Oral treatment with a zinc complex of acetylsalicylic acid prevents diabetic cardiomyopathy in a rat model of type-2 diabetes: activation of the Akt pathway.

BACKGROUND: Type-2 diabetics have an increased risk of cardiomyopathy, and heart failure is a major cause of death among these patients. Growing evidence indicates that proinflammatory cytokines may induce the development of insulin resistance, and that anti-inflammatory medications may reverse this process. We investigated the effects of the oral administration of zinc and acetylsalicylic acid, in the form of bis(aspirinato)zinc(II)-complex Zn(ASA)2, on different aspects of cardiac damage in Zucker diabetic fatty (ZDF) rats, an experimental model of type-2 diabetic cardiomyopathy. METHODS: Nondiabetic control (ZL) and ZDF rats were treated orally with vehicle or Zn(ASA)2 for 24 days. At the age of 29-30 weeks, the electrical activities, left-ventricular functional parameters and left-ventricular wall thicknesses were assessed. Nitrotyrosine immunohistochemistry, TUNEL-assay, and hematoxylin-eosin staining were performed. The protein expression of the insulin-receptor and PI3K/AKT pathway were quantified by Western blot. RESULTS: Zn(ASA)2-treatment significantly decreased plasma glucose concentration in ZDF rats (39.0 +/- 3.6 vs 49.4 +/- 2.8 mM, P < 0.05) while serum insulin-levels were similar among the groups. Data from cardiac catheterization showed that Zn(ASA)2 normalized the increased left-ventricular diastolic stiffness (end-diastolic pressure-volume relationship: 0.064 +/- 0.008 vs 0.084 +/- 0.014 mmHg/microl; end-diastolic pressure: 6.5 +/- 0.6 vs 7.9 +/- 0.7 mmHg, P < 0.05). Furthermore, ECG-recordings revealed a restoration of prolonged QT-intervals (63 +/- 3 vs 83 +/- 4 ms, P < 0.05) with Zn(ASA)2. Left-ventricular wall thickness, assessed by echocardiography, did not differ among the groups. However histological examination revealed an increase in the cardiomyocytes' transverse cross-section area in ZDF compared to the ZL rats, which was significantly decreased after Zn(ASA)2-treatment. Additionally, a significant fibrotic remodeling was observed in the diabetic rats compared to ZL rats, and Zn(ASA)2-administered ZDF rats showed a similar collagen content as ZL animals. In diabetic hearts Zn(ASA)2 significantly decreased DNA-fragmentation, and nitro-oxidative stress, and up-regulated myocardial phosphorylated-AKT/AKT protein expression. Zn(ASA)2 reduced cardiomyocyte death in a cellular model of oxidative stress. Zn(ASA)2 had no effects on altered myocardial CD36, GLUT-4, and PI3K protein expression. CONCLUSIONS: We demonstrated that treatment of type-2 diabetic rats with Zn(ASA)2 reduced plasma glucose-levels and prevented diabetic cardiomyopathy. The increased myocardial AKT activation could, in part, help to explain the cardioprotective effects of Zn(ASA)2. The oral administration of Zn(ASA)2 may have therapeutic potential, aiming to prevent/treat cardiac complications in type-2 diabetic patients

The Whereabouts of 2D Gels in Quantitative Proteomics

Two-dimensional gel electrophoresis has been instrumental in the development of proteomics. Although it is no longer the exclusive scheme used for proteomics, its unique features make it a still highly valuable tool, especially when multiple quantitative comparisons of samples must be made, and even for large samples series. However, quantitative proteomics using 2D gels is critically dependent on the performances of the protein detection methods used after the electrophoretic separations. This chapter therefore examines critically the various detection methods (radioactivity, dyes, fluorescence, and silver) as well as the data analysis issues that must be taken into account when quantitative comparative analysis of 2D gels is performed

Precision engineering for PRRSV resistance in pigs: Macrophages from genome edited pigs lacking CD163 SRCR5 domain are fully resistant to both PRRSV genotypes while maintaining biological function

