RESUMEN
We previously showed that mice with knockout in the peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PPARGC1A) gene encoding the PGC-1α protein, and nuclear factor erythroid 2 like 2 (NFE2L2) gene, exhibited some features of the age-related macular degeneration (AMD) phenotype. To further explore the mechanism behind the involvement of PGC-1α in AMD pathogenesis we used young (3-month) and old (12-month) mice with knockout in the PPARGC1A gene and age-matched wild-type (WT) animals. An immunohistochemical analysis showed age-dependent different expression of markers of oxidative stress defence, senescence and autophagy in the retinal pigment epithelium of KO animals as compared with their WT counterparts. Multivariate inference testing showed that senescence and autophagy proteins had the greatest impact on the discrimination between KO and WT 3-month animals, but proteins of antioxidant defence also contributed to that discrimination. A bioinformatic analysis showed that PGC-1α might coordinate the interplay between genes encoding proteins involved in antioxidant defence, senescence and autophagy in the ageing retina. These data support importance of PGC-1α in AMD pathogenesis and confirm the utility of mice with PGC-1α knockout as an animal model to study AMD pathogenesis.
Asunto(s)
Antioxidantes , Degeneración Macular , Ratones , Animales , Antioxidantes/metabolismo , Mitocondrias/metabolismo , Estrés Oxidativo , Envejecimiento , Degeneración Macular/metabolismo , Autofagia/genética , Epitelio Pigmentado de la Retina/metabolismo , Coactivador 1-alfa del Receptor Activado por Proliferadores de Peroxisomas gamma/genética , Coactivador 1-alfa del Receptor Activado por Proliferadores de Peroxisomas gamma/metabolismoRESUMEN
The aggregation of blood platelets is the pivotal step that leads to thrombosis. The risk of thrombotic events increases with age. Available data suggest that minerals taken with diet can affect the course of thrombosis. However, little is known about the relationship between platelet aggregability and mineral intake with diet among elderly people. Thus, we evaluated the associations between the reactivities of platelets to arachidonic acid, collagen or ADP and the estimated quantities of minerals consumed as a part of the daily diet in 246 subjects aged 60-65 years (124 men and 122 women). The found simple (not-adjusted) Spearman's rank negative correlations are as follows: 1. arachidonate-dependent aggregation and the amounts of potassium, zinc, magnesium, phosphorus, iron, copper and manganese; 2. collagen-dependent aggregation and the amounts of potassium, phosphorus, iron and zinc; and 3. ADP-dependent aggregation and the amounts of potassium, phosphorus and zinc. The negative associations between ADP-dependent platelet reactivity and the amount of potassium, phosphorus and zinc and between collagen-dependent aggregability and the amount of phosphorus were also noted after adjusting for a bunch of cardiovascular risk factors. Overall, in older subjects, the intake of minerals with diet is negatively related to blood platelet reactivity, especially in response to ADP. Diet fortification with some minerals may possibly reduce the thrombotic risk among elderly patients.
Asunto(s)
Trombosis , Zinc , Masculino , Anciano , Humanos , Femenino , Fósforo , Potasio , Agregación Plaquetaria , Minerales , Dieta , Hierro , ColágenoRESUMEN
The potential role of testosterone and dihydrotestosterone in the pathogenesis of depression in older subjects is poorly recognized and understood. The current study examines the symptoms of depression in males and females at the age of 60-65 using a short version (15 questions) of the Geriatric Depression Scale (GDS) questionnaire. Blood plasma levels of androgens were estimated by LC/MS/MS. Total GDS score calculated for males were not found to be significantly associated with plasma levels of testosterone or dihydrotestosterone. Older men with higher plasma testosteronemia were more likely to report being in good spirits most of the time, but more willing to stay at home than undertake outside activities. The men with higher plasma levels of dihydrotestosterone also perceived themselves as being in good spirits most of the time. Older men with higher testosterone were more likely to report having more problems with their memory than others. No significant associations were found between plasma levels of androgens and GDS scores in older women; however, some tendencies suggest that testosterone and dihydrotestosterone may act as antidepressants in older women.
