Sequence-selective DNA binding drugs mithramycin A and chromomycin A3 are potent inhibitors of neuronal apoptosis induced by oxidative stress and DNA damage in cortical neurons

2001 ◽  
Vol 49 (3) ◽  
pp. 345-354 ◽  
Author(s):  
Sukalyan Chatterjee ◽  
Khalequz Zaman ◽  
Hoon Ryu ◽  
Adriana Conforto ◽  
Rajiv R. Ratan
Keyword(s):  
Oxidative Stress ◽  
Dna Damage ◽  
Dna Binding ◽  
Cortical Neurons ◽  
Neuronal Apoptosis ◽  
Chromomycin A3 ◽  
Mithramycin A ◽  
Selective Dna Binding

scholarly journals Pink1 protects cortical neurons from thapsigargin-induced oxidative stress and neuronal apoptosis

2015 ◽  
Vol 35 (1) ◽  
Author(s):  
Lin Li ◽  
Guo-ku Hu
Keyword(s):  
Oxidative Stress ◽  
Cortical Neurons ◽  
Neuronal Apoptosis ◽  
Physiological Role ◽  
Cultured Neurons ◽  
Mitochondrial Oxidative Stress

Pink1 (PTEN-induced kinase 1) have a physiological role in mitochondrial maintenance, suppressing mitochondrial oxidative stress, fission, and autophagy. Our findings indicated that thapsigargin induced oxidative stress and neuronal apoptosis in cultured neurons is at least partly mediated inactivation of Pink1.

scholarly journals Neuroprotective Effect of Physical Exercise on Neuronal Apoptosis Induced by Tramadol in Cerebral Cortex of Rats

2020 ◽  
Vol 10 (6) ◽  
pp. 7209-7222
Keyword(s):  
Oxidative Stress ◽  
Cerebral Cortex ◽  
Physical Exercise ◽  
Cortical Neurons ◽  
Neuronal Apoptosis ◽  
Neuroprotective Effect ◽  
Physiological Saline ◽  
Male Rats ◽  
Control Group ◽  
Oxidative Stress Biomarkers

Tramadol is a centrally acting analgesic agent with low affinity for opioid receptors, used for treating moderate to severe pain. Tramadol, like other opioids, induces neuronal apoptosis, which causes multiple neuronal impairments. The current study was conducted to evaluate the potential neuroprotective role of physical exercises on tramadol-induced neuronal apoptosis in the cerebral cortex of rats. Thirty adult male rats were divided into three groups (n= 10) as follow; the control group was gavaged with physiological saline (0.9% NaCl); tramadol group was daily administered with tramadol (40 mg/kg) for 28 days, and physical exercise group was administered with the same dose as tramadol group, then rats were forced to run on the treadmill for 30 min, once a day for 28 days. Tramadol induced histopathological changes in the form of neuroses degeneration and apoptosis. These findings were confirmed by immunohistochemical and blotting studies, which showed upregulation of p53 and downregulation of Bcl-2. In addition, malondialdehyde (MDA), myeloperoxidase (MPO), and nuclear factor kappa B (NF-κB) significantly increased following tramadol administration. At the same time, glutathione (GSH) and glutathione peroxidase (GPx) were decreased. In contrast, physical exercise was found to protect cortical neurons from degeneration and apoptosis produced by tramadol. This was evidenced by the downregulation of p53 and upregulating Bcl-2 expression and the improved changes in the oxidative stress biomarkers in rats. Physical exercise reduced the neuronal apoptosis and degeneration in the cerebral cortex following tramadol administration through suppressing oxidative stress.

scholarly journals Elevated Oxidative Stress and DNA Damage in Cortical Neurons of Chemotherapy Patients

2021 ◽  
Author(s):  
Matthew Torre ◽  
Adwitia Dey ◽  
Jared K Woods ◽  
Mel B Feany
Keyword(s):  
Oxidative Stress ◽  
Dna Damage ◽  
Cancer Patients ◽  
Frontal Lobe ◽  
Cortical Neurons ◽  
Patient Morbidity ◽  
Significant Difference ◽  
Neurologic Sequelae ◽  
Markers Of Oxidative Stress ◽  
Chemotherapy Patients

