Transcriptional regulation of endothelin-1 expression by advanced glycation end-products in human aortic endothelium is mediated via NF-kappaΒ and AP-1

Advanced Glycation End-products (AGEs) are produced by the non-enzymatic glycation of proteins, lipids and nucleic acids, resulting in an overload of highly reactive molecules of endogenous or exogenous (dietary) origin. Increased AGE levels in circulation and concomitant elevated tissue deposition have been associated with diabetic complications, atheromatosis, ageing and more recently with polycystic ovary syndrome pathogenesis. Interaction of AGEs with their receptor RAGE (Receptor for AGEs) activates intracellular signaling pathways which induce targeted gene expression in endothelium including upregulation of cell adhesion molecules and endothelin-1 (ET-1), implicated in vascular injury and endothelial dysfunction. The purpose of this study is to explore the molecular mechanism of AGE-induced regulation of ET-1 gene/protein expression in human endothelial cells and investigate its functional relevance in normal rat vascular endothelium

The role of CXC-chemokine receptor CXCR2 and suppressor of cytokine signaling-3 (SOCS-3) in renal cell carcinoma

BACKGROUND: Chemokine receptor signaling pathways are implicated in the pathobiology of renal cell carcinoma (RCC). However, the clinical relevance of CXCR2 receptor, mediating the effects of all angiogenic chemokines, remains unclear. SOCS (suppressor of cytokine signaling)-3 is a negative regulator of cytokine-driven responses, contributing to interferon-α resistance commonly used to treat advanced RCC with limited information regarding its expression in RCC. METHODS: In this study, CXCR2 and SOCS-3 were immunohistochemically investigated in 118 RCC cases in relation to interleukin (IL)-6 and (IL)-8, their downstream transducer phosphorylated (p-)STAT-3, and VEGF expression, being further correlated with microvascular characteristics, clinicopathological features and survival. In 30 cases relationships with hypoxia-inducible factors, i.e. HIF-1a, p53 and NF-κΒ (p65/RelA) were also examined. Validation of immunohistochemistry and further investigation of downstream transducers, p-JAK2 and p-c-Jun were evaluated by Western immunoblotting in 5 cases. RESULTS: Both CXCR2 and IL-8 were expressed by the neoplastic cells their levels being interrelated. CXCR2 strongly correlated with the levels of HIF-1a, p53 and p65/RelA in the neoplastic cells. Although SOCS-3 was simultaneously expressed with p-STAT-3, its levels tended to show an inverse relationship with p-JAK-2 and p-c-Jun in Western blots and were positively correlated with HIF-1a, p53 and p65/p65/RelA expression. Neither CXCR2 nor SOCS-3 correlated with the extent of microvascular network. IL-8 and CXCR2 expression was associated with high grade, advanced stage and the presence/number of metastases but only CXCR2 adversely affected survival in univariate analysis. Elevated SOCS-3 expression was associated with progression, the presence/number of metastasis and shortened survival in both univariate and multivariate analysis. CONCLUSIONS: Our findings implicate SOCS-3 overexpression in RCC metastasis and biologic aggressiveness advocating its therapeutic targeting. IL-8/CXCR2 signaling also contributes to the metastatic phenotype of RCC cells but appears of lesser prognostic utility. Both CXCR2 and SOCS-3 appear to be related to transcription factors induced under hypoxia

Acetyl Cholinesterase Inhibitors and Cell-Derived Peripheral Inflammatory Cytokines in Early Stages of Alzheimer's Disease

Clinical and preclinical studies firmly support the involvement of the inflammation in the pathogenesis of Alzheimer's disease (AD). Despite acetylcholinesterase inhibitors (AChEI) being widely used in AD patients, there is no conclusive evidence about their impact on the inflammatory response.Funding was received from a program co-financed by the European Social Fund and the Greek State (GSRT LS5-3808)info:eu-repo/semantics/publishedVersio

Functional analysis of the core/core+1 coding region of the hepatitis C virus genome

