ABSTRACT
Inflammatory bowel diseases (IBDs) are chronic intestinal disorders often characterized by a dysregulation of T cells, specifically T helper (Th) 1, 17 and T regulatory (Treg) repertoire. Increasing evidence demonstrates that dietary polyphenols from Mangifera indica L. extract (MIE, commonly known as mango) mitigate intestinal inflammation and splenic Th17/Treg ratio. In this study, we aimed to dissect the immunomodulatory and anti-inflammatory properties of MIE using a reverse translational approach, by initially using blood from an adult IBD inception cohort and then investigating the mechanism of action in a preclinical model of T cell-driven colitis. Of clinical relevance, MIE modulates TNF-α and IL-17 levels in LPS spiked sera from IBD patients as an ex vivo model of intestinal barrier breakdown. Preclinically, therapeutic administration of MIE significantly reduced colitis severity, pathogenic T-cell intestinal infiltrate and intestinal pro-inflammatory mediators (IL-6, IL-17A, TNF-α, IL-2, IL-22). Moreover, MIE reversed colitis-induced gut permeability and restored tight junction functionality and intestinal metabolites. Mechanistic insights revealed MIE had direct effects on blood vascular endothelial cells, blocking TNF-α/IFN-γ-induced up-regulation of COX-2 and the DP2 receptors. Collectively, we demonstrate the therapeutic potential of MIE to reverse the immunological perturbance during the onset of colitis and dampen the systemic inflammatory response, paving the way for its clinical use as nutraceutical and/or functional food.
Subject(s)
Colitis , Inflammatory Bowel Diseases , Mangifera , Adult , Humans , Animals , Tumor Necrosis Factor-alpha/metabolism , Endothelial Cells/metabolism , Intestinal Mucosa , Disease Models, AnimalABSTRACT
Gadolinium-based contrast agents (GBCAs) are massively employed in radiology to increase the diagnostic power of MRI. However, investigations aiming at detecting possible metabolic perturbations or adverse health effects due to gadolinium deposition are still lacking. In this work, aqueous organs extract and plasma samples were analyzed by GC-MS and 1H-NMR, respectively, to investigate the effects of multiple administrations of one linear (Omniscan) and one macrocyclic (ProHance) GBCA, on the main metabolic pathways in healthy mice. Multivariate analysis revealed that plasma metabolome was not differently perturbed by the two GBCAs, while, the multiorgan analysis displayed a clear separation of the Omniscan-treated from the control and the ProHance-treated groups. Interestingly, the most affected organs were the brain, cerebellum and liver. Thus, this work paves the way to both the safest use of the commercially available GBCAs and the development of new GBCAs characterized by lower general toxicity.
Subject(s)
Gadolinium , Organometallic Compounds , Mice , Animals , Gadolinium/toxicity , Gadolinium/metabolism , Gadolinium DTPA/metabolism , Organometallic Compounds/toxicity , Contrast Media/toxicity , Contrast Media/metabolism , Brain/metabolism , Magnetic Resonance ImagingABSTRACT
INTRODUCTION: Guanine-rich DNA sequences can fold into four-stranded noncanonical secondary structures called G-quadruplexes (G4s) which are widely distributed in functional regions of the human genome, such as telomeres and gene promoter regions. Compelling evidence suggests their involvement in key genome functions such as gene expression and genome stability. Notably, the abundance of G4-forming sequences near transcription start sites suggests their potential involvement in regulating oncogenes. AREAS COVERED: This review provides an overview of current knowledge on G4s in human oncogene promoters. The most representative G4-binding ligands have also been documented. The objective of this work is to present a comprehensive overview of the most promising targets for the development of novel and highly specific anticancer drugs capable of selectively impacting the expression of individual or a limited number of genes. EXPERT OPINION: Modulation of G4 formation by specific ligands has been proposed as a powerful new tool to treat cancer through the control of oncogene expression. Actually, most of G4-binding small molecules seem to simultaneously target a range of gene promoter G4s, potentially influencing several critical driver genes in cancer, thus producing significant therapeutic benefits.