Iron at the Interface of Hepatocellular Carcinoma

Cancer incidence and mortality are rapidly growing, with liver cancer being the sixth most diagnosed cancer worldwide and the third leading cause of cancer death in 2020. A number of risk factors have been identified that trigger the progression to hepatocellular carcinoma. In this review, we focus on iron as a potential risk factor for liver carcinogenesis. Molecules involved in the regulation of iron metabolism are often upregulated in cancer cells, in order to provide a supply of this essential trace element for all stages of tumor development, survival, proliferation, and metastasis. Thus, cellular and systemic iron levels must be tightly regulated to prevent or delay liver cancer progression. Disorders associated with dysregulated iron metabolism are characterized with increased susceptibility to hepatocellular carcinoma. This review discusses the association of iron with metabolic disorders such as hereditary hemochromatosis, non-alcoholic fatty liver disease, obesity, and type 2 diabetes, in the background of hepatocellular carcinoma.     

Cross-TCR Antagonism Revealed by Optogenetically Tuning the Half-Life of the TCR Ligand Binding

Activation of T cells by agonistic peptide-MHC can be inhibited by antagonistic ones. However, the exact mechanism remains elusive. We used Jurkat cells expressing two different TCRs and tested whether stimulation of the endogenous TCR by agonistic anti-Vβ8 antibodies can be modulated by ligand-binding to the second, optogenetic TCR. The latter TCR uses phytochrome B tetramers (PhyBt) as ligand, the binding half-life of which can be altered by light. We show that this half-life determined whether the PhyBt acted as a second agonist (long half-life), an antagonist (short half-life) or did not have any influence (very short half-life) on calcium influx. A mathematical model of this cross-antagonism shows that a mechanism based on an inhibitory signal generated by early recruitment of a phosphatase and an activating signal by later recruitment of a kinase explains the data.     

Interrogating PP1 Activity in the MAPK Pathway with Optimized PP1-Disrupting Peptides

Protein phosphatase-1 (PP1)-disrupting peptides (PDPs) are selective chemical modulators of PP1 that liberate the active PP1 catalytic subunit from regulatory proteins; thus allowing the dephosphorylation of nearby substrates. We have optimized the original cell-active PDP3 for enhanced stability, and obtained insights into the chemical requirements for stabilizing this 23-mer peptide for cellular applications. The optimized PDP-Nal was used to dissect the involvement of PP1 in the MAPK signaling cascade. Specifically, we have demonstrated that, in human osteosarcoma (U2OS) cells, phosphoMEK1/2 is a direct substrate of PP1, whereas dephosphorylation of phosphoERK1/2 is indirect and likely mediated through enhanced tyrosine phosphatase activity after PDP-mediated PP1 activation. Thus, as liberators of PP1 activity, PDPs represent a valuable tool for identifying the substrates of PP1 and understanding its role in diverse signaling cascades.     

Antioxidant activity,functional properties and bioaccessibility of whey protein hydrolysates

The main objective of this study was to produce the functionally improved whey protein hydrolysate with high bioaccessible antioxidant activity. The hydrolysate with highest antioxidant activity, mainly composed of hydrophilic antioxidant peptides and suitable for preventing oxidation in polar food matrices, was produced by tryptic hydrolysis conducted at 37 °C and an enzyme/substrate (E/S) ratio of 0.5%. The hydrolysate exerted significantly improved antioxidant activity (80.0%), digestibility (95.9%) and bioaccessibility (124.6%) compared to the native whey proteins (32.1%, 87.1% and 106.3%, respectively) as widely used food supplement. The high bioaccessibility indicates the preservation of hydrolysate bioactivity during the process of gastrointestinal digestion, as a particular challenge in its application.     

Target tissue selectivity and burdens of diverse classes of brominated and chlorinated contaminants in polar bears (Ursus maritimus) from East Greenland

The tissue-specific composition of sum classes of brominated and chlorinated contaminants and metabolic/degradation byproducts was determined in adult male and female polar bears from East Greenland. Significantly (p < 0.05) higher concentrations of sigma-PCBs, various other organochlorines such as sigma-CHL, p,p'-DDE, sigma-CBz, sigma-HCHs, octachlorostyrene (OCS), sigma-mirex, dieldrin, the flame retardants sigma-PBDEs, and total-(alpha)-hexabromocyclododecane (HBCD), sigma-methylsulfonyl (MeSO2)-PCBs and 3-MeSO2-p,p'-DDE, were found in the adipose and liver tissues relative to whole blood and brain. In contrast, sigma-hydroxyl (OH)-PCB, 4-OH-heptachlorostyrene and sigma-OH-PBDE concentrations were significantly highest (p < 0.05) in whole blood, whereas the highest concentrations of sigma-OH-PBBs were found in the adipose tissue. Based on the total concentrations of all organohalogens in all three tissues and blood, the combined body burden was estimated to be 1.34 +/- 0.12 g, where > 91% of this amount was accounted for by the adipose tissue alone, followed by the liver, whole blood, and brain. These results show that factors such as protein association and lipid solubility appear to be differentially influencing the toxicokinetics, in terms of tissue composition/ localization and burden, of organohalogen classes with respect to chemical structure and properties such as the type of halogenation (e.g., chlorination or bromination), and the presence or absence of additional phenyl group substituents (e.g., MeO and OH groups). The tissue- and blood-specific accumulation (or retention) among organohalogen classes indicates that exposure and any potential contaminant-mediated effects in these polar bears are likely tissue or blood specific.     

Associating protein activities with their genes: rapid identification of a gene encoding a methylglyoxal reductase in the yeast Saccharomyces cerevisiae

Methylglyoxal is associated with a broad spectrum of biological effects, including cytostatic and cytotoxic activities. It is detoxified by the glyoxylase system or by its reduction to lactaldehyde by methylglyoxal reductase. We show that methylglyoxal reductase (NADPH-dependent) is encoded by GRE2 (YOL151w). We associated this activity with its gene by partially purifying the enzyme and identifying by MALDI-TOF the proteins in candidate bands on SDS-PAGE gels whose relative intensities correlated with specific activity through three purification steps. The candidate proteins were then purified using a glutathione-S-transferase tag that was fused to them, and tested for methylglyoxal reductase activity. The advantage of this approach is that only modest protein purification is required. Our approach should be useful for identifying many of the genes that encode the metabolic pathway enzymes that have not been associated with a gene (about 275 in S. cerevisiae, by our estimate).