Asunto(s)
Dihidrotestosterona , Testosterona , Anciano , Andrógenos , Depresión , Femenino , Humanos , Masculino , Espectrometría de Masas en TándemRESUMEN
Aging is a significant risk factor for the development of thrombotic diseases, dependent on blood platelet reactivity. However, the risk of thrombosis also appears to be significantly modulated by dietary nutrient content. The aim of the current study was to assess the relationship between the amount of amino acids present in the daily diet (not supplemented) and the reactivity of blood platelets to arachidonate, collagen and ADP in 246 women and men aged 60-65 years. Platelet reactivity was tested using whole blood impedance aggregometry. Amino acid intake was assessed with a 24-hour Recall Questionnaire and calculated with Dieta 5.0 software. Older subjects receiving higher amounts of all essential amino acids with their daily diet exhibit significantly lower platelet responsiveness to AA-, COL- and ADP in a sex-specific manner: dietary amino acid content was more closely associated with AA- and, to some extent, ADP-induced platelet reactivity in women, and with COL-induced platelet aggregability in men. Therefore, dietary amino acid content may be a novel factor responsible for attenuating platelet reactivity in a sex- and agonist-specific manner.
Asunto(s)
Aminoácidos , Agregación Plaquetaria , Adenosina Difosfato/farmacología , Aminoácidos Esenciales , Colágeno/farmacología , Dieta , Femenino , Humanos , MasculinoRESUMEN
The interaction of platelets with steroid hormones is poorly investigated. Age is one of the factors that increase the risk of pathological platelet reactivity and thrombosis. The aim of this study was to assess whether there were associations between platelet reactivity and plasma cortisol levels in volunteers aged 60-65 years. For this purpose, impedance aggregometry in whole blood measured after arachidonic acid, collagen, or ADP stimulation was used to estimate platelet reactivity and mass spectrometry was used to measure peripheral plasma cortisol concentration. Statistically significant negative correlations were observed between cortisol concentration and platelet reactivity in response to arachidonic acid and ADP, but not to collagen. The presented results suggest for the very first time that cortisol is a new endogenous modulator of platelet reactivity in the elderly population.
Asunto(s)
Hidrocortisona , Agregación Plaquetaria , Humanos , Anciano , Hidrocortisona/farmacología , Ácido Araquidónico/farmacología , Plaquetas , Colágeno/farmacología , Inhibidores de Agregación Plaquetaria/farmacología , Adenosina Difosfato/farmacologíaRESUMEN
Smoking accounts for almost 80-90% of lung cancer cases, which is also the most frequent cause of cancer-related deaths in humans. With over 60 carcinogens in tobacco smoke, cells dividing at the time of carcinogen exposure are at particular risk of neoplasia. The present study aimed to investigate global gene expression differences in lung adenocarcinoma (LUAD) tumour samples of current smokers and non-smokers, in an attempt to elucidate biological mechanisms underlying divergent smoking effects. Current and non-smoker tumour samples were analysed using bioinformatics tools, examining differences in molecular drivers of cancer initiation and progression, as well as evaluating the effect of smoking and sex on epithelial mesenchymal transition (EMT). As a result, we identified 1150 differentially expressed genes showing visible differences in the expression profiles between the smoking subgroups. The genes were primarily involved in cell cycle, DNA replication, DNA repair, VEGF, GnRH, ErbB and T cell receptor signalling pathways. Our results show that smoking clearly affected E2F transcriptional activity and DNA repair pathways including mismatch repair, base excision repair and homologous recombination. We observed that sex could modify the effects of PLA2G2A and PRG4 in LUAD tumour samples, whereas sex and smoking status might possibly have a biological effect on the EMT-related genes: HEY2, OLFM1, SFRP1 and STRAP. We also identified potential epigenetic changes smoking solely might have on EMT-related genes, which may serve as potential diagnostic and prognostic biomarkers for LUAD patients.