Antonios Chatzigeorgiou

CD40/CD40L signaling and its implication in health and disease.

CD40, a transmembrane receptor of the tumor necrosis factor gene superfamily is expressed on a variety of cells, such as monocytes, B‐cells, antigen presenting cells, endothelial, smooth muscle cells, and fibroblasts. The interaction between CD40 and CD40 ligand (CD40L) enhances the expression of cytokines, chemokines, matrix metalloproteinases, growth factors, and adhesion molecules, mainly through the stimulation of nuclear factor kappa B. The aim of this review is to summarize the molecular and cellular characteristics of CD40 and CD40L, the mechanisms that regulate their expression, the cellular responses they stimulate and finally their implication in the pathophysiology of inflammatory and autoimmune diseases.

The pattern of inflammatory/anti-inflammatory cytokines and chemokines in type 1 diabetic patients over time

Abstract Aims. To evaluate the profile of pro- and anti-inflammatory cytokines in type 1 diabetes mellitus (T1DM) and the way they are connected in co-regulated networks and determine whether disease duration influences their pattern. Methods. Plasma levels of 20 cytokines and soluble CD40 (sCD40) from 44 uncomplicated patients and 22 healthy controls (HCs) were measured using enzyme-linked immunosorbent assay (ELISA) and protein array technology. Results. Patients showed significantly higher levels of sCD40, IL-1a, IL-2, IL-4, IL-5, IL-10, granulocyte-macrophage colony-stimulating factor (GM-CSF), macrophage inflammatory protein (MIP)-1a, MIP-1b, regulated on activation normal T cell expressed and secreted (RANTES), matrix metalloproteinase (MMP)-9, and a trend to higher IL-6 than did HCs. RANTES and sCD40 discriminated significantly between diabetics and HCs. In patients with disease duration >6 months, cytokines were organized in two clusters mainly regulated by Th17 and Th1/Th2 cells respectively, while in those with disease duration ≤6 months a set of Th1-cytokines was separated apart from the second cluster. Monocyte chemotactic protein (MCP)-1 was revealed as the most discriminant factor between patients with disease duration of more than and less than 6 months. Conclusions. A parallel elevation of both inflammatory and anti-inflammatory cytokines was observed in patients compared with HCs. In T1DM patients with disease duration ≤6 months, Th1-cytokines were organized on a separate cluster, suggesting a possible role of Th1 cells in the progress of beta-cell destruction during the first period of the disease.

Sex differences in oxidant/antioxidant balance under a chronic mild stress regime.

The deterioration of homeostasis between oxidant/antioxidant species may represent an important mechanism linking psychological stress to cardiovascular risk despite the many sex differences in stress responsiveness. The goal of the present study was to investigate the influence of chronic mild stress (CMS), a widely accepted animal model of depression, on oxidative homeostasis-allostasis markers and sICAM-1, a marker of endothelial injury, in the serum of Wistar rats, by taking into account the effect of sex. After six weeks of exposure to mild unpredictable environmental stressors, both male and female rat groups displayed typical changes in hedonic status (anhedonia), which is a core symptom of human depression. Control female rats had higher (nitrite and nitrate) NOx, lower malondealdehyde (MDA) levels with lower activity of antioxidant enzymes and sICAM-1 levels than did control males. CMS induced oxidant/antioxidant responses in both sexes. Females tended to increase their nitric oxide (NO) levels further, while MDA levels did not reach those of males, thus retaining significantly higher NO bioavailability than in males. Concerning the antioxidant enzymes, CMS-females exhibited significantly higher glutathione peroxidase (GPx) activity and lower glutathione reductase (GR) and superoxide dismutase (SOD) activity compared to CMS-males. The CMS response in females was accompanied by lower sICAM-1 levels than in males, suggesting lower endothelial injury. In conclusion, the results of the present study showed that CMS induces different oxidative stress and compensatory responses in both sexes probably due to differences in the mechanisms regulating oxidant/antioxidant pathways.

