scholarly journals The Phosphorylated Form of the Histone H2AX (γH2AX) in the Brain from Embryonic Life to Old Age

Molecules ◽  
2021 ◽  
Vol 26 (23) ◽  
pp. 7198
Author(s):  
Adalberto Merighi ◽  
Nadia Gionchiglia ◽  
Alberto Granato ◽  
Laura Lossi
Keyword(s):  
Dna Damage ◽  
Old Age ◽  
Neuronal Cell Death ◽  
Neuronal Cell ◽  
Cell Cycle Checkpoints ◽  
Histone H2ax ◽  
Phosphorylated Form ◽  
Embryonic Life ◽  
Regulation Of Cell Cycle ◽  
The Brain

The γ phosphorylated form of the histone H2AX (γH2AX) was described more than 40 years ago and it was demonstrated that phosphorylation of H2AX was one of the first cellular responses to DNA damage. Since then, γH2AX has been implicated in diverse cellular functions in normal and pathological cells. In the first part of this review, we will briefly describe the intervention of H2AX in the DNA damage response (DDR) and its role in some pivotal cellular events, such as regulation of cell cycle checkpoints, genomic instability, cell growth, mitosis, embryogenesis, and apoptosis. Then, in the main part of this contribution, we will discuss the involvement of γH2AX in the normal and pathological central nervous system, with particular attention to the differences in the DDR between immature and mature neurons, and to the significance of H2AX phosphorylation in neurogenesis and neuronal cell death. The emerging picture is that H2AX is a pleiotropic molecule with an array of yet not fully understood functions in the brain, from embryonic life to old age.

scholarly journals The transcription factors TFE3 and TFEB amplify p53 dependent transcriptional programs in response to DNA damage

eLife ◽  
2018 ◽  
Vol 7 ◽  
Author(s):  
Eutteum Jeong ◽  
Owen A Brady ◽  
José A Martina ◽  
Mehdi Pirooznia ◽  
Ilker Tunc ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Dna Damage ◽  
Transcription Factors ◽  
P53 Protein ◽  
Cell Cycle Control ◽  
Cell Cycle Checkpoints ◽  
Dependent Manner ◽  
Double Knockout ◽  
Protein Levels ◽  
Regulation Of Cell Cycle

The transcription factors TFE3 and TFEB cooperate to regulate autophagy induction and lysosome biogenesis in response to starvation. Here we demonstrate that DNA damage activates TFE3 and TFEB in a p53 and mTORC1 dependent manner. RNA-Seq analysis of TFEB/TFE3 double-knockout cells exposed to etoposide reveals a profound dysregulation of the DNA damage response, including upstream regulators and downstream p53 targets. TFE3 and TFEB contribute to sustain p53-dependent response by stabilizing p53 protein levels. In TFEB/TFE3 DKOs, p53 half-life is significantly decreased due to elevated Mdm2 levels. Transcriptional profiles of genes involved in lysosome membrane permeabilization and cell death pathways are dysregulated in TFEB/TFE3-depleted cells. Consequently, prolonged DNA damage results in impaired LMP and apoptosis induction. Finally, expression of multiple genes implicated in cell cycle control is altered in TFEB/TFE3 DKOs, revealing a previously unrecognized role of TFEB and TFE3 in the regulation of cell cycle checkpoints in response to stress.

scholarly journals Induction of the Nrf2 Pathway by Sulforaphane Is Neuroprotective in a Rat Temporal Lobe Epilepsy Model

Antioxidants ◽  
2021 ◽  
Vol 10 (11) ◽  
pp. 1702
Author(s):  
Sereen Sandouka ◽  
Tawfeeq Shekh-Ahmad
Keyword(s):  
Oxidative Stress ◽  
Cell Death ◽  
Status Epilepticus ◽  
Temporal Lobe Epilepsy ◽  
Antioxidant Capacity ◽  
Temporal Lobe ◽  
Epileptiform Activity ◽  
Neuronal Cell Death ◽  
Neuronal Cell ◽  
The Brain

