Search results for " Damage"

RNase H2 Loss in Murine Astrocytes Results in Cellular Defects Reminiscent of Nucleic Acid-Mediated Autoinflammation

2018

Aicardi-Goutières syndrome (AGS) is a rare early onset childhood encephalopathy caused by persistent neuroinflammation of autoimmune origin. AGS is a genetic disorder and >50% of affected individuals bear hypomorphic mutations in ribonuclease H2 (RNase H2). All available RNase H2 mouse models so far fail to mimic the prominent CNS involvement seen in AGS. To establish a mouse model recapitulating the human disease, we deleted RNase H2 specifically in the brain, the most severely affected organ in AGS. Although RNase H2δGFAPmice lacked the nuclease in astrocytes and a majority of neurons, no disease signs were apparent in these animals. We additionally confirmed these results…

Genotoxicity and Epigenotoxicity of Carbazole-Derived Molecules on MCF-7 Breast Cancer Cells

2021

The carbazole compounds PK9320 (1-(9-ethyl-7-(furan-2-yl)-9H-carbazol-3-yl)-N-methylmethanamine) and PK9323 (1-(9-ethyl-7-(thiazol-4-yl)-9H-carbazol-3-yl)-N-methylmethanamine), second-generation analogues of PK083 (1-(9-ethyl-9H-carbazol-3-yl)-N-methylmethanamine), restore p53 signaling in Y220C p53-mutated cancer cells by binding to a mutation-induced surface crevice and acting as molecular chaperones. In the present paper, these three molecules have been tested for mutant p53-independent genotoxic and epigenomic effects on wild-type p53 MCF-7 breast adenocarcinoma cells, employing a combination of Western blot for phospho-γH2AX histone, Comet assay and methylation-sensitive arbitrarily pr…

Alzheimer's disease: Only prevention makes sense

2018

Alzheimer's disease therapeutics is one of the most important endeavours in today's clinical investigation. Over more than 30 years of research, no disease-modifying treatment has been approved by either the FDA or the EMA to treat Alzheimer's disease. Recently, the evidence of pathological alterations in the brain tissue has been gathered showing that the signs of brain damage appear more than 20 years before the onset of Alzheimer's dementia. The major aim of this review is to underpin the idea that in Alzheimer's therapeutics, only prevention makes sense. It is difficult to visualise that would-be patients may be treated with endovenous administration of antibodies for several years to d…

Is erythropoietin a worthy candidate for traumatic brain injury or are we heading the wrong way?

2016

Traumatic brain injury (TBI) is a leading cause of death and disability in the modern society. Although primary prevention is the only strategy that can counteract the primary brain damage, numerous preclinical studies have been accumulated in order to find therapeutic strategies against the secondary damage. In this scenario erythropoietin (EPO) has been shown to be a promising candidate as neuroprotective agent. A recent clinical trial, however, has shown that EPO has not an overall effect on outcomes following TBI thus renewing old concerns.  However, the results of a prespecified sensitivity analysis indicate that the effect of EPO on mortality remains still unclear. In the light of the…

Obesogenic Diets Cause Alterations on Proteins and Theirs Post-Translational Modifications in Mouse Brains

2021

Obesity constitutes a major global health threat and is associated with a variety of diseases ranging from metabolic and cardiovascular disease, cancer to neurodegeneration. The hallmarks of neurodegeneration include oxidative stress, proteasome impairment, mitochondrial dysfunction and accumulation of abnormal protein aggregates as well as metabolic alterations. As an example, in post-mortem brain of patients with Alzheimer’s disease (AD), several studies have reported reduction of insulin, insulin-like growth factor 1 and insulin receptor and an increase in tau protein and glycogen-synthase kinase-3β compared to healthy controls suggesting an impairment of metabolism in the AD patient’s …

Physical Exercise and DNA Injury

2017

Regular, low-intensity physical activity is currently advocated for lowering the risk of developing many acute and especially chronic diseases. However, several lines of evidence attest that strenuous exercise may enhance inflammation and trigger the generation of free radical-mediated damage, thus overwhelming the undisputable benefits of regular, medium-intensity physical activity. Since reactive oxygen species are actively generated during high-intensity exercise, and these reactive compounds are known to impact DNA stability, we review here the current evidence about strenuous exercise and DNA injury. Despite the outcome of the various studies cannot be pooled due to considerable variat…

X-linked protoporphyria: Iron supplementation improves protoporphyrin overload, liver damage and anaemia

2015

2019

Aging causes many changes in the human body, and is a high risk for various diseases. Dementia, a common age-related disease, is a clinical disorder triggered by neurodegeneration. Brain damage caused by neuronal death leads to cognitive decline, memory loss, learning inabilities and mood changes. Numerous disease conditions may cause dementia; however, the most common one is Alzheimer’s disease (AD), a futile and yet untreatable illness. Adult neurogenesis carries the potential of brain self-repair by an endogenous formation of newly-born neurons in the adult brain; however it also declines with age. Strategies to improve the symptoms of aging and age-related diseases have included differe…

CHK1-targeted therapy to deplete DNA replication-stressed, p53-deficient, hyperdiploid colorectal cancer stem cells.

2017

ObjectiveCancer stem cells (CSCs) are responsible for tumour formation and spreading, and their targeting is required for tumour eradication. There are limited therapeutic options for advanced colorectal cancer (CRC), particularly for tumours carrying RAS-activating mutations. The aim of this study was to identify novel CSC-targeting strategies.DesignTo discover potential therapeutics to be clinically investigated as single agent, we performed a screening with a panel of FDA-approved or investigational drugs on primary CRC cells enriched for CSCs (CRC-SCs) isolated from 27 patients. Candidate predictive biomarkers of efficacy were identified by integrating genomic, reverse-phase protein mic…

Wip1 phosphatase: between p53 and MAPK kinases pathways.

2016

IF 5.008; International audience; Cells undergoing oncogenic transformation frequently inactivate tumor suppressor pathways that could prevent their uncontrolled growth. Among those pathways p53 and p38MAPK pathways play a critical role in regulation of cell cycle, senescence and cell death in response to activation of oncogenes, stress and DNA damage. Consequently, these two pathways are important in determining the sensitivity of tumor cells to anti-cancer treatment. Wild type p53-induced phosphatase, Wip1, is involved in governance of both pathways. Recently, strategies directed to manipulation with Wip1 activity proposed to advance current day anticancer treatment and novel chemical com…