Effects of Acute and Chronic Cadmium Administration on the Vascular Reactivity of Rat Aorta

The effect of acute and chronic cadmium (Cd) administration on the vascular function of the rat aorta was studied. The rats were randomly divided into four main groups (A: saline controls under chronic administration, B: Cd-treated rats under chronic administration, C: saline controls under acute administration, D: Cd-treated rats under acute administration). After their sacrifice, the aortic rings were divided into rings with endothelium (E+) and without (E−), and suspended in an isolated organ bath with Krebs–Henseleit buffer. Maximal tension (T _max, in g) was measured in response to potassium chloride (KCl) and phenylephrine (PE) in all aortic rings. Relaxation response to acetylcholine (ACh) administration was expressed as percent of maximal tension induced by PE. Chronic administration: A statistically significant increase of the contraction was observed between groups B (i.m. Cd 0.5 mg/kg for 120 days) and A (i.m. 0.9% NaCl for 120 days) in response to KCl (20–60 mM) and the T _max as well (in both the E+ and the E− subgroups). No statistically significant difference was observed in response to PE and ACh exposure. Acute administration: A statistically significant increase was observed between group D(E+) (i.m. Cd 2 mg/kg, 8 h before sacrifice) and group C(E+) (i.m. 0.9% NaCl, 8 h before sacrifice) in response to 10–30 mM of KCl, and a significant decrease between D(E−) and C(E−) in response to 10⁻⁷–10⁻⁶ M of PE, though T _max was increased between D(E−) and C(E−) with PE exposure. The contractile response levels of the E+ aortic rings to PE and ACh showed no statistically significant difference.     

A novel functional translocator protein ligand for cancer imaging

The translocator protein (TSPO) is an attractive target for tumor imaging due to its up-regulation in numerous cancer cell types. Here, we report a series of functional TSPO ligands, n-TSPOmbb732, which can be conjugated to a variety of signaling moieties and are widely applicable in TSPO-targeted molecular imaging. Two fluorescent dye-labeled 6-TSPOmbb732 displayed nanomolar binding affinities to TSPO and were successfully imaged in vitro.     

Multicenter Epidemiological Study to Assess the Population of CKD Patients in Greece: Results from the PRESTAR Study

Background

Chronic Kidney Disease (CKD) is a relatively common condition not only associated with increased morbidity and mortality but also fuelling End Stage Renal Disease (ESRD). Among developed nations, Greece has one of the highest ESRD incidence rates, yet there is limited understanding of the epidemiology of earlier stages of CKD.

Methods

Cross-sectional survey of pre-dialysis CKD outpatients in nephrology clinics in the National Health Care system between October 2009 and October 2010. Demographics, cause of CKD, blood pressure, level of renal function, duration of CKD and nephrology care, and specialty of referral physician were collected and analyzed. Different methods for estimating renal function (Cockroft-Gault [CG], CKD-Epi and MDRD) and staging CKD were assessed for agreement.

Results

A total of 1,501 patients in 9 centers were enrolled. Diabetic nephropathy was the most common nephrologist assigned cause of CKD (29.7%). In total, 36.5% of patients had self-referred to the nephrologist; patients with diabetes or serum creatinine above 220 µmol/l (eGFR<40 ml/min/1.73 m²) were more likely to have been referred by a physician. Agreement between MDRD and CKD-Epi, but not between CG, the other estimating equations, was excellent. There was substantial heterogeneity with respect to renal diagnoses, referral patterns and blood pressure among participating centers.

Conclusions

In this first epidemiologic assessment of CKD in Greece, we documented delayed referral and high rates of self-referral among patients with CKD. eGFR reporting, currently offered by a limited number of laboratories, may facilitate detection of CKD at an earlier, more treatable stage.     

Identification of the Substrate Recognition and Transport Pathway in a Eukaryotic Member of the Nucleobase-Ascorbate Transporter (NAT) Family

Using the crystal structure of the uracil transporter UraA of Escherichia coli, we constructed a 3D model of the Aspergillus nidulans uric acid-xanthine/H(+) symporter UapA, which is a prototype member of the Nucleobase-Ascorbate Transporter (NAT) family. The model consists of 14 transmembrane segments (TMSs) divided into a core and a gate domain, the later being distinctly different from that of UraA. By implementing Molecular Mechanics (MM) simulations and quantitative structure-activity relationship (SAR) approaches, we propose a model for the xanthine-UapA complex where the substrate binding site is formed by the polar side chains of residues E356 (TMS8) and Q408 (TMS10) and the backbones of A407 (TMS10) and F155 (TMS3). In addition, our model shows several polar interactions between TMS1-TMS10, TMS1-TMS3, TMS8-TMS10, which seem critical for UapA transport activity. Using extensive docking calculations we identify a cytoplasm-facing substrate trajectory (D360, A363, G411, T416, R417, V463 and A469) connecting the proposed substrate binding site with the cytoplasm, as well as, a possible outward-facing gate leading towards the substrate major binding site. Most importantly, re-evaluation of the plethora of available and analysis of a number of herein constructed UapA mutations strongly supports the UapA structural model. Furthermore, modeling and docking approaches with mammalian NAT homologues provided a molecular rationale on how specificity in this family of carriers might be determined, and further support the importance of selectivity gates acting independently from the major central substrate binding site.