Aluminium blunts the proliferative response and increases apoptosis of cultured human cells: putative relationship to Alzheimer's disease

Aluminium (Al) has been investigated as a neurotoxic substance. Al ranks among the potential environmental risk factors for Alzheimer's disease (AD). Epidemiological studies tested the relationship between Al in drinking water and AD, showing a significant correlation between elevated levels of monomeric Al in water and AD, although data to date remain inconclusive with respect to total Al. The aim of this study was to test whether or not Al exacerbates cellular toxicity mediated by the amyloid beta (Abeta) peptide. We evaluated the role of Al in modulating programmed cell death (apoptosis) in human cell cultures. We used the osteosarcoma cell line monolayer (SaOs-2) to demonstrate that treatment of SaOs-2 cultures with the Abeta peptide mid-fragment (25 to 35) at nano M, followed by co-incubation with physiological concentrations of aluminium chloride, which release monomeric Al in solution, led to marked expression of caspase 3, but not caspase 9, key markers of the apoptotic process. The same experimental conditions were shown to blunt significantly the proliferative response of normal human peripheral blood mononuclear cells (PBMC) to phytohemagglutinin (PHA) stimulation. Our observations support the hypothesis that Al significantly impairs certain cellular immune responses, and confirm that Al-mediated cell toxicity may play an important role in AD.     

Role of the neuroendocrine system in aging

The study involves 3 aspects of neuroendocrine control over the organism functions in aging: the decline in reproductive functions, the reduction of growth hormone secretion and the decrease in thymic functional activity and the altered relationship between neuroendocrine and immune systems. The role that an age-related decrease in dopamine and noradrenaline production by hypothalamic neurones plays in the above age changes in neuroendocrine control has been traced. The age-related decrease in functions of hypothalamic catecholaminergic neurones is apparently caused by the damaging effect of hormones (prolactin, glucocorticoids and, especially, estrogen), free radicals and toxins, both of the endogenous and exogenous origin. The restrained nutrition increases lifespan of the experimental animal owing to reduced "wear out" of the neuroendocrine system and organs and tissues that are controlled by this system.     

Experimental study of the effect of corticosteroid preparations on the adhesion of Candida genus fungi to the epitheliocytes of mucous membranes

The effect of corticosteroids on the adherence of Candida cells to epithelial cells was studied with the use of the original modification of the in vitro adherence assay. The administration of hydrocortisone acetate to mice resulted in the increased adherence of the pathogenic fungi to epithelial cells: after 10-day hormone treatment the adherence number and the adherence index increased, respectively, to 230% and 360% of control values. After 20-day treatment these characteristics increased, respectively, to 260% and 700%. The adherence of C. albicans to vaginal epithelial cells in female mice receiving corticosteroids increased in comparison with that in the control animals at estrus: the adherence number increased to 220% and the adherence index, to 470% of the level observed in the controls.     

Intracellular and intercellular signal transduction pathways and age alterations of proliferative activity and apoptosis intensity in cells of immune system

The paper considers age-associated alterations of intracellular and intercellular cascades of transduction of proliferative, differentiating, pro- and antiapoptotic signals, their interaction and influence on proliferative activity, differentiation and apoptosis of the immune system cells. One of initial causes of these alterations is accumulation with age of a growing number of antigens exposed on the surface of antigen-presenting cells. As a result of chronic antigenic stimulation, caused by this factor, an insufficient quantity or a slowed down appearance of growth factor receptors (in particular, IL-2 receptor) and costimulation molecules, primarily CD28, on T-cells membrane is observed. Because of this proliferative and antiapoptotic signals, received by T-cells, have a smaller intensity that predetermine reduction of their proliferative activity, and also activity of telomerase, and a greater susceptibility to apoptosis. Permanent activation of immune system is also reflected in age-related increase of expression of CD95 and type I tumour necrosis factor receptor by lymphocytes (that aggravates their susceptibility to apoptosis), and in intensification of proinflammatory cytokine synthesis. The second main cause of alterations in the immune system is an age-related decrease in the synthesis of growth factors that are necessary for cell survival and proliferation. In particular, because of the lack of IL-7, apoptosis intensity of maturing T-cells increases in thymus. Thymic stromal cells remain without contact signals and growth factors generated by lymphocytes, and also undergo apoptosis that causes further reduction of T-lymphopoiesis. Similar events also occur in bone marrow that predetermines age-related decrease in B-lymphopoiesis and in telomerase activity of haemopoietic stem cells, and also their proliferative potential reduction.     

Substrate-induced polarisation of cultured epitheliocytes and fibroblasts: non-reactivity of Ras-transformed cells

Non-transformed epitheliocytes and fibroblasts undergo modulations between the less polarised and more polarised phenotypes depending on the nature of the substrate. In contrast, transformed cells express polarised phenotype regardless of the substrate.     

Ammonia-induced apoptosis is accelerated at higher pH in gastric surface mucous cells

Gastric luminal ammonia produced by Helicobacter pylori has been shown to cause gastric mucosal injury. This study was conducted to examine the mechanisms by which gastric luminal ammonia causes apoptosis of gastric epithelial cells. Monolayers of GSM06 cells, developed from murine gastric surface mucous cells, were cultured in the absence or presence of 10-30 mM NH(4)Cl at ambient pH of 5.0, 6.0, and 7.0. In the presence of luminal NH(4)Cl, GSM06 cells showed 1) cell shrinkage and nuclear chromatin condensation, 2) DNA fragmentation into oligonucleosomes, 3) leakage of cytochrome c into cytosolic fraction without affecting bax expression, and 4) increases in activity of caspases-3 and -9. These changes were accentuated when the cells were cultured at pH 7.0. In the absence of NH(4)Cl, none of these changes was detected at any pH examined. These results suggest that gastric luminal ammonia, at concentrations detected in H. pylori-infected subjects, induces apoptosis of gastric epithelial cells by release of cytochrome c from mitochondria, followed by activation of caspases-9 and -3, especially at higher ambient pH.     

