Thus, no significant differences in the studied polymorphism frequencies were observed. It is then suggested that the studied polymorphisms, although probably good candidates in other tissue cancer types, might not be good predictive factors in breast cancer risk or development in Caucasians.
Phytosterols have been proposed to act as potent anticancer agents. However the mechanism of their action has not been elucidated yet. Thus, the aim of our study was to determine whether plant sterols and their thermal processing products (in physiological concentration range) could influence the viability of cancer cells and thus could be considered as positive diet complements. Additionally we decided to study potential specificity of those natural compounds against cells showing high multidrug resistance. In this study we show that the cytotoxic effect of β-sitosterol was observed in both, estrogen-dependent and estrogen-independent cells. It was also shown that the β-sitosterol was significantly more cytotoxic in cells with basal ABCB1 expression (MCF7) than in multidrug resistant NCI/ADR-RES. Surprisingly, 5a,6a-epoxysitosterol did not decrease the viability of any investigated cells but on the contrary, it provoked their increased proliferation. It was shown that oxyphytosterols blocked the cell cycle of MCF7 cells in G0/G1 phase while did not affect NCI/ADR-RES cell cycle in physiological concentration range. We also show that PgP activity (responsible for Multidrug Resistance phenomena) is inhibited by β-sitosterol. Thus, the phytosterols are supposed to act at various mechanisms but, what is most interesting, can target cells showing high multidrug resistance potential.
present even in the pre-plaque stages. Conclusions: Proteomic characterization of the rat model of Alzheimer's disease compared to wild type controls reveals early dysregulation of molecular pathways that are expected to contribute to AD pathology, as well as additional pathways that may represent novel targets for therapeutic intervention. These early changes might well represent preclinical features of the Abeta-driven pathology. Further characterization of this transgenic rat model will include analysis of biomarker profiles.Background: Alzheimer's disease (AD) is a progressive neurodegenerative disorder that causes cognitive and behavioral impairment. It is characterized by the accumulation of amyloid plaques and neurofibrillary tangles. Histochemical analyses of AD brain tissue have shown BuChE to be present in ß-amyloid (Aß) plaques and neurofibrillary tangles (NFTs). In addition, it has been found that when BuChE is associated with plaques that they are in a more malignant, ß-pleated, thioflavin-S positive form. It is not clear whether the BuChE associated with Aß plaques is causative of AD, interferes with disease progression or is an epiphenomenon. An animal model that develops similar BuChE-associated Aß plaques, could help elucidate the role of BuChE in this pathology. Methods: The B6.Cg-Tg (APP SWE / PSEN1dE9) 85Dbo/j transgenic mouse was used to determine if BuChE associates with Aß plaques in a mouse model of AD. Four mice, aged 15.5 months, were used in this study. Brain tissue was stained using Aß immunohistochemistry, thioflavin-S and BuChE histochemistry. Plaque loads were quantified using NIH ImageJ software and recorded as a percentage of the total area. Results: We found that this animal model develops Aß and thioflavin-S plaques with BuChE activity (Figure 1). The pathology seen, in terms of morphology, distribution and abundance of Aß, thioflavin-S and BuChE plaques, closely resembled many aspects seen in AD. There was a high correlation in the distribution and abundance of Aß, thioflavin-S and BuChE plaques. Furthermore, based on the percent of area covered by pathology, BuChE staining was less than Aß staining but more than thioflavin-S staining. Ab, thioflavin-S and BuChE plaques were found in cortical and hippocampal areas as well as in olfactory structures, amygdala and the cerebellum. There were few scattered plaques in the thalamus, striatum and certain fibre tracts as well. Conclusions: Based on the work with this APP/PS1 Cg-Tg mouse model, BuChE association with Aß plaques may represent an intermediate stage in the development of malignant, ß-pleated, thioflavin-S positive plaques. Further study with this animal model may help elucidate the role of BuChE in AD pathology. Figure 1. b-amyloid immunohistochemistry, thioflavin-S staining and butyrylcholinesterase histochemistry in a 15.5 month old B6. Cg-Tg (APPSWE/PSEN1dE9) 85Dbo/j mouse. scale bar ¼ 1mm.Background: Alzheimer's disease (AD) is one of the most important neurodegenerative diseases. Mutations in amyloid precursor protein...
Background: TAR DNA binding protein 43 (TDP-43) plays a central role in amyotrophic lateral sclerosis and related TDP-43 proteinopathies. Whether TDP-43 neurotoxicity is related to a gain or loss of its normal function is not known. Methods: We have combined whole transcriptome sequencing with in vivo genetic validation in gain and loss of function TDP-43 mutants in Drosophila. Results: Gain and loss of TDP-43 strongly deregulated expression of the neuronal microtubule associated protein Map205 leading to cytoplasmic accumulation of the ecdysteroid receptor (EcR) and in turn to apoptotic neuronal death. Gene network analysis showed that TDP-43 dysfunction rendered EcR unable to shut down the transcription factor broad resulting in failed transcriptional program switching from a pupal to adult pattern. Conclusions: Our results establish disrupted EcR signaling as a cellular mechanism underlying dTDP-43 neurotoxicity in Drosophila and support a loss-of-function mechanism in TDP-43 proteinopathies. P2- Background:In double transgenic mouse model of Alzheimer's disease (AD) mutation of APP695 is associated with familial AD. Aged-transgenic mice elevated level of Ab which may cause to generate of free radicals and oxidize of macromolecules (DNA). OGG1 is a main DNA repair enzyme that excises of 8-oxoguanine from DNA. It was postulated that decreased expression of OGG1 may lead to higher background mutation frequency and could increase the DNA damages risk. 8-Oxo2dG is known to induce GC-TA transversion type point mutations, and this type of mutation is commonly observed in the tumor suppressor p53 gene. Moreover, in mice OGG1 coupled with lower level of TNF-alpha protein. P53 protein by changes of Bcl-2 family proteins expression and TNF-alpha protein may induce apoptosis in the cell. Methods: The aim of the study was to analyze of OGG1, TNFalpha Bcl-2, Bax proteins, in the brain of double transgenic mouse model of AD and controls. The studies were performed on female mice 6.0-8.0-months-old transgenic (B6.Cg-Tg (APP695)3DBo Tg(PSEN1dE9)S9Dbo/ J stain, Jackson Lab., USA), and 8.0-12.0-weeks-old controls (C57BL/6J stain). Brains of animals were divided into three structures: cerebral grey matter (GM), subcortical white matter (WM) and cerebellum (C). The level of OGG1, TNF-alpha, Bax, Bcl-2 proteins was determined with Western Blot method. Results: Shown, that the level of OGG1 and TNF-alpha proteins was similar in all analyzed structures of the mouse brain. Simultaneously, the level of OGG1 protein was only insignificant lower in GM of transgenic mice but TNF-alpha insignificant higher in all analyzed structures of transgenic mice as compared to the controls. However, the level of Bax and Bcl-2 proteins was higher in all analyzed structures of the brain of transgenic mice, in GM (Bax, P <0.001; Bcl-2, P <0.01), WM (Bax, We set out to determine whether C. elegans could be used to study molecular mechanisms and potential medical treatments for APP-induced neurodegeneration. We generated strains that used a pan-neurona...
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