Phenotype characteristic of colonic intraepithelial lymphocytes in patients with Crohn's disease

Intraepithelial lymphocytes (IEL) play a critical role in maintaining the immune balance of the gut and provide the first line of mucosal defense against luminal antigens as well as rapidly respond to epithelial injury. Recently, IEL have received a lot of attention as key mediators of aberrant immune response resulted in persistent immune activation, inflammation and altered intestinal barrier function, seen in Crohn's disease (CD). This study describes for the first time subsets of colonic IEL in CD patients as compared to healthy controls aimed at characterization of altered IEL contribution to the pathogenesis of Crohn's disease.The peripheral venous blood and colon tissues were obtained from 10 CD patients and 6 donors. IEL were isolated from the mucosa by incubation the tissue in a predigesting solution. Lymphoid cells phenotype was investigated using monoclonal antibodies and flow cytometry.The majority of colonic IEL was identified as СD3+T lymphocytes and no significant differences were found in their numbers in investigated groups. However, changes in T cell subsets composition have been shown: the ratio of СD3+СD4+IEL and СD3+СD8+IEL was 1:1 in colon of CD patients and correlated with T cells in peripheral blood (R = 0.7; p < 0.05) while donor tissues were characterized by expected СD3+СD8+T killers prevalence and the ratio reached 1:2 (p < 0.05). The increase of unconventional γδIEL (mainly due to V81+T cells) and СD161+T cells in association with TNK cells decrease were revealed in colon (p < 0.01) as well as in peripheral blood (p < 0.05) of CD patients as compared to donors. Moreover, the number of colonic γδIEL was correlated with disease location (R = -0.6; p < 0.05), and disease behavior (R = 0.7; p < 0.01) according to Montreal classification.The observed data indicates changes in colonic IEL composition in CD patients that may provide valuable insight into the contribution of T helpers, γδT cells and mucosa-associated СD161+T cells in autoimmune intestinal inflammation but need further possible mechanisms discussion

Effects of ketogenic diet and ketone bodies on the cardiovascular system: Concentration matters

International audienceKetone bodies have emerged as central mediators of metabolic health, and multiple beneficial effects of a ketogenic diet, impacting metabolism, neuronal pathologies and, to a certain extent, tumorigenesis, have been reported both in animal models and clinical research. Ketone bodies, endogenously produced by the liver, act pleiotropically as metabolic intermediates, signaling molecules, and epigenetic modifiers. The endothelium and the vascular system are central regulators of the organism's metabolic state and become dysfunctional in cardiovascular disease, atherosclerosis, and diabetic micro- and macrovascular complications. As physiological circulating ketone bodies can attain millimolar concentrations, the endothelium is the first-line cell lineage exposed to them. While in diabetic ketoacidosis high ketone body concentrations are detrimental to the vasculature, recent research revealed that ketone bodies in the low millimolar range may exert beneficial effects on endothelial cell (EC) functioning by modulating the EC inflammatory status, senescence, and metabolism. Here, we review the long-held evidence of detrimental cardiovascular effects of ketoacidosis as well as the more recent evidence for a positive impact of ketone bodies-at lower concentrations-on the ECs metabolism and vascular physiology and the subjacent cellular and molecular mechanisms. We also explore arising controversies in the field and discuss the importance of ketone body concentrations in relation to their effects. At low concentration, endogenously produced ketone bodies upon uptake of a ketogenic diet or supplemented ketone bodies (or their precursors) may prove beneficial to ameliorate endothelial function and, consequently, pathologies in which endothelial damage occurs

The Epigenetic Profile of Tumor Endothelial Cells. Effects of Combined Therapy with Antiangiogenic and Epigenetic Drugs on Cancer Progression

Tumors require a constant supply of nutrients to grow which are provided through tumor blood vessels. To metastasize, tumors need a route to enter circulation, that route is also provided by tumor blood vessels. Thus, angiogenesis is necessary for both tumor progression and metastasis. Angiogenesis is tightly regulated by a balance of angiogenic and antiangiogenic factors. Angiogenic factors of the vascular endothelial growth factor (VEGF) family lead to the activation of endothelial cells, proliferation, and neovascularization. Significant VEGF-A upregulation is commonly observed in cancer cells, also due to hypoxic conditions, and activates endothelial cells (ECs) by paracrine signaling stimulating cell migration and proliferation, resulting in tumor-dependent angiogenesis. Conversely, antiangiogenic factors inhibit angiogenesis by suppressing ECs activation. One of the best-known anti-angiogenic factors is thrombospondin-1 (TSP-1). In pathological angiogenesis, the balance shifts towards the proangiogenic factors and an angiogenic switch that promotes tumor angiogenesis. Here, we review the current literature supporting the notion of the existence of two different endothelial lineages: normal endothelial cells (NECs), representing the physiological form of vascular endothelium, and tumor endothelial cells (TECs), which are strongly promoted by the tumor microenvironment and are biologically different from NECs. The angiogenic switch would be also important for the explanation of the differences between NECs and TECs, as angiogenic factors, cytokines and growth factors secreted into the tumor microenvironment may cause genetic instability. In this review, we focus on the epigenetic differences between the two endothelial lineages, which provide a possible window for pharmacological targeting of TECs