Concanavalin A-induced suppressor cell activity for T-cell proliferative responses: Autologous and allogeneic suppression in aging humans

Peripheral blood mononuclear cells from 48 healthy subjects of ages varying from 20 to 94 years were evaluated for the ability to generate suppressor cell activity following in vitro incubation with concanavalin A. The suppression of proliferative responses by autologous and young, allogeneic lymphocytes to phytohemagglutinin was assessed using suppressor/ responder cell ratios ($\text{S}\text{R}$) of 2:1 and 1:1 and by using a summation index. Inducible suppressor cell activity for autologous responder cells was comparable between 24 aged (76.0 ± 10.9 years) and 20 young (26.8 ± 4.6 years) subjects. However, aged subjects exhibited a significant decrease in suppressor cell activity ($\text{S}\text{R}\text{= 1}$) when allogeneic responder cells were utilized. Our results indicate that autologous inducible suppressor cell activity is preserved in the aged population, whereas allogeneic activity is impaired.     

17beta-estradiol signaling in skeletal muscle cells and its relationship to apoptosis

17beta-estradiol exerts an antiapoptotic action in skeletal muscle cells through extranuclear ERalpha and beta. This protective action, mainly involves a non-genomic mechanism of ERK1/2 and PI3K/Akt activation and BAD phosphorylation. ERbeta plays a major role in the inhibition of apoptosis by 17beta-estradiol at the level of mitochondria, whereas ERalpha and ERbeta mediate the activation of Akt to the same extent, suggesting differential involvement of ER isoforms depending on the step of the apoptotic/survival pathway involved. The myopathies associated to estrogen deficit states may be related to the mechanisms by which estrogen regulates apoptosis.     

Increased susceptibility to intermittent hypoxia in aging rats: changes in proteasomal activity,neuronal apoptosis and spatial function

Obstructive sleep apnea (OSA) is a frequent medical condition characterized by intermittent hypoxia (IH) during sleep, and is associated with neurodegenerative changes in several brain regions along with learning deficits. We hypothesized that aging rats exposed to IH during sleep would be particularly susceptible. Young (3-4 months) and aging (20-22 months) Sprague-Dawley rats were therefore exposed to either room air or IH for 14 days. Learning and memory was assessed with a standard place-training version of the Morris water maze. Aging rats exposed to room air (RA) or IH displayed significant spatial learning impairments compared with similarly exposed young rats; furthermore, the decrements in performance between RA and IH were markedly greater in aging compared with young rats (p < 0.01), and coincided with the magnitude of IH-induced decreases in cyclic AMP response element binding (CREB) phosphorylation. Furthermore, decreases in proteasomal activity occurred in both young and aging rats exposed to IH, but were substantially greater in the latter (p < 0.001). Neuronal apoptosis, as shown by cleaved caspase 3 expression, was particularly increased in aging rats exposed to IH (p < 0.01 versus young rats exposed to IH). Collectively, these findings indicate unique vulnerability of the aging rodent brain to IH, which is reflected at least in part, by the more prominent decreases in CREB phosphorylation and a marked inability of the ubiquitin-proteasomal pathway to adequately clear degraded proteins.     

DNA damage and repair in brain: relationship to aging.

The usefulness of conducting DNA damage and repair studies in a postmitotic tissue like brain is emphasized. We review studies that use brain as a tissue to test the validity of the DNA damage and repair hypothesis of aging. As far as the accumulation of age dependent DNA damage is concerned, the data appear to overwhelmingly support the hypothesis. However, attempts to demonstrate a decline in DNA repair capacity as a function of age are conflicting and equally divided. Possible reasons for this discrepancy are discussed. It is suggested that assessment of the repair capacity of neurons with respect to a specific type of damage in a specific gene might yield more definitive answers regarding the role of DNA repair potential in the aging process and as a longevity assurance system.     

Developmental changes in proliferative activity of cells of the murine Rathke's pouch

Summary To clarify proliferative activity in the cells of the Rathke's pouch of the rat, we studied the labeling index using bromodeoxyuridine-immunohistochemistry. Rat fetuses were removed 1 h after transplacental injection of bromodeoxyuridine on day 11.5–21.5 of gestation, and were subsequently used to examine cellular proliferation. Although the labeling index within the Rathke's pouch was 30% on day 12.5, it decreased with development and by day 18.5 of gestation had a value of about 5%. The labeling index within Rathke's pouch was not homogeneous throughout the entire pouch, but tended to be higher in regions where cells were more densely packed. This heterogeneous pattern of distribution of labeling index values continued until day 15. On that day, immunoreactive ACTH cells first appeared in the region where the labeling index was low. From day 17 of gestation, the uneven distribution of the labeling index became vague and, simultaneously, the distribution of ACTH cells became homogeneous throughout the pouch. It was concluded that proliferation of the epithelium of Rathke's pouch is heavily involved in the growth of the pouch until at least the appearance of ACTH cells.