[…] Στη παρούσα μελέτη αναπτύξαμε μια ανοσοενζυμική μέθοδο “home made ELISA” για να ανιχνεύσουμε αντισώματα έναντι της core+1 πρωτεΐνης σε διαφορετικές ομάδες ασθενών. Βασικός στόχος αυτής της μελέτης είναι η εύρεση πιθανών διαφορών στα ποσοστά θετικότητας μεταξύ ορών ασθενών με HCV και ηπατοκυτταρικό καρκίνο και ορών ασθενών με άλλα στάδια HCV λοίμωξης. Επίσης προσπαθήσαμε να κατασκευάσουμε σταθερά ελεγχόμενες κυτταρικές σειρές που θα μας επιτρέψουν να ερευνήσουμε τη βιολογική σημασία της core/core+1 πρωτεΐνης σε ένα in vitro σύστημα. Τρίτον, χρησιμοποιήσαμε μια κυτταρική σειρά από αθανατοποιημένα ανθρώπινα ηπατικά αστεροειδή κύτταρα (hepatic stellate cells) για την διερεύνηση της πιθανής επιρροής της πρωτεΐνης core/core+1 στην διαδικασία διαφοροποίησης και δημιουργίας ίνωσης αυτών των ηπατικών κυττάρων. Τέλος, ερευνήσαμε την επίδρασης της πρωτεΐνης core/core+1 στην ρύθμιση του υποκινητή του γονιδίου της ANGPTL-3 (Angiopoietin Like 3) που παράγει μια πρωτεΐνη η έκφραση της οποίας περιορίζεται κυρίως στο ήπαρ και μπορεί να παίζει ρόλο στην εξέλιξη της μόλυνσης του ιού της ηπατίτιδας C και στην δημιουργία ηπατοκυτταρικού καρκίνου

Polycystin-1: Function as a mechanosensor

Polycystin-1 (PC1), encoded by the Pkd1 gene, is a large transmembrane protein whose mutation is involved in autosomal dominant polycystic kidney disease. When expressed, PC1 activates a G-protein signaling pathway that subsequently modulates Ca2+. channels. PC1 is highly expressed in developing tissue and via its C-terminus tail forms a complex with polycystin-2; this complex, found to be located at the primary cilia, seems to act as a mechanosensor that could affect proliferation, differentiation and apoptosis of cells. Also, loss of polycystins correlates with disruption of flow-dependent and steady-state intracellular Ca2+. signaling. Despite the lack of clarity on the role of the polycystins as mechanosensor molecules, a new interest in this PCs/primary cilium complex is providing continuously new insights. In this review, some of the known features of PC1 such as structure, function, signaling pathways involved and its role as a possible therapeutic target are being discussed. (c) 2010 Elsevier Ltd. All rights reserved

Is androgen receptor targeting an emerging treatment strategy for triple negative breast cancer?

Triple negative breast cancer (TNBC) is an aggressive breast cancer subtype. The absence of expression and/or amplification of estrogen and progesterone receptor as well as ERBB-2 prevent the use of currently available endocrine options and/or ERBB-2-directed drugs and indicates chemotherapy as the main current therapy. TNBC represents approximately 15% of breast cancer cases with high index of heterogeneity. Here, we review the role of androgen receptor in breast carcinogenesis and its association with alterations in the expression pattern and functional roles of regulatory molecules and signal transduction pathways in TNBC. Additionally, based on the so far preclinical and clinical published data, we evaluate the perspectives for using and/or developing androgen receptor targeting strategies for specific TNBC subtypes. (C) 2015 Elsevier Ltd. All rights reserved

ER targeting and retention of the HCV NS4B protein relies on the concerted action of multiple structural features including its transmembrane domains.

International audienceThe Hepatitis C virus (HCV) NS4B protein, a multispanning endoplasmic reticulum (ER) membrane protein, generates intracellular rearrangements of ER-derived membranes, essential for HCV replication. In this study, we characterized NS4B elements involved in the process of targeting, association and retention in the ER membrane. We investigated the localization and membrane association of a number of C- or N-terminal NS4B deletions expressed as GFP chimeras by biochemical and fluorescence microscopy techniques. A second set of GFP-NS4B chimeras containing the plasma membrane ecto-ATPase CD39 at the C-terminus of each NS4B deletion mutant was used to further examine the role of N-terminal NS4B sequences in ER retention. Several structural elements, besides the first two transmembrane domains (TMs), within the NS4B N-terminal half (residues 1-130) were found to mediate association of the NS4B-GFP chimeras with ER membranes. Both TM1 and TM2 are required for ER anchoring and retention but are not sufficient for ER retention. Sequences upstream of TM1 are also required. These include two putative amphipathic alpha-helices and a Leucine Rich Repeat-like motif, a sequence highly conserved in all HCV genotypes. The N-terminal 55peptidic sequence, containing the 1st amphipathic helix, mediates association of the 55N-GFP chimera with cellular membranes including the ER, but is dispensable for ER targeting of the entire NS4B molecule. Importantly, the C-terminal 70peptidic sequence can associate with membranes positive for ER markers in the absence of any predicted TMs. In conclusion, HCV NS4B targeting and retention in the ER results from the concerted action of several NS4B structural elements