Search results for "PAI"
showing 10 items of 10553 documents
A dual role of caspase-8 in triggering and sensing proliferation-associated DNA damage, a key determinant of liver cancer development.
2017
Summary Concomitant hepatocyte apoptosis and regeneration is a hallmark of chronic liver diseases (CLDs) predisposing to hepatocellular carcinoma (HCC). Here, we mechanistically link caspase-8-dependent apoptosis to HCC development via proliferation- and replication-associated DNA damage. Proliferation-associated replication stress, DNA damage, and genetic instability are detectable in CLDs before any neoplastic changes occur. Accumulated levels of hepatocyte apoptosis determine and predict subsequent hepatocarcinogenesis. Proliferation-associated DNA damage is sensed by a complex comprising caspase-8, FADD, c-FLIP, and a kinase-dependent function of RIPK1. This platform requires a non-apop…
Inhibition of DNA damage response at telomeres improves the detrimental phenotypes of Hutchinson–Gilford Progeria Syndrome
2019
Hutchinson–Gilford progeria syndrome (HGPS) is a genetic disorder characterized by premature aging features. Cells from HGPS patients express progerin, a truncated form of Lamin A, which perturbs cellular homeostasis leading to nuclear shape alterations, genome instability, heterochromatin loss, telomere dysfunction and premature entry into cellular senescence. Recently, we reported that telomere dysfunction induces the transcription of telomeric non-coding RNAs (tncRNAs) which control the DNA damage response (DDR) at dysfunctional telomeres. Here we show that progerin-induced telomere dysfunction induces the transcription of tncRNAs. Their functional inhibition by sequence-specific telomer…
FANCD2 modulates the mitochondrial stress response to prevent common fragile site instability
2021
Common fragile sites (CFSs) are genomic regions frequently involved in cancer-associated rearrangements. Most CFSs lie within large genes, and their instability involves transcription- and replication-dependent mechanisms. Here, we uncover a role for the mitochondrial stress response pathway in the regulation of CFS stability in human cells. We show that FANCD2, a master regulator of CFS stability, dampens the activation of the mitochondrial stress response and prevents mitochondrial dysfunction. Genetic or pharmacological activation of mitochondrial stress signaling induces CFS gene expression and concomitant relocalization to CFSs of FANCD2. FANCD2 attenuates CFS gene transcription and pr…
Motivators, barriers and strategies of weight management: A cross-sectional study among Finnish adults.
2018
Abstract Background Weight management (WM) is an ongoing global challenge. The purpose of this study was to analyze motivators, barriers, and strategies of WM among Finnish adults. Methods Data were collected in the ‘KULUMA’ (Consumers at the Weight Management Market) project among 667 community-dwelling adults in Eastern and Central Finland (Kuopio and Jyvaskyla). The self-reported questionnaire collected background information and responses to motivators, barriers, and strategy items. Principal component analysis (PCA) was used to extract components of motivators, barriers, and strategies of WM, along with K-means clustering to categorize the participants. Results About 55% of the respond…
Dietary Assesment of Free-Living Elderly Spanish People with Disabilities.
2017
Nutritional research in elderly disabled is difficult in noninstitutionalized people. The dietary intake of a noninstitutionalized disabled population of the eastern region of Spain was evaluated to detect possible nutritional deviations. A total of 329 participants aged 65 and over were recruited. Most participants were overweight. Carbohydrates did not reach 50% of total Kcal/day. Insufficient micronutrient intakes and high consumption of simple carbohydrates and saturated fats (SFA) were found. A decreasing trend of water intake (p < .05) as well as an increasing trend of alcohol consumption (p < .05) with increasing age was found. The area of residence had a relevant impact on nutrition…
How can dementia and disability be prevented in older adults: where are we today and where are we going?
2021
Abstract Ageing of the population, together with population growth, has brought along an ample increase in the number of older individuals living with dementia and disabilities. Dementia is the main cause of disability in old age, and promoting healthy brain ageing is considered as a key element in diminishing the burden of age‐related disabilities. The World Health Organization recently launched the first risk reduction guidelines for cognitive impairment and dementia. According to recent estimates, approximately 40% of dementia cases worldwide could be attributable to 12 modifiable risk factors: low education; midlife hypertension and obesity; diabetes, smoking, excessive alcohol use, phy…
A New Frailty Score for Experimental Animals Based on the Clinical Phenotype: Inactivity as a Model of Frailty.
2016
The development of animal models to study human frailty is important to test interventions to be translated to the clinical practice. The aim of this work was to develop a score for frailty in experimental animals based in the human frailty phenotype. We also tested the effect of physical inactivity in the development of frailty as determined by our score. Male C57Bl/6J mice, individually caged, were randomly assigned to one of two groups: sedentary (inactive) or spontaneous wheel-runners. We compared the sedentary versus the active lifestyle in terms of frailty by evaluating the clinical criteria used in humans: unintentional weight loss; poor endurance (running time); slowness (running sp…
Singlet Oxygen Attack on Guanine: Reactivity and Structural Signature within the B-DNA Helix
2016
International audience; Oxidatively generated DNA lesions are numerous and versatile, and have been the subject of intensive research since the discovery of 8-oxoguanine in 1984. Even for this prototypical lesion, the precise mechanism of formation remains elusive due to the inherent difficulties in characterizing high-energy intermediates. We have probed the stability of the guanine endoperoxide in B-DNA as a key intermediate and determined a unique activation free energy of around 6 kcal mol−1 for the formation of the first C−O covalent bond upon the attack of singlet molecular oxygen (1O2) on the central guanine of a solvated 13 base-pair poly(dG-dC), described by means of quantum mechan…
Role of the DNA repair glycosylase OGG1 in the activation of murine splenocytes
2017
OGG1 (8-oxoguanine-DNA glycosylase) is the major DNA repair glycosylase removing the premutagenic DNA base modification 8-oxo-7,8-dihydroguanine (8-oxoG) from the genome of mammalian cells. In addition, there is accumulating evidence that OGG1 and its substrate 8-oxoG might function in the regulation of certain genes, which could account for an attenuated immune response observed in Ogg1-/- mice in several settings. Indications for at least two different mechanisms have been obtained. Thus, OGG1 could either act as an ancillary transcription factor cooperating with the lysine-specific demethylase LSD1 or as an activator of small GTPases. Here, we analysed the activation by lipopolysaccaride…
Oxidatively generated base modifications in DNA: Not only carcinogenic risk factor but also regulatory mark?
2016
The generation of DNA modifications in cells is in most cases accidental and associated with detrimental consequences such as increased mutation rates and an elevated risk of malignant transformation. Accordingly, repair enzymes involved in the removal of the modifications have primarily a protective function. Among the well-established exceptions of this rule are 5-methylcytosine and uracil, which are generated in DNA enzymatically under controlled conditions and fulfill important regulatory functions in DNA as epigenetic marks and in antibody diversification, respectively. More recently, considerable evidence has been obtained that also 8-oxo-7,8-dihydroguanine (8-oxoG), a frequent pro-mu…