Abstract The unintended neurologic sequelae of chemotherapy contribute to significant patient morbidity. Chemotherapy-related cognitive impairment (CRCI) is observed in up to 80% of cancer patients treated with chemotherapy and involves multiple cognitive domains including executive functioning. The pathophysiology underlying CRCI and the neurotoxicity of chemotherapy is incompletely understood, but oxidative stress and DNA damage are highly plausible mechanisms based on preclinical data. Unfortunately, validating pathways relevant to CRCI in humans is limited by an absence of relevant neuropathologic studies of patient brain tissue. In the present study, we stained sections of frontal lobe autopsy tissue from cancer patients treated with chemotherapy (n = 15), cancer patients not treated with chemotherapy (n = 10), and patients without history of cancer (n = 10) for markers of oxidative stress (nitrotyrosine, 4-hydroxynonenal) and DNA damage (pH2AX, pATM). Cancer patients treated with chemotherapy had increased staining for markers of oxidative stress and DNA damage in frontal lobe cortical neurons compared to controls. We detected no statistically significant difference in oxidative stress and DNA damage by the duration between last administration of chemotherapy and death. The study highlights the potential relevance of oxidative stress and DNA damage in the pathophysiology of CRCI and the neurotoxicity of chemotherapy.

scholarly journals Impaired NHEJ repair in amyotrophic lateral sclerosis is associated with TDP-43 mutations

2020 ◽  
Vol 15 (1) ◽  
Author(s):  
Anna Konopka ◽  
Donna R. Whelan ◽  
Md Shafi Jamali ◽  
Emma Perri ◽  
Hamideh Shahheydari ◽  
...  
Keyword(s):  
Dna Damage ◽  
Dna Repair ◽  
Amyotrophic Lateral Sclerosis ◽  
Dna Binding ◽  
Single Molecule ◽  
Cortical Neurons ◽  
Small Interfering Rnas ◽  
Granule Formation ◽  
Als Patients ◽  
Lateral Sclerosis

Abstract Background Pathological forms of TAR DNA-binding protein 43 (TDP-43) are present in motor neurons of almost all amyotrophic lateral sclerosis (ALS) patients, and mutations in TDP-43 are also present in ALS. Loss and gain of TDP-43 functions are implicated in pathogenesis, but the mechanisms are unclear. While the RNA functions of TDP-43 have been widely investigated, its DNA binding roles remain unclear. However, recent studies have implicated a role for TDP-43 in the DNA damage response. Methods We used NSC-34 motor neuron-like cells and primary cortical neurons expressing wildtype TDP-43 or TDP-43 ALS associated mutants (A315T, Q331K), in which DNA damage was induced by etoposide or H2O2 treatment. We investigated the consequences of depletion of TDP-43 on DNA repair using small interfering RNAs. Specific non homologous end joining (NHEJ) reporters (EJ5GFP and EJ2GFP) and cells lacking DNA-dependent serine/threonine protein kinase (DNA-PK) were used to investigate the role of TDP-43 in DNA repair. To investigate the recruitment of TDP-43 to sites of DNA damage we used single molecule super-resolution microscopy and a co-immunoprecipitation assay. We also investigated DNA damage in an ALS transgenic mouse model, in which TDP-43 accumulates pathologically in the cytoplasm. We also examined fibroblasts derived from ALS patients bearing the TDP-43 M337V mutation for evidence of DNA damage. Results We demonstrate that wildtype TDP-43 is recruited to sites of DNA damage where it participates in classical NHEJ DNA repair. However, ALS-associated TDP-43 mutants lose this activity, which induces DNA damage. Furthermore, DNA damage is present in mice displaying TDP-43 pathology, implying an active role in neurodegeneration. Additionally, DNA damage triggers features typical of TDP-43 pathology; cytoplasmic mis-localisation and stress granule formation. Similarly, inhibition of NHEJ induces TDP-43 mis-localisation to the cytoplasm. Conclusions This study reveals that TDP-43 functions in DNA repair, but loss of this function triggers DNA damage and is associated with key pathological features of ALS.

