Epigenetics Offer New Horizons for Colorectal Cancer Prevention

In recent years, colorectal cancer (CRC) incidence has been increasing to become a major cause of morbidity and mortality worldwide from cancers, with high rates in westernized societies and increasing rates in developing countries. Epigenetic modifications including changes in DNA methylation, histone modifications, and non-coding RNAs play a critical role in carcinogenesis. Epidemiological data suggest that, in comparison to other cancers, these alterations are particularly common within the gastrointestinal tract. To explain these observations, environmental factors and especially diet were suggested to both prevent and induce CRC. Epigenetic alterations are, in contrast to genetic modifications, potentially reversible, making the use of dietary agents a promising approach in CRC for the development of chemopreventive strategies targeting epigenetic mechanisms. This review focuses on CRC-related epigenetic alterations as a rationale for various levels of prevention strategies and their potential modulation by natural dietary compounds

Control of retinal isomerization in bacteriorhodopsin in the high-intensity regime

A learning algorithm was used to manipulate optical pulse shapes and optimize retinal isomerization in bacteriorhodopsin, for excitation levels up to 1.8 × 1016 photons per square centimeter. Below 1/3 the maximum excitation level, the yield was not sensitive to pulse shape. Above this level the learning algorithm found that a Fourier-transform-limited (TL) pulse maximized the 13-cis population. For this optimal pulse the yield increases linearly with intensity well beyond the saturation of the first excited state. To understand these results we performed systematic searches varying the chirp and energy of the pump pulses while monitoring the isomerization yield. The results are interpreted including the influence of 1-photon and multiphoton transitions. The population dynamics in each intermediate conformation and the final branching ratio between the all-trans and 13-cis isomers are modified by changes in the pulse energy and duration

A microwave interferometer for small and tenuous plasma density measurements

The non-intrusive density measurement of the thin plasma produced by a mini-helicon space thruster (HPH.com project) is a challenge, due to the broad density range (between 1016 m 123 and 10^19 m 123) and the small size of the plasma source (2 cm of diameter). A microwave interferometer has been developed for this purpose. Due to the small size of plasma, the probing beam wavelength must be small (\u3bb = 4 mm), thus a very high sensitivity interferometer is required in order to observe the lower density values. A low noise digital phase detector with a phase noise of 0.02\ub0 has been used, corresponding to a density of 0.5 7 10^16 m 123

Familial Alzheimer\ue2\u20ac\u2122s Disease presenilin mutants reduce calcium levels of intracellular stores. A critical revaluation of the \ue2\u20ac\u153calcium overload\ue2\u20ac\u9d hypothesis

Background: Presenilin-1 and -2 (PS1 and PS2) mutations, the major cause of Familial Alzheimer\u2019s Disease (FAD), have been causally implicated in the pathogenesis of neuronal cell death through a perturbation of cellular Ca2+ homeostasis. We have recently shown that, at variance with previous suggestions obtained in cells expressing other FAD-linked PS mutations, PS2-M239I and PS2-T122R cause a reduction and not an increase in cytosolic Ca2+ rises induced by Ca2+ release from stores (1,2). Objective(s): In this study we aim at investigating whether other FAD-linked PS mutations induce a similar dysregulation of Ca2+ homeostasis. Methods: Different cell models have been used: human fibroblasts from controls and FAD patients, cell lines (SH-SY5Y, HeLa, HEK293, MEFs) and rat primary neurons expressing a number of PS mutations, e.g. P117L, M146L, L286V, and A246E in PS1 and M239I, T122R, and N141I in PS2. The effects of FAD-linked PS mutations on cytosolic Ca2+ changes have been monitored either by using fura-2 or recombinant cytosolic aequorin as the probe. Results: Independently of the cell model or the employed probe, the cytosolic Ca2+ increases, caused by agonist stimulation or full store depletion by drug treatment, were reduced or unchanged in cells expressing the PS mutations. Using aequorins, targeted to the endoplasmic reticulum or the Golgi apparatus, we here show that FAD-linked PS mutants lower the Ca2+ content of intracellular stores. The phenomenon was most prominent in cells expressing PS2 mutants, and was observed also in cells expressing the non-pathogenic, \u201closs-of-function\u201d PS2-D366A mutation. Conclusions: Taken as a whole, our findings, while confirming the capability of presenilins to modify Ca2+ homeostasis, suggest a re-evaluation of the \u201cCa2+ hypothesis\u201d in AD and a new working hypothesis is presented. 1. Zatti G, Ghidoni R, Barbiero L, Binetti G, Pozzan T, Fasolato C, Pizzo P. (2004). Neurobiology of disease, 15, 269-278. 2. Giacomello M, Barbiero L, Zatti G, Squitti R, Binetti G, Pozzan T, Fasolato C, Ghidoni R, Pizzo P. (2005). Neurobiology of disease, 18, 638-648

Selective Non-nucleoside Inhibitors of Human DNA Methyltransferases Active in Cancer Including in Cancer Stem Cells

DNA methyltransferases (DNMTs) are important enzymes involved in epigenetic control of gene expression and represent valuable targets in cancer chemotherapy. A number of nucleoside DNMT inhibitors (DNMTi) have been studied in cancer, including in cancer stem cells, and two of them (azacytidine and decitabine) have been approved for treatment of myelodysplastic syndromes. However, only a few non-nucleoside DNMTi have been identified so far, and even fewer have been validated in cancer. Through a process of hit-to-lead optimization, we report here the discovery of compound 5 as a potent non-nucleoside DNMTi that is also selective toward other AdoMet-dependent protein methyltransferases. Compound 5 was potent at single-digit micromolar concentrations against a panel of cancer cells and was less toxic in peripheral blood mononuclear cells than two other compounds tested. In mouse medulloblastoma stem cells, 5 inhibited cell growth, whereas related compound 2 showed high cell differentiation. To the best of our knowledge, 2 and 5 are the first non-nucleoside DNMTi tested in a cancer stem cell line. © 2014 American Chemical Society

Ubiquitin-dependent degradation of HDAC4, a new regulator of random cell motility

Histone deacetylase 4 (HDAC4) controls several cellular responses and is subjected to multiple levels of regulation. Here it is shown that HDAC4 is under the regulation of the proteasome, in a growth factor- and GSK3β-dependent manner. Degradation of HDAC4 could contribute to the attenuation of random cell motility observed in cells in the G0 phase of the cell cycle