Atomic force microscopy probing in the measurement of cell mechanics

Atomic force microscope (AFM) has been used incrementally over the last decade in cell biology. Beyond its usefulness in high resolution imaging, AFM also has unique capabilities for probing the viscoelastic properties of living cells in culture and, even more, mapping the spatial distribution of cell mechanical properties, providing thus an indirect indicator of the structure and function of the underlying cytoskeleton and cell organelles. AFM measurements have boosted our understanding of cell mechanics in normal and diseased states and provide future potential in the study of disease pathophysiology and in the establishment of novel diagnostic and treatment options

Antiatherogenic effects of vitamin E: the search for the Holy Grail

Vitamin E, a naturally occurring antioxidant, has been found to reduce atherosclerotic lesion formation in animal models as well as cardiovascular morbidity in several observational studies. However, a number of case-control and prospective cohort studies failed to confirm its value in the primary and secondary prevention of morbidity and mortality from coronary artery disease. Several small or larger randomized interventional trials completed to date failed to resolve the conflict. Notably, even in large, well-conducted prospective epidemiologic studies, the potential effects of residual confounding may be on the same order of magnitude as the reported benefit. The response to vitamin E supplementation in specific patient subpopulations with chronic inflammation and/or higher degrees of oxidative stress has not been studied as yet. Therefore, further large randomized interventional trials are warranted to clarify accurately the role of vitamin E in the primary and secondary prevention of atherosclerotic coronary disease in these patient groups

Pleiotropic vasoprotective effects of statins: The chicken or the egg?

Statins (3-hydroxy-3-methyl glutaryl coenzyme A [HMG-CoA] reductase inhibitors) are the most commonly used lipid-lowering drugs. Their main lipid-lowering effect is achieved by an increase in the expression of low-density lipoprotein cholesterol receptors associated with inhibition of cholesterol synthesis through inhibition of HMG-CoA reductase – the first and rate-limiting step in cholesterol synthesis. However, beyond cholesterol synthesis inhibition, inhibition of the HMG-CoA reductase affects as well the synthesis of other molecules with significant roles in different, yet often intercalating, metabolic pathways. On this basis, and supported by an increasing series of advocating epidemiological and experimental data, an extended dialogue has been established over the last few years regarding the nonlipid or “pleiotropic” actions of statins

Serum Lipid Profile Constituents as Markers of Cardiovascular Morbidity in Patients on Chronic Hemodialysis

We designed the present case-control study in order to examine the validity of apolipoprotein (apo) A-I, B, apoB/apoA-I ratio and Lp(a) as alternative markers of cardiovascular morbidity in end-stage renal disease (ESRD) patients undergoing chronic hemodialysis (HD). Twenty-five HD patients (18 males, mean age 63, range 52–69 years) comprised the group with prevalent cardiovascular disease (CVD) and 50 HD patients (35 males, mean age 62, range 40–77 years) with non evident cardiovascular disease history constituted the second study group. Patients with CVD had significantly higher concentrations of serum apoB, apoB/apoA-I ratio and Lp(a), and lower levels of apoA-I compared to patients without incident CVD. All three parameters studied were correlated with cardiovascular morbidity, i.e. apoA-I negatively and apoB and apoB/apoA-I ratio positively (r = −0.6, P < 0.05; r = 0.659, P < 0.01; and r = 0.614, P < 0.01, respectively). Furthermore, logCRP exhibited as well a significant positive correlation with cardiovascular morbidity (r = 0.704, P < 0.001), not this being the case for Lp(a) which was not found to exhibit such a correlation (r = 0.05, P = NS). Among them, apoB and apoB/apoA-I ratio exhibited the characteristics most coherent to CVD. The age- and sex-adjusted OR for the presence of CVD was 2.3 and 2.0, respectively, which remained independent of any confounding effect of inflammation. In conclusion, serum apoB levels and apoB/apoA-I ratio exhibit characteristics of credible independent markers of in HD patients

Histone acetyltransferase NAA40 modulates acetyl-CoA levels and lipid synthesis.