Epilepsy is a chronic disease of the brain that affects over 65 million people worldwide. Acquired epilepsy is initiated by neurological insults, such as status epilepticus, which can result in the generation of ROS and induction of oxidative stress. Suppressing oxidative stress by upregulation of the transcription factor, nuclear factor erythroid 2-related factor 2 (Nrf2) has been shown to be an effective strategy to increase endogenous antioxidant defences, including in brain diseases, and can ameliorate neuronal damage and seizure occurrence in epilepsy. Here, we aim to test the neuroprotective potential of a naturally occurring Nrf2 activator sulforaphane, in in vitro epileptiform activity model and a temporal lobe epilepsy rat model. Sulforaphane significantly decreased ROS generation during epileptiform activity, restored glutathione levels, and prevented seizure-like activity-induced neuronal cell death. When given to rats after 2 h of kainic acid-induced status epilepticus, sulforaphane significantly increased the expression of Nrf2 and related antioxidant genes, improved oxidative stress markers, and increased the total antioxidant capacity in both the plasma and hippocampus. In addition, sulforaphane significantly decreased status epilepticus-induced neuronal cell death. Our results demonstrate that Nrf2 activation following an insult to the brain exerts a neuroprotective effect by reducing neuronal death, increasing the antioxidant capacity, and thus may also modify epilepsy development.

scholarly journals Peroxiredoxin II Maintains the Mitochondrial Membrane Potential against Alcohol-Induced Apoptosis in HT22 Cells

Antioxidants ◽  
2019 ◽  
Vol 9 (1) ◽  
pp. 1
Author(s):  
Mei-Hua Jin ◽  
Jia-Bin Yu ◽  
Hu-Nan Sun ◽  
Ying-Hua Jin ◽  
Gui-Nan Shen ◽  
...  
Keyword(s):  
Membrane Potential ◽  
Mitochondrial Membrane Potential ◽  
Mitochondrial Membrane ◽  
Neuronal Cell Death ◽  
Neuronal Cell ◽  
Ht22 Cells ◽  
Apoptotic Protein ◽  
Intracellular Ros ◽  
Induced Apoptosis ◽  
The Brain

Excessive alcohol intake can significantly reduce cognitive function and cause irreversible learning and memory disorders. The brain is particularly vulnerable to alcohol-induced ROS damage; the hippocampus is one of the most sensitive areas of the brain for alcohol neurotoxicity. In the present study, we observed significant increasing of intracellular ROS accumulations in Peroxiredoxin II (Prx II) knockdown HT22 cells, which were induced by alcohol treatments. We also found that the level of ROS in mitochondrial was also increased, resulting in a decrease in the mitochondrial membrane potential. The phosphorylation of GSK3β (Ser9) and anti-apoptotic protein Bcl2 expression levels were significantly downregulated in Prx II knockdown HT22 cells, which suggests that Prx II knockdown HT22 cells were more susceptible to alcohol-induced apoptosis. Scavenging the alcohol-induced ROS with NAC significantly decreased the intracellular ROS levels, as well as the phosphorylation level of GSK3β in Prx II knockdown HT22 cells. Moreover, NAC treatment also dramatically restored the mitochondrial membrane potential and the cellular apoptosis in Prx II knockdown HT22 cells. Our findings suggest that Prx II plays a crucial role in alcohol-induced neuronal cell apoptosis by regulating the cellular ROS levels, especially through regulating the ROS-dependent mitochondrial membrane potential. Consequently, Prx II may be a therapeutic target molecule for alcohol-induced neuronal cell death, which is closely related to ROS-dependent mitochondria dysfunction.

scholarly journals Neuroprotective Effect of Antioxidants in the Brain

2020 ◽  
Vol 21 (19) ◽  
pp. 7152 ◽  
Author(s):  
Kyung Hee Lee ◽  
Myeounghoon Cha ◽  
Bae Hwan Lee
Keyword(s):  
Oxidative Stress ◽  
Neurodegenerative Diseases ◽  
Intracellular Signaling ◽  
Neuronal Damage ◽  
Neuroprotective Effect ◽  
Neuronal Cell Death ◽  
Neuronal Cell ◽  
High Energy ◽  
Antioxidant Compounds ◽  
The Brain

The brain is vulnerable to excessive oxidative insults because of its abundant lipid content, high energy requirements, and weak antioxidant capacity. Reactive oxygen species (ROS) increase susceptibility to neuronal damage and functional deficits, via oxidative changes in the brain in neurodegenerative diseases. Overabundance and abnormal levels of ROS and/or overload of metals are regulated by cellular defense mechanisms, intracellular signaling, and physiological functions of antioxidants in the brain. Single and/or complex antioxidant compounds targeting oxidative stress, redox metals, and neuronal cell death have been evaluated in multiple preclinical and clinical trials as a complementary therapeutic strategy for combating oxidative stress associated with neurodegenerative diseases. Herein, we present a general analysis and overview of various antioxidants and suggest potential courses of antioxidant treatments for the neuroprotection of the brain from oxidative injury. This review focuses on enzymatic and non-enzymatic antioxidant mechanisms in the brain and examines the relative advantages and methodological concerns when assessing antioxidant compounds for the treatment of neurodegenerative disorders.

scholarly journals Down-Regulation of miR-23a-3p Mediates Irradiation-Induced Neuronal Apoptosis