Dietary glycotoxins affect scavenger receptor expression and the hormonal profile of female rats

The levels of advanced glycation end products (AGEs) are increased under conditions of impaired glucose metabolism and/or oxidative stress, promoting insulin resistance and other endocrine abnormalities. AGEs play a major role in the pathogenesis of several diseases such as diabetes, atherosclerosis, polycystic ovary syndrome and Alzheimers disease, contributing to progressive ageing. Receptor-based clearance of AGEs by the receptor for AGE (RAGE) and/or the macrophage scavenger receptor A (SR-A) is considered as a main factor for the regulation of the concentration of AGEs under these conditions. This study aimed to investigate the expression of RAGE (AGER) and SR-A (MSR1) under high/low-dietary AGE conditions in vivo and their potential contribution to the metabolic and sex hormonal profile of female rats. Female Wistar rats were fed a low-AGE or high-AGE diet for 3 months. Serum samples were collected at baseline and at the completion of the 3-month period for the measurements of metabolic and hormonal parameters. Peripheral blood mononuclear cells (PBMCs) were isolated for the determination of the expression of RAGE and SR-A. The high-AGE diet-fed rats exhibited increased glucose, insulin and testosterone levels as well as decreased oestradiol and progesterone levels compared with the low-AGE diet-fed ones, thus indicating a metabolic and hormonal dysregulation attributed to high-AGE dietary exposure. The expression of RAGE was significantly down-regulated in the PBMCs of the high-AGE diet-fed rats (P=0.041), and it was correlated negatively with insulin and testosterone levels and positively with progesterone levels. The expression of SR-A was also decreased in the high-AGE diet-fed rats to marginal significance. Decreased monocytic expression of scavenger receptors such as RAGE and SR-A may result in a higher deposition of AGEs in peripheral endocrine tissues, thus promoting endocrine-related abnormalities and diseases.

Alterations in biomarkers of endothelial function following on-pump coronary artery revascularization.

Background: Cardiopulmonary bypass (CPB) has been associated with activation and injury of endothelial cells, probably responsible for the systemic inflammatory response syndrome (SIRS) taking place in these patients. Methods: We measured plasma concentrations of soluble P‐selectin (sP‐s), E‐selectin (sE‐s), tetranectin (TN), vonWillebrand factor (vWF) levels, and angiotensin‐converting enzyme (ACE) activity in 31 adult patients undergoing elective coronary artery bypass grafting, just before and up to three days after surgery, and in 25 healthy volunteers. Results: Patients showed higher plasma sP‐s and sE‐s and ACE concentrations, just before surgery, but significantly lower TN levels, compared with controls. During the first three postoperative days (PD), the concentration of each of the molecules followed a different and independent pattern, although in the third PD, the levels of sP‐s, sE‐s and ACE were higher and those of vWF and TN lower, compared with the preoperative ones. However, patients had higher sP‐s (P=0.06), sE‐s (P=0.07), and vWF (P=0.005), but lower TN concentrations (P=0.02) on the third PD compared with controls. Conclusions: CPB is characterised by pronounced changes in plasma sP‐s, sE‐s, TN, vWF levels, and ACE activity, which are associated with significant alteration in the intra‐ and early postoperative endothelial function observed in open heart surgery. J. Clin. Lab. Anal. 24:389–398, 2010.

Extracellular matrix-associated (GAGs, CTGF), angiogenic (VEGF) and inflammatory factors (MCP-1, CD40, IFN-γ) in type 1 diabetes mellitus nephropathy.

Abstract Background: The aim of the present study was to evaluate the role of extracellular matrix-associated glycosaminoglycans (GAGs), connective tissue growth factor (CTGF), angiogenic vascular endothelial growth factor (VEGF) and inflammatory factors (MCP-1, CD40, IFN-γ) in the development of diabetic nephropathy in type 1 diabetes (T1DM). Methods: Plasma and urine samples from 30 T1DM patients and 20 healthy controls were used to measure the levels of CTGF, VEGF, MCP-1, CD40 and IFN-γ by ELISA. Plasma and urine GAGs were measured using a spectrophotometric method. Results: Plasma levels of GAGs, CD40 and MCP-1 and urine levels of GAGs and CTGF were significantly elevated in normoalbuminuric T1DM patients. A tendency to higher plasma VEGF levels was found in patients compared to controls. The urine/plasma GAGs ratio of T1DM patients was almost similar to that of healthy subjects (HS), whereas the urine/plasma CTGF ratio was about three times greater in diabetic patients compared to HS. Conclusions: Conclusively, increased GAGs and CTGF excretion are evident in T1DM normoalbuminuric juveniles, possibly reflecting early renal injury signs, before the initiation of albuminuria.