Health-promoting properties of food bioactives: the case study of quercetin. Preliminary results.

The results here described are part of a wider experimental plan aimed at studying the fate of quercetin contained in model systems simulating apple or its derivatives during the gastrointestinal process. To this purpose, the effect of in-vitro digestion on quercetin antioxidant activity was assessed. Quercetin’s effect on the inhibition of intestinal α-glucosidase in a colorectal adenocarcinoma cell line Caco-2 was also investigate

Food and food bioactive fighting chronic inflammation

The aim of this project is to evaluate the influence of bioactive compounds contained in raw and processed plant-based foods, and their industrial processing by-products on the immune landscape and homeostasis of the gut affected by chronic inflammation

The second AT-hook of the architectural transcription factor HMGA2 is determinant for nuclear localization and function

High Mobility Group A (HMGA) is a family of architectural nuclear factors which play an important role in neoplastic transformation. HMGA proteins are multifunctional factors that associate both with DNA and nuclear proteins that have been involved in several nuclear processes including transcription. HMGA localization is exclusively nuclear but, to date, the mechanism of nuclear import for these proteins remains unknown. Here, we report the identification and characterization of a nuclear localization signal (NLS) for HMGA2, a member of the HMGA family. The NLS overlaps with the second of the three AT-hooks, the DNA-binding domains characteristic for this group of proteins. The functionality of this NLS was demonstrated by its ability to target a heterologous β-galactosidase/green fluorescent protein fusion protein to the nucleus. Mutations to alanine of basic residues within the second AT-hook resulted in inhibition of HMGA2 nuclear localization and impairment of its function in activating the cyclin A promoter. In addition, HMGA2 was shown to directly interact with the nuclear import receptor importin-α2 via the second AT-hook. HMGA proteins are overexpressed and rearranged in a variety of tumors; our findings can thus help elucidating their role in neoplastic transformation

Mast Cell: An Emerging Partner in Immune Interaction

Mast cells (MCs) are currently recognized as effector cells in many settings of the immune response, including host defense, immune regulation, allergy, chronic inflammation, and autoimmune diseases. MC pleiotropic functions reflect their ability to secrete a wide spectrum of preformed or newly synthesized biologically active products with pro-inflammatory, anti-inflammatory and/or immunosuppressive properties, in response to multiple signals. Moreover, the modulation of MC effector phenotypes relies on the interaction of a wide variety of membrane molecules involved in cell–cell or cell-extracellular-matrix interaction. The delivery of co-stimulatory signals allows MC to specifically communicate with immune cells belonging to both innate and acquired immunity, as well as with non-immune tissue-specific cell types. This article reviews and discusses the evidence that MC membrane-expressed molecules play a central role in regulating MC priming and activation and in the modulation of innate and adaptive immune response not only against host injury, but also in peripheral tolerance and tumor-surveillance or -escape. The complex expression of MC surface molecules may be regarded as a measure of connectivity, with altered patterns of cell–cell interaction representing functionally distinct MC states. We will focalize our attention on roles and functions of recently discovered molecules involved in the cross-talk of MCs with other immune partners

Endonuclease and redox activities of human apurinic/apyrimidinic endonuclease 1 have distinctive and essential functions in IgA class switch recombination

The base excision repair (BER) pathway is an important DNA repair pathway and is essential for immune responses. In fact, it regulates both the antigen-stimulated somatic hypermutation (SHM) process and plays a central function in the process of class switch recombination (CSR). For both processes, a central role for apurinic/apyrimidinic endonuclease 1 (APE1) has been demonstrated. APE1 acts also as a master regulator of gene expression through its redox activity. APE1's redox activity stimulates the DNA-binding activity of several transcription factors, including NF-\u3baB and a few others involved in inflammation and in immune responses. Therefore, it is possible that APE1 has a role in regulating the CSR through its function as a redox coactivator. The present study was undertaken to address this question. Using the CSR-competent mouse B-cell line CH12F3 and a combination of specific inhibitors of APE1's redox (APX3330) and repair (compound 3) activities, APE1-deficient or -reconstituted cell lines expressing redox-deficient or endonuclease-deficient proteins, and APX3330-treated mice, we determined the contributions of both endonuclease and redox functions of APE1 in CSR. We found that APE1's endonuclease activity is essential for IgA-class switch recombination. We provide evidence that the redox function of APE1 appears to play a role in regulating CSR through the interleukin-6 signaling pathway and in proper IgA expression. Our results shed light on APE1's redox function in the control of cancer growth through modulation of the IgA CSR process

Inhibition of APE1-endonuclease activity affects cell metabolism in colon cancer cells via a p53-dependent pathway