2020 ◽  
Vol 21 (10) ◽  
pp. 3695 ◽  
Author(s):  
Boris Sabirzhanov ◽  
Oleg Makarevich ◽  
James Barrett ◽  
Isabel L. Jackson ◽  
Alan I. Faden ◽  
...  
Keyword(s):  
Dna Damage ◽  
Cell Death ◽  
Cytochrome C ◽  
Neuronal Apoptosis ◽  
Neuronal Cell Death ◽  
Neuronal Cell ◽  
Negative Regulator ◽  
Down Regulation ◽  
Bcl2 Family ◽  
Mitochondrial Outer Membrane Permeabilization

Radiation-induced central nervous system toxicity is a significant risk factor for patients receiving cancer radiotherapy. Surprisingly, the mechanisms responsible for the DNA damage-triggered neuronal cell death following irradiation have yet to be deciphered. Using primary cortical neuronal cultures in vitro, we demonstrated that X-ray exposure induces the mitochondrial pathway of intrinsic apoptosis and that miR-23a-3p plays a significant role in the regulation of this process. Primary cortical neurons exposed to irradiation show the activation of DNA-damage response pathways, including the sequential phosphorylation of ATM kinase, histone H2AX, and p53. This is followed by the p53-dependent up-regulation of the pro-apoptotic Bcl2 family molecules, including the BH3-only molecules PUMA, Noxa, and Bim, leading to mitochondrial outer membrane permeabilization (MOMP) and the release of cytochrome c, which activates caspase-dependent apoptosis. miR-23a-3p, a negative regulator of specific pro-apoptotic Bcl-2 family molecules, is rapidly decreased after neuronal irradiation. By increasing the degradation of PUMA and Noxa mRNAs in the RNA-induced silencing complex (RISC), the administration of the miR-23a-3p mimic inhibits the irradiation-induced up-regulation of Noxa and Puma. These changes result in an attenuation of apoptotic processes such as MOMP, the release of cytochrome c and caspases activation, and a reduction in neuronal cell death. The neuroprotective effects of miR-23a-3p administration may not only involve the direct inhibition of pro-apoptotic Bcl-2 molecules downstream of p53 but also include the attenuation of secondary DNA damage upstream of p53. Importantly, we demonstrated that brain irradiation in vivo results in the down-regulation of miR-23a-3p and the elevation of pro-apoptotic Bcl2-family molecules PUMA, Noxa, and Bax, not only broadly in the cortex and hippocampus, except for Bax, which was up-regulated only in the hippocampus but also selectively in isolated neuronal populations from the irradiated brain. Overall, our data suggest that miR-23a-3p down-regulation contributes to irradiation-induced intrinsic pathways of neuronal apoptosis. These regulated pathways of neurodegeneration may be the target of effective neuroprotective strategies using miR-23a-3p mimics to block their development and increase neuronal survival after irradiation.

scholarly journals Heme–Hemopexin Complex Attenuates Neuronal Cell Death and Stroke Damage

2009 ◽  
Vol 29 (5) ◽  
pp. 953-964 ◽  
Author(s):  
Rung-chi Li ◽  
Sofiyan Saleem ◽  
Gehua Zhen ◽  
Wangsen Cao ◽  
Hean Zhuang ◽  
...  
Keyword(s):  
Cortical Neurons ◽  
Neuronal Cell Death ◽  
Neuronal Cell ◽  
Artery Occlusion ◽  
Neuronal Cultures ◽  
Tert Butyl Hydroperoxide ◽  
Primary Mouse ◽  
Free Heme ◽  
Cerebral Artery Occlusion ◽  
The Brain

Hemoproteins undergo degradation during hypoxic/ischemic conditions, but the prooxidant free heme that is released cannot be recycled and must be degraded. The extracellular heme associates with its high-affinity binding protein, hemopexin (HPX). Hemopexin is shown here to be expressed by cortical neurons and it is present in mouse cerebellum, cortex, hippocampus, and striatum. Using the transient ischemia model (90-min middle cerebral artery occlusion followed by 96-h survival), we provide evidence that HPX is protective in the brain, as neurologic deficits and infarct volumes were significantly greater in HPX−/− than in wild-type mice. Addressing the potential protective HPX cellular pathway, we observed that exogenous free heme decreased cell survival in primary mouse cortical neuron cultures, whereas the heme bound to HPX was not toxic. Heme-HPX complexes induce HO1 and, consequently, protect primary neurons against the toxicity of both heme and prooxidant tert-butyl hydroperoxide; such protection was decreased in HO1−/− neuronal cultures. Taken together, these data show that HPX protects against heme-induced toxicity and oxidative stress and that HO1 is required. We propose that the heme-HPX system protects against stroke-related damage by maintaining a tight balance between free and bound heme. Thus, regulating extracellular free heme levels, such as with HPX, could be neuroprotective.

