The Brain Uncoupling Protein UCP4 Attenuates Mitochondrial Toxin-Induced Cell Death: Role of Extracellular Signal-Regulated Kinases in Bioenergetics Adaptation and Cell Survival

2009 ◽  
Vol 16 (1) ◽  
pp. 14-29 ◽  
Author(s):  
Zelan Wei ◽  
Srinivasulu Chigurupati ◽  
Pamela Bagsiyao ◽  
Alicia Henriquez ◽  
Sic L. Chan
Keyword(s):  
Cell Death ◽  
Cell Survival ◽  
Uncoupling Protein ◽  
Extracellular Signal ◽  
Mitochondrial Toxin ◽  
The Brain

scholarly journals Glutathione Suppresses Cerebral Infarct Volume and Cell Death after Ischemic Injury: Involvement of FOXO3 Inactivation and Bcl2 Expression

2015 ◽  
Vol 2015 ◽  
pp. 1-11 ◽  
Author(s):  
Juhyun Song ◽  
Joohyun Park ◽  
Yumi Oh ◽  
Jong Eun Lee
Keyword(s):  
Cell Death ◽  
Ischemic Stroke ◽  
Cerebral Infarction ◽  
Infarct Size ◽  
Cell Survival ◽  
Ischemia Reperfusion ◽  
Ischemic Injury ◽  
Cerebral Infarct ◽  
Ros Scavenging ◽  
The Brain

Ischemic stroke interrupts the flow of blood to the brain and subsequently results in cerebral infarction and neuronal cell death, leading to severe pathophysiology. Glutathione (GSH) is an antioxidant with cellular protective functions, including reactive oxygen species (ROS) scavenging in the brain. In addition, GSH is involved in various cellular survival pathways in response to oxidative stress. In the present study, we examined whether GSH reduces cerebral infarct size after middle cerebral artery occlusionin vivoand the signaling mechanisms involved in the promotion of cell survival after GSH treatment under ischemia/reperfusion conditionsin vitro. To determine whether GSH reduces the extent of cerebral infarction, cell death after ischemia, and reperfusion injury, we measured infarct size in ischemic brain tissue and the expression of claudin-5 associated with brain infarct formation. We also examined activation of the PI3K/Akt pathway, inactivation of FOXO3, and expression of Bcl2 to assess the role of GSH in promoting cell survival in response to ischemic injury. Based on our results, we suggest that GSH might improve the pathogenesis of ischemic stroke by attenuating cerebral infarction and cell death.

scholarly journals Osteopontin Expression in the Brain Triggers Localized Inflammation and Cell Death When Immune Cells Are Activated by Pertussis Toxin

2014 ◽  
Vol 2014 ◽  
pp. 1-12 ◽  
Author(s):  
Maria Cecilia Garibaldi Marcondes ◽  
Ryan Ojakian ◽  
Nikki Bortell ◽  
Claudia Flynn ◽  
Bruno Conti ◽  
...  
Keyword(s):  
Cell Death ◽  
Pertussis Toxin ◽  
Inflammatory Cells ◽  
Brain Inflammation ◽  
Molecular Pattern ◽  
Expression Site ◽  
Pattern Characteristic ◽  
Peripheral Cells ◽  
The Brain

Upregulation of osteopontin (OPN) is a characteristic of central nervous system pathologies. However, the role of OPN in inflammation is still controversial, since it can both prevent cell death and induce the migration of potentially damaging inflammatory cells. To understand the role of OPN in inflammation and cell survival, we expressed OPN, utilizing an adenoviral vector, in the caudoputamen of mice deficient in OPN, using beta-galactosidase- (β-gal-) expressing vector as control. The tissue pathology and the expression of proinflammatory genes were compared in both treatments. Interestingly, inflammatory infiltrate was only found when the OPN-vector was combined with a peripheral treatment with pertussis toxin (Ptx), which activated peripheral cells to express the OPN receptor CD44v6. Relative toβ-gal, OPN increased the levels of inflammatory markers, including IL13Rα1, CXCR3, and CD40L. In Ptx-treated OPN KOs, apoptotic TUNEL+ cells surrounding the OPN expression site increased, compared toβ-gal. Together, these results show that local OPN expression combined with a peripheral inflammatory stimulus, such as Ptx, may be implicated in the development of brain inflammation and induction of cell death, by driving a molecular pattern characteristic of cytotoxicity. These are characteristics of inflammatory pathologies of the CNS in which OPN upregulation is a hallmark.

