Vitamine D et prévention du cancer colorectal associé à la colite ulcéreuse : modèles murins

Les patients atteints de maladies inflammatoires de l'intestin (MII) ont un risque accru de développer un cancer colorectal dû aux lésions épithéliales secondaires à l’inflammation chronique. La vitamine D (vD) régule NOD2, gène impliqué dans la réponse inflammatoire et dans la susceptibilité aux MII, et induit son expression dans les monocytes et dans l’épithélium intestinal. Dans ce projet, nous avons d’abord induit le cancer colorectal associé à la colite ulcéreuse (CAC) en administrant un traitement combiné d’azoxyméthane (AOM) et de dextran de sulfate de sodium (DSS) aux souris C57BL/6J. Par la suite, nous avons étudié l'effet d’une carence en vD3 sur le développement du CAC et évalué la capacité préventive d’une supplémentation en vD3 sur la tumorigenèse, et vérifié si cet effet est médié par NOD2, en utilisant les souris Nod2-/-. Les C57BL/6J et les Nod2-/-, ayant reçu une diète déficiente en vD3, étaient moins résistantes au CAC par rapport aux souris supplémentées. Le pourcentage de perte de poids, l’indice d’activation de la maladie (DAI), le taux de mortalité et le poids relatif du côlon (mg/cm) chez les souris déficientes en vD3 étaient plus élevés en comparaison avec celles supplémentées en vD3. Une augmentation du score d'inflammation et de la multiplicité tumorale corrélait avec une expression accentuée de l’Il6 dans les colonocytes des souris déficientes en vD3. La vD3 régulait l’expression génétique de Cyp24, Vdr et de gènes pro-inflammatoires chez les C57BL/6, comme chez les Nod2-/-. En conclusion, la supplémentation en vD3 peut prévenir le développement du CAC indépendamment de NOD2.Patients with inflammatory bowel disease (IBD) have an increased risk of developing colorectal cancer due to continuing epithelial cell injury from the chronic inflammatory process. Vitamin D (vD) regulates NOD2, a gene involved in the inflammatory response and in IBD susceptibility, and induces its expression in monocytes and intestinal epithelial cells. In this project, we first established an azoxymethane (AOM)/dextran sodium sulfate (DSS) murine model of colitis-associated colorectal cancer (CAC) using C57Bl/6J. We then investigated the effect of vD3 deficiency on CAC development, and evaluated the ability of vD3 supplementation to prevent tumorigenesis. Lastly, we assessed whether the preventive benefits of vD3 on colon carcinogenesis are mediated via NOD2 using Nod2 knockout mice (Nod2-/-). vD3 deficient C57Bl/6J and Nod2-/- mice displayed increased severity of AOM/DSS-induced CAC compared to mice given vD3 supplemented diets. In vD3 deficient mice, body weight loss, Disease Activity Index (DAI), mortality rate and the colon weight/length ratio were higher compared to vD3-supplemented mice. An increased inflammation score was observed in the mucosa of vD3 deficient mice along with augmentation in the expression level of IL-6. Higher tumour multiplicity was also observed in vD3 deficient groups compared to vD3-supplemented groups. In both C57Bl/6J and Nod2-/- mice, vD3 regulated Cyp24, Vdr and pro-inflammatory genes. In conclusion, vD3 supplementation can prevent CAC independently of NOD2

The Role of Transporters in the Pharmacokinetics of Orally Administered Drugs

Drug transporters are recognized as key players in the processes of drug absorption, distribution, metabolism, and elimination. The localization of uptake and efflux transporters in organs responsible for drug biotransformation and excretion gives transporter proteins a unique gatekeeper function in controlling drug access to metabolizing enzymes and excretory pathways. This review seeks to discuss the influence intestinal and hepatic drug transporters have on pharmacokinetic parameters, including bioavailability, exposure, clearance, volume of distribution, and half-life, for orally dosed drugs. This review also describes in detail the Biopharmaceutics Drug Disposition Classification System (BDDCS) and explains how many of the effects drug transporters exert on oral drug pharmacokinetic parameters can be predicted by this classification scheme

Global histone modification fingerprinting in human cells using epigenetic reverse phase protein array

The balance between acetylation and deacetylation of histone proteins plays a critical role in the regulation of genomic functions. Aberrations in global levels of histone modifications are linked to carcinogenesis and are currently the focus of intense scrutiny and translational research investments to develop new therapies, which can modify complex disease pathophysiology through epigenetic control. However, despite significant progress in our understanding of the molecular mechanisms of epigenetic machinery in various genomic contexts and cell types, the links between epigenetic modifications and cellular phenotypes are far from being clear. For example, enzymes controlling histone modifications utilize key cellular metabolites associated with intra- and extracellular feedback loops, adding a further layer of complexity to this process. Meanwhile, it has become increasingly evident that new assay technologies which provide robust and precise measurement of global histone modifications are required, for at least two pressing reasons: firstly, many approved drugs are known to influence histone modifications and new cancer therapies are increasingly being developed towards targeting histone deacetylases (HDACs) and other epigenetic readers and writers. Therefore, robust assays for fingerprinting the global effects of such drugs on preclinical cell, organoid and in vivo models is required; and secondly, robust histone-fingerprinting assays applicable to patient samples may afford the development of next-generation diagnostic and prognostic tools. In our study, we have used a panel of monoclonal antibodies to determine the relative changes in the global abundance of post-translational modifications on histones purified from cancer cell lines treated with HDAC inhibitors using a novel technique, called epigenetic reverse phase protein array. We observed a robust increase in acetylation levels within 2–24 h after inhibition of HDACs in different cancer cell lines. Moreover, when these cells were treated with N-acetylated amino acids in addition to HDACs, we detected a further increase in histone acetylation, demonstrating that these molecules could be utilized as donors of the acetyl moiety for protein acetylation. Consequently, this study not only offers a novel assay for diagnostics and drug screening but also warrants further research of the novel class of inexpensive, non-toxic natural compounds that could potentiate the effects of HDAC inhibitors and is therefore of interest for cancer therapeutics