T cells and delayed graft function

Ischemia-reperfusion injury (IRI) in kidney transplantation is the major cause of delayed graft function (DGF), an event associated with an increased risk of acute rejection. The aim of this study was to evaluate T helper (Th) cell phenotype in renal transplants with DGF. T-bet (Th1), GATA-3 (Th2) and IL-17 (Th17) protein expression was investigated in pretransplant biopsies, DGF and acute tubular damage (ATD) caused by calcineurin-inhibitor toxicity. Intracytofluorimetric analysis of IFN-γ, IL-4 and IL-17 was performed to analyze Th1, Th2 and Th17 responses in peripheral blood mononuclear cells of recipients with early graft function (EGF) and DGF, before (T0) and 24 h after transplantation (T24). In pretransplant biopsies, T-bet(+) , GATA-3(+) and IL-17(+) cells were barely detectable. In DGF, T-bet(+) and IL-17(+) cells were significantly increased compared with pretransplant and ATD. More than 90% of T-bet(+) and less then 5% of IL-17(+) cells were CD4(+) . GATA-3(+) cells were increased to a lower extent. T-bet(+) /GATA-3(+) cell ratio was significantly higher in DGF. Peripheral CD4(+) IFN-γ/IL-4 ratio was significantly decreased in DGF, while CD4(+) /IL-17(+) cells did not differ between T0 and T24 in DGF. Our data suggest that DGF is characterized by a prevalent Th1 phenotype within the graft. This event might represent a link between DGF and acute rejection

CHF2819: pharmacological profile of a novel acetylcholinesterase inhibitor

CHF2819 is a novel orally active acetylcholinesterase inhibitor (AChEI) developed for the treatment of Alzheimer's disease (AD). CHF2819 is a selective inhibitor of AChE, it is 115 times more potent against this enzyme than against butyrylcholinesterase (BuChE). Moreover, CHF2819 is more selective for inhibition of central (brain) AChE than peripheral (heart) AChE. In vivo CHF2819, 0.5, 1.5, and 4.5 mg/kg p.o., significantly and in dose-dependent manner increased acetylcholine (ACh) levels in hippocampus of young adult rats. Moreover, aging animals, with lower basal ACh levels than young adult rats, also exhibit a marked increase in hippocampal levels of this neurotransmitter after administration of CHF2819. At 1.5 mg/kg p.o. CHF2819 attenuated scopolamine-induced amnesia in a passive avoidance task. Furthermore, it decreased dopamine (DA) levels and increased extracellular levels of 5-hydroxytryptamine (5-HT) in the hippocampus, without modifying norepinephrine (NE) levels. By oral administration to young adult rats CHF2819 did not affect extracellular hippocampal levels of glutamate (Glu), aspartate (Asp), gamma-aminobutyric acid (GABA), taurine (Tau), arginine (Arg) or citrulline (Cit). Functional observational battery (FOB) screening demonstrated that CHF2819 (1.5 and 4.5 mg/kg p.o.) does not affect activity, excitability, autonomic, neuromuscular, and sensorimotor domains, as well as physiological endpoints (body weight and temperature). CHF2819 induced, however, involuntary motor movements (ranging from mild tremors to myoclonic jerks) in a dose-dependent manner. The neurochemical and behavioral profiles of CHF2819 suggest that this orally active novel AChEI could be of clinical interest for the treatment of Alzheimer-type dementia associated with multiple neurotransmitter abnormalities in the brain. In particular, CHF2819 might be a useful therapeutic drug for AD patients with cognitive impairment accompanied by depression

Regulation of TGF-beta 1 expression by Androgen Deprivation Therapy of prostate cancer