scholarly journals A sart1 Zebrafish Mutant Results in Developmental Defects in the Central Nervous System

Cells ◽  
2020 ◽  
Vol 9 (11) ◽  
pp. 2340
Author(s):  
Hannah E. Henson ◽  
Michael R. Taylor
Keyword(s):  
Central Nervous System ◽  
Cell Death ◽  
Nervous System ◽  
Developmental Defects ◽  
Whole Exome ◽  
The Central Nervous System ◽  
And Function ◽  
Upregulated Genes ◽  
The Brain

The spliceosome consists of accessory proteins and small nuclear ribonucleoproteins (snRNPs) that remove introns from RNA. As splicing defects are associated with degenerative conditions, a better understanding of spliceosome formation and function is essential. We provide insight into the role of a spliceosome protein U4/U6.U5 tri-snRNP-associated protein 1, or Squamous cell carcinoma antigen recognized by T-cells (Sart1). Sart1 recruits the U4.U6/U5 tri-snRNP complex to nuclear RNA. The complex then associates with U1 and U2 snRNPs to form the spliceosome. A forward genetic screen identifying defects in choroid plexus development and whole-exome sequencing (WES) identified a point mutation in exon 12 of sart1 in Danio rerio (zebrafish). This mutation caused an up-regulation of sart1. Using RNA-Seq analysis, we identified additional upregulated genes, including those involved in apoptosis. We also observed increased activated caspase 3 in the brain and eye and down-regulation of vision-related genes. Although splicing occurs in numerous cells types, sart1 expression in zebrafish was restricted to the brain. By identifying sart1 expression in the brain and cell death within the central nervous system (CNS), we provide additional insights into the role of sart1 in specific tissues. We also characterized sart1’s involvement in cell death and vision-related pathways.

Functional NK Cell Repertoires Are Determined By Survival Mechanisms Through IL-2Ra and FasL

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 786-786
Author(s):  
Martin Felices ◽  
Todd Lenvik ◽  
Dave Ankarlo ◽  
Bree Foley ◽  
Julie Curtsinger ◽  
...  
Keyword(s):  
Cell Death ◽  
Cell Survival ◽  
Nk Cells ◽  
Nk Cell ◽  
Fold Increase ◽  
Myelogenous Leukemia ◽  
Cell Numbers ◽  
Transplant Patients ◽  
Cmv Reactivation