The pathogenesis of colorectal cancer (CRC) involves different mechanisms, such as genomic and microsatellite instabilities. Recently, a contribution of the base excision repair (BER) pathway in CRC pathology has been emerged. In this context, the involvement of APE1 in the BER pathway and in the transcriptional regulation of genes implicated in tumor progression strongly correlates with chemoresistance in CRC and in more aggressive cancers. In addition, the APE1 interactome is emerging as an important player in tumor progression, as demonstrated by its interaction with Nucleophosmin (NPM1). For these reasons, APE1 is becoming a promising target in cancer therapy and a powerful prognostic and predictive factor in several cancer types. Thus, specific APE1 inhibitors have been developed targeting: i) the endonuclease activity; ii) the redox function and iii) the APE1-NPM1 interaction. Furthermore, mutated p53 is a common feature of advanced CRC. The relationship between APE1 inhibition and p53 is still completely unknown. Here, we demonstrated that the inhibition of the endonuclease activity of APE1 triggers p53-mediated effects on cell metabolism in HCT-116 colon cancer cell line. In particular, the inhibition of the endonuclease activity, but not of the redox function or of the interaction with NPM1, promotes p53 activation in parallel to sensitization of p53-expressing HCT-116 cell line to genotoxic treatment. Moreover, the endonuclease inhibitor affects mitochondrial activity in a p53-dependent manner. Finally, we demonstrated that 3D organoids derived from CRC patients are susceptible to APE1-endonuclease inhibition in a p53-status correlated manner, recapitulating data obtained with HCT-116 isogenic cell lines. These findings suggest the importance of further studies aimed at testing the possibility to target the endonuclease activity of APE1 in CRC

Relationship between cytokine release and stress hyperglycemia in patients hospitalized with COVID-19 infection

Introduction: Stress hyperglycemia is a frequent finding in patients with COVID-19 infection and could affect the outcome of disease. Cytokines released in response to infection could have adverse effects on insulin sensitivity and pancreatic beta-cell function. The aim of the study was to examine the relationships of stress hyperglycemia with cytokines and clinical outcomes in hospitalized patients with COVID-19. Methods: In a cross-sectional analysis of 150 patients hospitalized for COVID-19 infection who were included in the GIRA-COVID database, we identified patients with stress hyperglycemia by calculation of the Stress Hyperglycemia Ratio (SHR) and use of a cut-off of 1.14. Plasma levels of cytokines principally involved in COVID-19 infection-related cytokine storm were measured. Outcome variables were use of mechanical ventilation and death within 60 days from hospital admission. Results: Patients with SHR > 1.14 had significantly higher plasma insulin, HOMA-index, and levels of interleukin-10 (IL-10), interleukin-10/tumor necrosis factor-a ratio (IL-10/TNF-α), and CXC motif chemokine ligand 10 (CXCL10) than patients with SHR ≤ 1.14. IL-10, IL-10/TNF-α ratio, CXCL10, and IFN-γ were significantly and directly related with SHR in univariate analysis and multivariate logistic regression models showed that IL-10, IL-10/TNF-α ratio, and CXCL10 were independently associated with SHR>1.14. In a multivariate logistic model, stress hyperglycemia predicted use of mechanical ventilation (OR 2.453; CI 1.078–6.012) and death (OR 2.281; CI 1.049–7.369) independently of diabetes and other major confounders. Conclusions: In patients hospitalized for COVID-19 infection, stress hyperglycemia is associated with worse clinical outcomes and is independently related to levels of cytokines that might impair glucose homeostasis

Mast Cells Respond to Candida albicans Infections and Modulate Macrophages Phagocytosis of the Fungus

Mast cells (MCs) are long-lived immune cells widely distributed at mucosal surfaces and are among the first immune cell type that can get in contact with the external environment. This study aims to unravel the mechanisms of reciprocal influence between mucosal MCs and Candida albicans as commensal/opportunistic pathogen species in humans. Stimulation of bone marrow-derived mast cells (BMMCs) with live forms of C. albicans induced the release of TNF-α, IL-6, IL-13, and IL-4. Quite interestingly, BMMCs were able to engulf C. albicans hyphae, rearranging their α-tubulin cytoskeleton and accumulating LAMP1+ vesicles at the phagocytic synapse with the fungus. Candida-infected MCs increased macrophage crawling ability and promoted their chemotaxis against the infection. On the other side, resting MCs inhibited macrophage phagocytosis of C. albicans in a contact-dependent manner. Taken together, these results indicate that MCs play a key role in the maintenance of the equilibrium between the host and the commensal fungus C. albicans, limiting pathological fungal growth and modulating the response of resident macrophages during infections

IL-9 and Mast Cells Are Key Players of Candida albicans Commensalism and Pathogenesis in the Gut

Summary: Candida albicans is implicated in intestinal diseases. Identifying host signatures that discriminate between the pathogenic versus commensal nature of this human commensal is clinically relevant. In the present study, we identify IL-9 and mast cells (MCs) as key players of Candida commensalism and pathogenicity. By inducing TGF-β in stromal MCs, IL-9 pivotally contributes to mucosal immune tolerance via the indoleamine 2,3-dioxygenase enzyme. However, Candida-driven IL-9 and mucosal MCs also contribute to barrier function loss, dissemination, and inflammation in experimental leaky gut models and are upregulated in patients with celiac disease. Inflammatory dysbiosis occurs with IL-9 and MC deficiency, indicating that the activity of IL-9 and MCs may go beyond host immunity to include regulation of the microbiota. Thus, the output of the IL-9/MC axis is highly contextual during Candida colonization and reveals how host immunity and the microbiota finely tune Candida behavior in the gut. : Deciphering the mechanisms by which Candida albicans promotes either pathology or protective tolerance in the gut could be clinically relevant. Renga et al. show a key role for IL-9 and mast cells in promoting either inflammatory dysbiosis and pathology or tolerance in leaky gut models and human celiac disease. Keywords: IL-9, mast cells, Candida albicans, intestinal inflammation, IDO1, celiac diseas