In this paper we studied the in vivo neoadjuvant Androgen Deprivation Therapy (ADT) effect on the expression of TGF-beta 1 and its receptor T beta-RII. Mechanisms of androgen dependence are critical to understanding prostate cancer progression to androgen independence associated with disease mortality, and TGF-beta is thought to support prostatic apoptosis as its expression coincides with androgen ablation in benign and cancer tissues. Increase of both mRNA and protein level were shown for the first time only in the patients who underwent neoadjuvant ADT for 1-month. This transient increase of TGF-beta expression after androgen ablation suggested cooperation of the pathways in prostate regression. Since no alteration was observed in the gene transcriptional activity, the molecular mechanism of this cooperation, probably act at the post-transcriptional level. TGF-beta 1 and T beta-RII specific signals were co-localized within the neoplastic prostate epithelium. our results suggests that the androgens deprivation by means of ADT for 1-month, involves a shift of the TGF-beta 1 mechanism in prostate cancer, suggesting that the TGF-beta 1 promotes prostate epithelial cell proliferation and inhibits apoptosis in a autocrine way. (C) 2011 Elsevier Ireland Ltd. All rights reserved

BMP-2 induces a profibrotic phenotype in adult renal progenitor cells through Nox4 activation

Adult renal progenitor cells (ARPCs) isolated from human kidney may contribute to repair featuring acute kidney injury (AKI). Bone morphogenetic proteins (BMPs) regulate differentiation, modeling and regeneration processes in several tissues. Aim of the study was to evaluate the biological actions of BMP-2 in ARPCs in vitro and in vivo. BMP-2 was expressed in ARPCs of normal adult human kidney and it was up-regulated in vivo after delayed graft function (DGF) of renal transplant, condition of AKI. ARPCs expressed BMP-Receptors suggesting their potential responsiveness to BMP-2. Incubation of ARPCs with this growth factor enhanced ROS production, NADPH oxidase activity and Nox4 protein expression. In vivo, Nox4 was localized in BMP-2-expressing CD133+ cells at tubular level after DGF. BMP-2 incubation induced α-SMA, collagen-I and fibronectin protein expression in ARPCs. Moreover, α-SMA co-localized with CD133 in vivo after DGF. The oxidative stimulus (H(2)O(2)) induced α-SMA expression in ARPCs, while the anti-oxidant N-acetyl-cysteine inhibited BMP-2-induced α-SMA expression. Nox4 silencing abolished BMP-2-induced NADPH oxidase activation and myofibroblastic induction. We showed that: a) ARPCs express BMP-2; b) this expression is increased in a model of AKI; c) BMP-2 may induce the commitment of ARPCs towards a myofibroblastic phenotype in vitro and in vivo; d) this pro-fibrotic effect is mediated by Nox4 activation. Our findings suggest a novel mechanism linking AKI with progressive renal damage

The possible role of ChemR23/Chemerin axis in the recruitment of dendritic cells in lupus nephritis.

Dendritic cells (DCs) have a pivotal role in the autoimmune response of systemic lupus erythematosus. Plasmacytoid DCs infiltrate the kidney of patients with lupus nephritis, but factors regulating their recruitment to the kidney are unknown. Chemerin is the recently identified natural ligand of ChemR23, a receptor highly expressed by plasmacytoid DCs. We performed immunohistochemical and immunofluorescence analysis to study the ChemR23/Chemerin axis in renal biopsies from patients with lupus nephritis. We found ChemR23-positive DCs had infiltrated the kidney tubulointerstitium in patients with severe lupus nephritis. Chemerin association with tubular epithelial cells and renal lymphatic endothelial cells was found in patients with lupus nephritis but not in normal kidneys. Proximal tubular epithelial cells produced Chemerin in vitro, which was significantly down-modulated by added tumor necrosis factor (TNF)-α and interferon-γ as measured by quantitative PCR and enzyme-linked immunosorbent assay. Interestingly, TNF-α was capable of inducing a functionally active form of renal Chemerin, resulting in an efficient transendothelial migration of plasmacytoid DCs measured in transwell systems. Thus, the ChemR23/Chemerin axis may have a role in the recruitment of DCs within the kidney in patients affected by lupus nephritis.Journal ArticleResearch Support, Non-U.S. Gov'tSCOPUS: ar.jinfo:eu-repo/semantics/publishe