Abstract NK cell based immunotherapy can be used to treat advanced acute myelogenous leukemia and data shows that success depends on the function of NK cells and how long the cells are maintained in the recipient. An important determinant of NK cell function is expression of Killer-cell immunoglobulin-like receptors (KIRs), which are involved in the maintenance of self tolerance and acquisition of NK cell functional competence, a process termed education. Little is known about how NK cell education influences NK cell survival. Utilizing a serum starvation assay we found that KIR+ and educated NK cells survived better when compared to those that did not have a KIR or KIR matching cognate HLA-ligand respectively (Figure 1A and 1B). Under basal conditions both KIR+ and educated NK cells had more anti-apoptotic proteins (Bcl-2 and Bcl-xL) and expressed less Fas. When NK cells were incubated with serum and IL-15 (10 ng/ml) followed by IL-15 withdrawal, a substantial increase of pro-apoptotic Bim was found on uneducated NK cells (1.4 fold increase; P = 0.01). Under this same condition educated NK cells expressed more FasL (1.5 fold increase; P = 0.0003), indicating that they could be driving cell death on neighboring NK cells when cytokine is limiting. Since both NK cell survival and homeostasis are mediated by cytokine signaling, we studied expression of IL-15 and IL-2 signaling components. The most significant change was IL-2Ra, which was expressed at higher levels on uneducated NK cells (3 fold increase; P = 0.0004) when the cells were stimulated with serum and IL-15 (1 ng/ml) for 72 hrs. Higher IL-2Ra expression correlated well with cell death and Bim expression so we decided to test if modulating its expression would alter NK cell survival in an IL-15 withdrawal setting. Compared to the control, transient overexpression of IL-2Ra lead to a 1.55 fold decrease in NK cell numbers (P = 0.01) while siRNA knockdown of IL-2Ra lead to a 1.5 fold increase in NK cell numbers (P = 0.07). Importantly, at the time of harvest there was a 1.4 fold decrease in cell death in the IL-2Ra knockdown condition when compared to the control (P = 0.0007). Given that no IL-2 or crosslinking signals were present, the mechanism must differ from the well-described role of IL-2 on activation induced cell death. Since FasL is upregulated on educated NK cells when IL-15 is limiting and IL-2Ra renders NK cells more sensitive to cell death, we tested if educated cells could drive cell death of IL-2Rahi NK cells when survival signals are scarce using a co-culturing assay and FasL blocking antibodies. IL-2Rahi NK cells were more sensitive to apoptosis when co-cultured with KIR+ NK cells (presumably enriched for educated subsets) than with KIR- NK cells from the same donor that were subjected to IL-15 stimulation and withdrawal (34±4.8% vs. 20.6±4.7%; P = 0.002). The effect was reduced when FasL was blocked (P = 0.003), and no differences in killing were seen on the IL-2Ralo NK cells regardless of the treatment. Taken together these findings indicate that educated NK cells outlive their counterparts through two mechanisms: decreased expression of proteins involved in cell death and by killing competing NK cells when IL-15 is limiting. Finally, since we have previously reported on expansion of educated NK cells on transplant patients post CMV reactivation and since CMV reactivation can be associated with decreased relapse, we wanted to investigate if CMV reactivation could alter NK cell survival. There was increased survival on the NK cells from adult donor HCT (2 fold increase at 6 months; P = 0.03) and umbilical cord blood (3 fold increase at 100 days; P = 0.01) allogeneic transplant patients that had undergone CMV reactivation supporting the physiologic role of NK cell survival in vivo from a pathologic challenge. Taken together, these findings show that NK cell functional repertoires are determined by class I interactions, infection, and NK-NK interactions through IL-2Ra, Bim, and FasL to mediate clonal dominance that might be exploited in order to enhance NK cell survival and function after adoptive transfer of allogeneic NK cells for therapeutic use in cancer. Disclosures: No relevant conflicts of interest to declare.

scholarly journals DR5 Knockout Mice Are Compromised in Radiation-Induced Apoptosis

2005 ◽  
Vol 25 (5) ◽  
pp. 2000-2013 ◽  
Author(s):  
Niklas Finnberg ◽  
Joshua J. Gruber ◽  
Peiwen Fei ◽  
Dorothea Rudolph ◽  
Anka Bric ◽  
...  
Keyword(s):  
Cell Death ◽  
Null Mouse ◽  
Organ Specific ◽  
Radiation Induced ◽  
Induced Apoptosis ◽  
The Brain ◽  
Necrosis Factor