BACKGROUND: Epigenetic regulation relies on the activity of enzymes that use sentinel metabolites as cofactors to modify DNA or histone proteins. Thus, fluctuations in cellular metabolite levels have been reported to affect chromatin modifications. However, whether epigenetic modifiers also affect the levels of these metabolites and thereby impinge on downstream metabolic pathways remains largely unknown. Here, we tested this notion by investigating the function of N-alpha-acetyltransferase 40 (NAA40), the enzyme responsible for N-terminal acetylation of histones H2A and H4, which has been previously implicated with metabolic-associated conditions such as age-dependent hepatic steatosis and calorie-restriction-mediated longevity. RESULTS: Using metabolomic and lipidomic approaches, we found that depletion of NAA40 in murine hepatocytes leads to significant increase in intracellular acetyl-CoA levels, which associates with enhanced lipid synthesis demonstrated by upregulation in de novo lipogenesis genes as well as increased levels of diglycerides and triglycerides. Consistently, the increase in these lipid species coincide with the accumulation of cytoplasmic lipid droplets and impaired insulin signalling indicated by decreased glucose uptake. However, the effect of NAA40 on lipid droplet formation is independent of insulin. In addition, the induction in lipid synthesis is replicated in vivo in the Drosophila melanogaster larval fat body. Finally, supporting our results, we find a strong association of NAA40 expression with insulin sensitivity in obese patients. CONCLUSIONS: Overall, our findings demonstrate that NAA40 affects the levels of cellular acetyl-CoA, thereby impacting lipid synthesis and insulin signalling. This study reveals a novel path through which histone-modifying enzymes influence cellular metabolism with potential implications in metabolic disorders

Role of STAT3 and vitamin D receptor in EZH2 ‐mediated invasion of human colorectal cancer

The polycomb group protein enhancer of zeste homologue 2 ( EZH2 ), which has histone methyltransferase ( HMT ) activity, is overexpressed in malignant tumours. However, the role of EZH2 in colorectal cancer ( CRC ) invasion is little known. Here we investigated the clinical significance, biological effects, and mechanisms of EZH2 signalling. Knockdown of EZH2 significantly reduced cell invasion and secretion of matrix metalloproteinases 2/9 ( MMP2 /9) in in vitro studies. Knockdown of EZH2 dramatically increased overall survival and decreased metastasis of lung in in vivo studies. Conversely, overexpression of EZH2 significantly increased lung metastasis and shortened overall survival when compared with control tumours. EZH2 ‐induced CRC cell invasion may depend on down‐regulation of vitamin D receptor ( VDR ), which is considered to be a marker of CRC invasion. EZH2 regulates the histone trimethylation of lysine 27 ( H3K27me3 ) in the VDR promoter. Moreover, we found that STAT3 directly binds to the EZH2 promoter and regulates VDR down‐regulation in CRC cells. Significant inverse correlations were observed between the expression of EZH2 and pSTAT3 and that of VDR in CRC tissues compared with normal tissue in patients. We show the role of EZH2 in CRC metastasis and identify VDR as a target gene of EZH2 . EZH2 expression may be directly regulated by STAT3 , and STAT3 may play an important role in EZH2 ‐mediated VDR down‐regulation in CRC . This pathway may provide potential targets in aggressive CRC . Copyright © 2013 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/98269/1/path4179-sup-0004-FigureS3.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/98269/2/path4179-sup-0002-FigureS1.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/98269/3/path4179.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/98269/4/path4179-sup-0003-FigureS2.pd

Histone Modifications as an Intersection Between Diet and Longevity

Histone modifications are key epigenetic regulators that control chromatin structure and gene transcription, thereby impacting on various important cellular phenotypes. Over the past decade, a growing number of studies have indicated that changes in various histone modifications have a significant influence on the aging process. Furthermore, it has been revealed that the abundance and localization of histone modifications are responsive to various environmental stimuli, such as diet, which can also affect gene expression and lifespan. This supports the notion that histone modifications can serve as a main cellular platform for signal integration. Hence, in this review we focus on the role of histone modifications during aging, report the data indicating that diet affects histone modification levels and explore the idea that histone modifications may function as an intersection through which diet regulates lifespan. A greater understanding of the epigenetic mechanisms that link environmental signals to longevity may provide new strategies for therapeutic intervention in age-related diseases and for promoting healthy aging