Oxidative stress-induced CREB upregulation promotes DNA damage repair prior to neuronal cell death protection

2016 ◽  
Vol 425 (1-2) ◽  
pp. 9-24 ◽  
Author(s):  
Nicolás Pregi ◽  
Laura María Belluscio ◽  
Bruno Gabriel Berardino ◽  
Daniela Susana Castillo ◽  
Eduardo Tomás Cánepa
Keyword(s):  
Oxidative Stress ◽  
Dna Damage ◽  
Cell Death ◽  
Dna Damage Repair ◽  
Neuronal Cell Death ◽  
Neuronal Cell ◽  
Damage Repair

scholarly journals Persisting Rickettsia typhi Causes Fatal Central Nervous System Inflammation

2016 ◽  
Vol 84 (5) ◽  
pp. 1615-1632 ◽  
Author(s):  
Anke Osterloh ◽  
Stefanie Papp ◽  
Kristin Moderzynski ◽  
Svenja Kuehl ◽  
Ulricke Richardt ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Neuronal Cell Death ◽  
Neuronal Cell ◽  
Rickettsia Typhi ◽  
Content Type ◽  
Inflammatory Phenotype ◽  
Obligate Intracellular Bacteria ◽  
Immunocompromised Mice ◽  
The Brain

Rickettsioses are emerging febrile diseases caused by obligate intracellular bacteria belonging to the familyRickettsiaceae. Rickettsia typhibelongs to the typhus group (TG) of this family and is the causative agent of endemic typhus, a disease that can be fatal. In the present study, we analyzed the course ofR. typhiinfection in C57BL/6 RAG1−/−mice. Although these mice lack adaptive immunity, they developed only mild and temporary symptoms of disease and survivedR. typhiinfection for a long period of time. To our surprise, 3 to 4 months after infection, C57BL/6 RAG1−/−mice suddenly developed lethal neurological disorders. Analysis of these mice at the time of death revealed high bacterial loads, predominantly in the brain. This was accompanied by a massive expansion of microglia and by neuronal cell death. Furthermore, high numbers of infiltrating CD11b+macrophages were detectable in the brain. In contrast to the microglia, these cells harboredR. typhiand showed an inflammatory phenotype, as indicated by inducible nitric oxide synthase (iNOS) expression, which was not observed in the periphery. Having shown thatR. typhipersists in immunocompromised mice, we finally asked whether the bacteria are also able to persist in resistant C57BL/6 and BALB/c wild-type mice. Indeed,R. typhicould be recultivated from lung, spleen, and brain tissues from both strains even up to 1 year after infection. This is the first report demonstrating persistence and reappearance ofR. typhi, mainly restricted to the central nervous system in immunocompromised mice.

scholarly journals Mud sticks after all: Chronically implanted microelectrodes but not electrical stimulation cause c-fos expression along their trajectory

2017 ◽  
Author(s):  
Patrick Pflüger ◽  
Richard C. Pinnell ◽  
Nadja Martini ◽  
Ulrich G. Hofmann
Keyword(s):  
Brain Tissue ◽  
Neuronal Cell Death ◽  
Neuronal Cell ◽  
Cell Loss ◽  
Glial Scar ◽  
Tissue Response ◽  
High Frequency Stimulation ◽  
Dorsolateral Striatum ◽  
Frequency Stimulation ◽  
The Brain

ABSTRACTThe goal of CNS implanted devices is to build a stable brain-machine-interface. The brain tissue response to the foreign body limits the functionality and viability of this brain-machine connection. Notably the astrocytic glial scar formation and inflammation with resulting neuronal cell loss is considered to be responsible for the signal deterioration over time. We chronically implanted a polyimide microelectrode in the dorsolateral striatum of rats. First, we analyzed the c-fos immunoreactivity following high frequency stimulation (HFS) of the dorsolateral striatum and second, using GFAP and ED1 immunocytochemistry, the brain tissue response. Acute as well as chronic HFS showed no significant change of neuronal c-fos expression in the dorsolateral striatum and corresponding cortical areas. We found that the sole chronic implantation of a polyimide microelectrode leads to a reaction of the surrounding neurons, i.e. c-fos expression, along the implantation trajectory. We also observed the formation of a glial scar around the microelectrode with a low number of inflammation cells. Histological and statistical analysis of NeuN positive cells showed no ‘kill zone’, which accompanied neuronal cell death around the implantation site.

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