ABSTRACT DR5 (also called TRAIL receptor 2 and KILLER) is an apoptosis-inducing membrane receptor for tumor necrosis factor-related apoptosis-inducing ligand (also called TRAIL and Apo2 ligand). DR5 is a transcriptional target of p53, and its overexpression induces cell death in vitro. However, the in vivo biology of DR5 has remained largely unexplored. To better understand the role of DR5 in development and in adult tissues, we have created a knockout mouse lacking DR5. This mouse is viable and develops normally with the exception of having an enlarged thymus. We show that DR5 is not expressed in developing embryos but is present in the decidua and chorion early in development. DR5-null mouse embryo fibroblasts expressing E1A are resistant to treatment with TRAIL, suggesting that DR5 may be the primary proapoptotic receptor for TRAIL in the mouse. When exposed to ionizing radiation, DR5-null tissues exhibit reduced amounts of apoptosis compared to wild-type thymus, spleen, Peyer's patches, and the white matter of the brain. In the ileum, colon, and stomach, DR5 deficiency was associated with a subtle phenotype of radiation-induced cell death. These results indicate that DR5 has a limited role during embryogenesis and early stages of development but plays an organ-specific role in the response to DNA-damaging stimuli.

scholarly journals Conventional protein kinase C in the brain: 40 years later

2017 ◽  
Vol 1 (2) ◽  
Author(s):  
Julia A. Callender ◽  
Alexandra C. Newton
Keyword(s):  
Cell Death ◽  
Protein Kinase C ◽  
Protein Kinase ◽  
Loss Of Function ◽  
Membrane Phospholipids ◽  
Kinase C ◽  
Pkc Isozymes ◽  
Hydrolysis Of ◽  
The Brain

Protein kinase C (PKC) is a family of enzymes whose members transduce a large variety of cellular signals instigated by the receptor-mediated hydrolysis of membrane phospholipids. While PKC has been widely implicated in the pathology of diseases affecting all areas of physiology including cancer, diabetes, and heart disease—it was discovered, and initially characterized, in the brain. PKC plays a key role in controlling the balance between cell survival and cell death. Its loss of function is generally associated with cancer, whereas its enhanced activity is associated with neurodegeneration. This review presents an overview of signaling by diacylglycerol (DG)-dependent PKC isozymes in the brain, and focuses on the role of the Ca2+-sensitive conventional PKC isozymes in neurodegeneration.

scholarly journals SIRT1 Promotes Cell Survival under Stress by Deacetylation-Dependent Deactivation of Poly(ADP-Ribose) Polymerase 1

2009 ◽  
Vol 29 (15) ◽  
pp. 4116-4129 ◽  
Author(s):  
Senthilkumar B. Rajamohan ◽  
Vinodkumar B. Pillai ◽  
Madhu Gupta ◽  
Nagalingam R. Sundaresan ◽  
Konstantin G. Birukov ◽  
...  
Keyword(s):  
Dna Damage ◽  
Cell Death ◽  
Cell Survival ◽  
Cross Talk ◽  
Gene Promoter ◽  
Stress Conditions ◽  
Transcriptional Level ◽  
A Cell

ABSTRACT Poly(ADP-ribose) polymerase 1 (PARP1) and SIRT1 deacetylase are two NAD-dependent enzymes which play major roles in the decision of a cell to live or to die in a stress situation. Because of the dependence of both enzymes on NAD, cross talk between them has been suggested. Here, we show that PARP1 is acetylated after stress of cardiomyocytes, resulting in the activation of PARP1, which is independent of DNA damage. SIRT1 physically binds to and deacetylates PARP1. Increased acetylation of PARP1 was also detected in hearts of SIRT1−/− mice, compared to that detected in the hearts of SIRT1+/+ mice, confirming a role of SIRT1 in regulating the PARP1 acetylation in vivo. SIRT1-dependent deacetylation blocks PARP1 activity, and it protects cells from PARP1-mediated cell death. We also show that SIRT1 negatively regulates the activity of the PARP1 gene promoter, thus suggesting that the deacetylase controls the PARP1 activity at the transcriptional level as well. These data demonstrate that the activity of PARP1 is under the control of SIRT1, which is necessary for survival of cells under stress conditions.

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