Review of Structural Features and Binding Capacity of Polyphenols to Gluten Proteins and Peptides In Vitro: Relevance to Celiac Disease.

Polyphenols have been extensively studied due to their beneficial effects on human health, particularly for the prevention and treatment of diseases related to oxidative stress. Nevertheless, they are also known to have an anti-nutritional effect in relation to protein metabolism. This effect is a consequence of its binding to digestive enzymes and/or protein substrates. Dietary gluten is the main trigger of celiac disease, a common immune-based disease of the small intestine and for which the only treatment available is the adherence to a gluten-free diet. Recent studies have addressed the use of dietary polyphenols to interact with gluten proteins and avoid its downstream deleterious effects, taking the advantage of the anti-nutritive nature of polyphenols by protein sequestering. Flavonoids, coumarins and tannins have shown the ability to form insoluble complexes with gluten proteins. One of the most promising molecules has been epigallocatechin-3-gallate, which through its binding to gliadins, was able to reduce gliadins digestibility and its ability to stimulate monolayer permeability and transepithelial transport of immunodominant peptides in cell models. This review focuses on the structural features and binding capacity of polyphenols to gluten proteins and peptides, and the prospects of developing an adjuvant therapy in celiac disease.

Hydrogen peroxide regulates angiogenesis-related factors in tumor cells.

Tumor angiogenesis is required for tumor development and growth, and is regulated by several factors including ROS. H2O2 is a ROS with an important role in cell signaling, but how H2O2 regulates tumor angiogenesis is still poorly understood. We have xenografted tumor cells with altered levels of H2O2 by catalase overexpression into zebrafish embryos to study redox-induced tumor neovascularization. We found that vascular recruitment and invasion were impaired if catalase was overexpressed. In addition, the overexpression of catalase altered the transcriptional levels of several angiogenesis-related factors in tumor cells, including TIMP-3 and THBS1. These two anti-angiogenic factors were found to be H2O2-regulated by two different mechanisms: TIMP-3 expression in a cell-autonomous manner; and, THBS1 expression that was non-cell-autonomous. Our work shows that intracellular H2O2 regulates the expression of angiogenic factors and the formation of a vessel network. Understanding the molecular mechanisms that govern this multifunctional effect of H2O2 on tumor angiogenesis could be important for the development of more efficient anti-angiogenic therapies.

Data on intracellular localization of RPSA upon alteration of its redox state.

Ribosomal Protein SA (RPSA), a component of the 40S ribosomal subunit, was identified as a H2O2 target in HeLa cells [1]. In order to analyze the intracellular localization of RPSA in different redox states we overexpressed wild-type RPSA (RPSAwt) or RPSA containing two cysteine to serine residue substitutions at positions 148 and 163 (RPSAmut) in HeLa cells. The transfected cells were exposed to H2O2 or N-acetylcysteine (NAC) and RPSA subcellular localization was assessed by immunofluorescence in permeabilized cells. In addition, co-immunofluorescence for RPSA and Ribosomal Protein S6 (RPS6) was performed in cells overexpressing RPSAwt or RPSAmut. Finally, the ribosomal expression of endogenous RPSA in the presence or absence of H2O2 was analyzed by Western blot. The data presented in this work is related to the research article entitled "Hydrogen peroxide regulates cell adhesion through the redox sensor RPSA" [1].

Hydrogen peroxide regulates cell adhesion through the redox sensor RPSA.

To become metastatic, a tumor cell must acquire new adhesion properties that allow migration into the surrounding connective tissue, transmigration across endothelial cells to reach the blood stream and, at the site of metastasis, adhesion to endothelial cells and transmigration to colonize a new tissue. Hydrogen peroxide (H2O2) is a redox signaling molecule produced in tumor cell microenvironment with high relevance for tumor development. However, the molecular mechanisms regulated by H2O2 in tumor cells are still poorly known. The identification of H2O2-target proteins in tumor cells and the understanding of their role in tumor cell adhesion are essential for the development of novel redox-based therapies for cancer. In this paper, we identified Ribosomal Protein SA (RPSA) as a target of H2O2 and showed that RPSA in the oxidized state accumulates in clusters that contain specific adhesion molecules. Furthermore, we showed that RPSA oxidation improves cell adhesion efficiency to laminin in vitro and promotes cell extravasation in vivo. Our results unravel a new mechanism for H2O2-dependent modulation of cell adhesion properties and identify RPSA as the H2O2 sensor in this process. This work indicates that high levels of RPSA expression might confer a selective advantage to tumor cells in an oxidative environment.

The extracellular matrix modulates H2O2 degradation and redox signaling in endothelial cells.

The molecular processes that are crucial for cell function, such as proliferation, migration and survival, are regulated by hydrogen peroxide (H2O2). Although environmental cues, such as growth factors, regulate redox signaling, it was still unknown whether the ECM, a component of the cell microenvironment, had a function in this process. Here, we showed that the extracellular matrix (ECM) differently regulated H2O2 consumption by endothelial cells and that this effect was not general for all types of cells. The analysis of biophysical properties of the endothelial cell membrane suggested that this modification in H2O2 consumption rates was not due to altered membrane permeability. Instead, we found that the ECM regulated GPx activity, a known H2O2 scavenger. Finally, we showed that the extent of PTEN oxidation was dependent on the ECM, indicating that the ECM was able to modulate H2O2-dependent protein oxidation. Thus, our results unraveled a new mechanism by which the ECM regulates endothelial cell function by altering redox balance. These results pinpoint the ECM as an important component of redox-signaling.