A Crosstalk Between Brain Cholesterol Oxidation and Glucose Metabolism in Alzheimer’s Disease

In Alzheimer’s disease (AD), both cholesterol and glucose dysmetabolism precede the onset of memory deficit and contribute to the disease’s progression. It is indeed now believed that oxidized cholesterol in the form of oxysterols and altered glucose uptake are the main triggers in AD affecting production and clearance of Aβ, and tau phosphorylation. However, only a few studies highlight the relationship between them, suggesting the importance of further extensive studies on this topic. Recently, a molecular link was demonstrated between cholesterol oxidative metabolism and glucose uptake in the brain. In particular, 27-hydroxycholesterol, a key linker between hypercholesterolemia and the increased AD risk, is considered a biomarker for reduced glucose metabolism. In fact, its excess increases the activity of the renin-angiotensin system in the brain, thus reducing insulin-mediated glucose uptake, which has a major impact on brain functioning. Despite this important evidence regarding the role of 27-hydroxycholesterol in regulating glucose uptake by neurons, the involvement of other cholesterol oxidation products that have been clearly demonstrated to be key players in AD cannot be ruled out. This review highlights the current understanding of the potential role of cholesterol and glucose dysmetabolism in AD progression, and the bidirectional crosstalk between these two phenomena

Calcium regulates HCC proliferation as well as EGFR recycling/degradation and could be a new therapeutic target in HCC

Calcium is the most abundant element in the human body. Its role is essential in physiological and biochemical processes such as signal transduction from outside to inside the cell between the cells of an organ, as well as the release of neurotransmitters from neurons, muscle contraction, fertilization, bone building, and blood clotting. As a result, intra- and extracellular calcium levels are tightly regulated by the body. The liver is the most specialized organ of the body, as its functions, carried out by hepatocytes, are strongly governed by calcium ions. In this work, we analyze the role of calcium in human hepatoma (HCC) cell lines harboring a wild type form of the Epidermal Growth Factor Receptor (EGFR), particularly its role in proliferation and in EGFR downmodulation. Our results highlight that calcium is involved in the proliferative capability of HCC cells, as its subtraction is responsible for EGFR degradation by proteasome machinery and, as a consequence, for EGFR intracellular signaling downregulation. However, calcium-regulated EGFR signaling is cell line-dependent. In cells responding weakly to the epidermal growth factor (EGF), calcium seems to have an opposite effect on EGFR internalization/degradation mechanisms. These results suggest that besides EGFR, calcium could be a new therapeutic target in HCC

TGF-β and the Tissue Microenvironment: Relevance in Fibrosis and Cancer

Transforming growth factor-β (TGF-β) is a cytokine essential for the induction of the fibrotic response and for the activation of the cancer stroma. Strong evidence suggests that a strong cross-talk exists among TGF-β and the tissue extracellular matrix components. TGF-β is stored in the matrix as part of a large latent complex bound to the latent TGF-β binding protein (LTBP) and matrix binding of latent TGF-β complexes, which is required for an adequate TGF-β function. Once TGF-β is activated, it regulates extracellular matrix remodelling and promotes a fibroblast to myofibroblast transition, which is essential in fibrotic processes. This cytokine also acts on other cell types present in the fibrotic and tumour microenvironment, such as epithelial, endothelial cells or macrophages and it contributes to the cancer-associated fibroblast (CAF) phenotype. Furthermore, TGF-β exerts anti-tumour activity by inhibiting the host tumour immunosurveillance. Aim of this review is to update how TGF-β and the tissue microenvironment cooperate to promote the pleiotropic actions that regulate cell responses of different cell types, essential for the development of fibrosis and tumour progression. We discuss recent evidences suggesting the use of TGF-β chemical inhibitors as a new line of defence against fibrotic disorders or cancer

Heavy metals modulate DNA compaction and methylation at CpG sites in the metal hyperaccumulator Arabidopsis halleri

Excess heavy metals affect plant physiology by inducing stress symptoms, however several species have evolved the ability to hyperaccumulate metals in above-ground tissues without phytotoxic effects. In this study we assume that at subcellular level, different strategies were adopted by hyperaccumulator versus the non-accumulator plant species to face the excess of heavy metals. At this purpose the comet assay was used to investigate the nucleoid structure modifications occurring in response to Zn and Cd treatments in the I16 and PL22 populations of the hyperaccumulator Arabidopsis halleri versus the nonaccumulator species Arabidopsis thaliana. Methy-sens comet assay and RT-qPCR were also performed to associate metal induced variations in nucleoids with possible epigenetic modifications. The comet assay showed that Zn induced a mild but non significant reduction in the tail moment in A. thaliana and in both I16 and PL22. Cd treatment induced an increase in DNA migration in nuclei of A. thaliana, whereas no differences in DNA migration was observed for I16, and a significant increase in nucleoid condensation was found in PL22 Cd treated samples. This last population showed higher CpG DNA methylation upon Cd treatment than in control conditions, and an upregulation of genes involved in symmetric methylation and histone deacetylation. Our data support the hypothesis of a possible role of epigenetic modifications in the hyperaccumulation trait to cope with the high Cd shoot concentrations. In addition, the differences observed between PL22 and I16 could reinforce previous suggestions of divergent strategies for metals detoxification developing in the two metallicolous populations

DNA methylation is enhanced during Cd hyperaccumulation in Noccaea caerulescens ecotype Ganges

In this study, we assess the DNA damage occurring in response to cadmium (Cd) in the Cd hyperaccumulator Noccaea caerulescens Ganges (GA) vs the non-accumulator and close-relative species Arabidopsis thaliana. At this purpose, the alkaline comet assay was utilized to evaluate the Cd-induced variations in nucleoids and the methy-sens comet assay, and semiquantitative real-time (qRT)-PCR were also performed to associate nucleus variations to possible DNA modifications. Cadmium induced high DNA damages in nuclei of A. thaliana while only a small increase in DNA migration was observed in N. caerulescens GA. In addition, in N. caerulescens GA, CpG DNA methylation increase upon Cd when compared to control condition, along with an increase in the expression of MET1 gene, coding for the DNA-methyltransferase. N. caerulescens GA does not show any oxidative stress under Cd treatment, while A. thaliana Cd-treated plants showed an upregulation of transcripts of the respiratory burst oxidase, accumulation of reactive oxygen species, and enhanced superoxide dismutase activity. These data suggest that epigenetic modifications occur in the N. caerulescens GA exposed to Cd to preserve genome integrity, contributing to Cd tolerance