
Human Hepatocellular Carcinoma Cells ◽  
And Oxidative Stress

PTG is a protein that is critical for glycogen accumulation in various tissues such as the liver. Our present study shows that its loss sensitizes liver cancer cells towards metabolic and oxidative stress.

scholarly journals ATRT-02. THE DUAL MTORC1/2 INHIBITOR, TAK-228 COMBINES SYNERGISTICALLY WITH THE BH3 MIMETIC, OBATOCLAX TO IMPROVE SURVIVAL IN MICE BEARING ORTHOTOPIC XENOGRAFTS OF AT/RT

2021 ◽  
Vol 23 (Supplement_1) ◽  
pp. i1-i1
Author(s):  
Tyler Findlay ◽  
Ashlyn Parkhurst ◽  
Sabrina Wang ◽  
Charles Eberhart ◽  
Eric Raabe ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Cell Death ◽  
Transcription Factor ◽  
Western Blot ◽  
Leucine Zipper ◽  
T Test ◽  
Normal Brain ◽  
Cell Viability Assay ◽  
Orthotopic Xenografts ◽  
Bh3 Mimetic

Abstract mTOR activation drives tumorigenicity by regulating transcription factor expression and downstream growth and survival pathways. We have previously shown that mTORC1 and mTORC2 are highly activated in AT/RT and the dual mTORC1/2 inhibitor, TAK-228 (Sapanisertib) improves survival in mice bearing orthotopic xenografts of AT/RT. To design a rational combination therapy that enhances TAK-228’s efficacy and durability, we performed RNASeq 4 hours after TAK-228 treatment of AT/RT cell models. Pathway analysis revealed disruption of the NRF2-mediated stress response. NRF2 is a cap’n’collar leucine zipper transcription factor that regulates expression of genes involved in redox homeostasis, energy metabolism, cell proliferation, and survival. Analysis of publicly available RNASeq data on 32 human tumors identified elevated expression of NRF2 in AT/RT (median expression 40.78, normal brain 18.81). Short-hairpin knockdown of NRF2 decreased the expression of NRF2 as well as the anti-apoptotic proteins MCL-1, BCL-xL, and BCL-2 (western blot), and intracellular concentrations of reduced glutathione (p<0.005, t-test). TAK-228 similarly decreased expression of NRF2, MCL-1, and glutathione (p<0.005, t-test) demonstrating that TAK-228 compromises AT/RT defenses against oxidative stress and cell death. The brain-penetrant BH3 mimetic, Obatoclax increases oxidative stress and induces apoptosis in AT/RT (MUSE oxidative stress, cPARP western blot, t-test p<0.05). These complementary mechanisms of action synergize to slow AT/RT cell growth (MUSE Cell viability assay, ANOVA p<0.05) and induce high rates of cell death (MUSE ANNEXIN V assay, ANOVA p<0.05, Western blot for cPARP, Compusyn Synergy analysis CI<1.0). Once-weekly treatments of TAK-228 combined with Obatoclax in orthotopic mouse models of AT/RT is well tolerated, slows tumor growth (bioluminescence imaging, ANOVA p<0.05) and significantly extends median survival from 35 to 55 days (Log-rank p<0.05). These findings support a new clinical trial aimed at improving AT/RT survival.

scholarly journals Salubrinal Enhances Cancer Cell Death during Glucose Deprivation through the Upregulation of xCT and Mitochondrial Oxidative Stress

Biomedicines ◽  
2021 ◽  
Vol 9 (9) ◽  
pp. 1101
Author(s):  
Mei-Chun Chen ◽  
Li-Lin Hsu ◽  
Sheng-Fan Wang ◽  
Yi-Ling Pan ◽  
Jeng-Fan Lo ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Cell Death ◽  
Cancer Cells ◽  
Cancer Cell ◽  
Redox Homeostasis ◽  
Glucose Deprivation ◽  
Metabolic Flexibility ◽  
Mitochondrial Oxidative Stress ◽  
Cancer Cell Death ◽  
Adaptation Response

Cancer cells have the metabolic flexibility to adapt to heterogeneous tumor microenvironments. The integrated stress response (ISR) regulates the cellular adaptation response during nutrient stress. However, the issue of how the ISR regulates metabolic flexibility is still poorly understood. In this study, we activated the ISR using salubrinal in cancer cells and found that salubrinal repressed cell growth, colony formation, and migration but did not induce cell death in a glucose-containing condition. Under a glucose-deprivation condition, salubrinal induced cell death and increased the levels of mitochondrial reactive oxygen species (ROS). We found that these effects of salubrinal and glucose deprivation were associated with the upregulation of xCT (SLC7A11), which functions as an antiporter of cystine and glutamate and maintains the level of glutathione to maintain redox homeostasis. The upregulation of xCT did not protect cells from oxidative stress-mediated cell death but promoted it during glucose deprivation. In addition, the supplementation of ROS scavenger N-acetylcysteine and the maintenance of intracellular levels of amino acids via sulfasalazine (xCT inhibitor) or dimethyl-α-ketoglutarate decreased the levels of mitochondrial ROS and protected cells from death. Our results suggested that salubrinal enhances cancer cell death during glucose deprivation through the upregulation of xCT and mitochondrial oxidative stress.

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