scholarly journals Low K+ Promotes NF-κB/DNA Binding in Neuronal Apoptosis Induced by K+ Loss

2006 ◽  
Vol 26 (3) ◽  
pp. 1038-1050 ◽  
Author(s):  
Yanmei Tao ◽  
Dong Yan ◽  
Qiaoyun Yang ◽  
Rui Zeng ◽  
Yizheng Wang
Keyword(s):  
Dna Binding ◽  
Cortical Neurons ◽  
Neuronal Apoptosis ◽  
Transcriptional Activity ◽  
Target Genes ◽  
Nuclear Translocation ◽  
Direct Action ◽  
Direct Effects ◽  
Proapoptotic Protein ◽  
Low K

ABSTRACT Low intracellular K+ concentration ([K+]i) promotes apoptosis and blocking K+ loss prevents apoptosis, but the mechanism of action of low [K+]i remains unclear. Here, we show that low [K+]i increases NF-κB transcriptional activity by enhancing its binding to the promoter of target genes without affecting its activation and nuclear translocation in cortical neurons deprived of serum. Low K+ concentration promotes NF-κB/DNA binding through direct effects on the interaction of NF-κB dimers with DNA. Up-regulation of proapoptotic protein Bcl-XS and neuronal apoptosis induced by serum deprivation are blocked by inhibition and/or down-regulation of NF-κB and by prevention of K+ loss. Thus, a direct action of K+ on NF-κB/DNA binding regulates gene transcription related to neuronal apoptosis.

scholarly journals Ubiquitin-Specific Protease 29 Exacerbates Cerebral Ischemia-Reperfusion Injury in Mice

2021 ◽  
Vol 2021 ◽  
pp. 1-16
Author(s):  
Jia-Bao Hou ◽  
Qian-Ni Shen ◽  
Xing Wan ◽  
Xu-Ke Liu ◽  
Yuan Yu ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Cortical Neurons ◽  
Neuronal Apoptosis ◽  
Ischemia Reperfusion ◽  
Primary Cortical Neurons ◽  
Cerebral Ischemia Reperfusion ◽  
Specific Protease ◽  
Ubiquitin Specific Protease ◽  
The Brain

Oxidative stress and apoptosis contribute to the progression of cerebral ischemia/reperfusion (I/R) injury. Ubiquitin-specific protease 29 (USP29) is abundantly expressed in the brain and plays critical roles in regulating oxidative stress and cell apoptosis. The purpose of the present study is to investigate the role and underlying mechanisms of USP29 in cerebral I/R injury. Neuron-specific USP29 knockout mice were generated and subjected to cerebral I/R surgery. For USP29 overexpression, mice were stereotactically injected with the adenoassociated virus serotype 9 vectors carrying USP29 for 4 weeks before cerebral I/R. And primary cortical neurons were isolated and exposed to oxygen glucose deprivation/reperfusion (OGD/R) stimulation to imitate cerebral I/R injury in vitro. USP29 expression was elevated in the brain and primary cortical neurons upon I/R injury. Neuron-specific USP29 knockout significantly diminished, whereas USP29 overexpression aggravated cerebral I/R-induced oxidative stress, apoptosis, and neurological dysfunction in mice. In addition, OGD/R-induced oxidative stress and neuronal apoptosis were also attenuated by USP29 silence but exacerbated by USP29 overexpression in vitro. Mechanistically, neuronal USP29 enhanced p53/miR-34a-mediated silent information regulator 1 downregulation and then promoted the acetylation and suppression of brain and muscle ARNT-like protein, thereby aggravating oxidative stress and apoptosis upon cerebral I/R injury. Our findings for the first time identify that USP29 upregulation during cerebral I/R may contribute to oxidative stress, neuronal apoptosis, and the progression of cerebral I/R injury and that inhibition of USP29 may help to develop novel therapeutic strategies to treat cerebral I/R injury.

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