Porcine Reproductive and Respiratory Syndrome (PRRS) is a panzootic infectious disease of pigs, causing major economic losses to the world-wide pig industry. PRRS manifests differently in pigs of all ages but primarily causes late-term abortions and stillbirths in sows and respiratory disease in piglets. The causative agent of the disease is the positive-strand RNA PRRS virus (PRRSV). PRRSV has a narrow host cell tropism, limited to cells of the monocyte/macrophage lineage. CD163 has been described as a fusion receptor for PRRSV, whereby the scavenger receptor cysteine-rich domain 5 (SRCR5) region was shown to be an interaction site for the virus in vitro. CD163 is expressed at high levels on the surface of macrophages, particularly in the respiratory system. Here we describe the application of CRISPR/Cas9 to pig zygotes, resulting in the generation of pigs with a deletion of Exon 7 of the CD163 gene, encoding SRCR5. Deletion of SRCR5 showed no adverse effects in pigs maintained under standard husbandry conditions with normal growth rates and complete blood counts observed. Pulmonary alveolar macrophages (PAMs) and peripheral blood monocytes (PBMCs) were isolated from the animals and assessed in vitro. Both PAMs and macrophages obtained from PBMCs by CSF1 stimulation (PMMs) show the characteristic differentiation and cell surface marker expression of macrophages of the respective origin. Expression and correct folding of the SRCR5 deletion CD163 on the surface of macrophages and biological activity of the protein as hemoglobin-haptoglobin scavenger was confirmed. Challenge of both PAMs and PMMs with PRRSV genotype 1, subtypes 1, 2, and 3 and PMMs with PRRSV genotype 2 showed complete resistance to viral infections assessed by replication. Confocal microscopy revealed the absence of replication structures in the SRCR5 CD163 deletion macrophages, indicating an inhibition of infection prior to gene expression, i.e. at entry/fusion or unpacking stages

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Περιέχει την περίληψηΜέσα στα πλαίσια της Κοινωνίας της Πληροφορίας οι βιβλιοθηκονόμοι διεκδικούν, άλλοτε πετυχημένα, άλλοτε όχι και τόσο, ένα πιο ενεργό και απαιτητικό ρόλο, προβάλλοντας το επιχείρημα πώς όσο μεγαλύτερη είναι η παραγωγή πληροφορίας και γνώσης και η παροχή πληροφόρησης τόσο mo απαιτητική είναι και η διαδικασία που αναγκάζεται να ακολουθήσει ο χρήστης ώστε να ικανοποιήσει τις ανάγκες του. Αλλά, η αναγκαιότητα του βιβλιοθηκονόμου (ως επιστήμονα της πληροφόρησης πλέον), του διαμεσολαβητή, δηλαδή, ανάμεσα στην πληροφορία και στον χρήστη, δικαιολογεί απαραιτήτως και την αναγκαιότητα για την ίδια τη Βιβλιοθήκη; Τεκμηριώνεται, δηλαδή, η ύπαρξη αυτού του οργανισμού ως μη κερδοσκοπικού, πολιτιστικού ιδρύματος που εξυπηρετεί όχι μόνο πληροφοριακές αλλά και ψυχαγωγικές, εκπαιδευτικές, κοινωνικοοικονομικές ανάγκες των επισκεπτών του; Και τότε, το έργο του βιβλιοθηκονόμου πώς προδιαγράφεται; Ποιο το περιεχόμενο και ο τρόπος της διαμεσολάβησης; Πρόκειται για σύνθεση ή μηχανιστική διάδοση της πληροφορίας; Αν η Πληροφορία διακινείται, στις μέρες μας κυρίως και πρωτίστως, με ηλεκτρονικά μέσα, τότε το αυτονόητο της ύπαρξης ενός απτού οικοδομήματος που στεγάζει την πληροφορία παύει να ισχύει και είτε πρέπει να καταλυθεί, είτε να εφευρεθεί από την αρχή, προσδίδοντας νέα επίκαιρα χαρακτηριστικά σε ένα αρχαιότατο κατασκεύασμα

Missing link in the growth of lead-based Zintl clusters: isolation of the dimeric plumbaspherene [Cu4Pb22]4–

We report here the structure of an endohedral plumbaspherene, [Cu4Pb22]4–, the gold analogue of which was previously postulated to be a “missing link” in the growth of larger clusters containing three and four icosahedral subunits. The cluster contains two [Cu2Pb11]2– subunits linked through a Cu2Pb4 trigonal antiprism. Density functional theory reveals that the striking ability of mixed Pb/coinage metal Zintl clusters to oligomerize and, in the case of Au, to act as a site of nucleation for additional metal atoms, is a direct consequence of their nd10(n + 1)s0 configuration, which generates both a low-lying (n + 1)s-based LUMO and also a high-lying Pb-centered HOMO. Cluster growth and nucleation is then driven by this amphoteric character, allowing the clusters to form donor–acceptor interactions between adjacent icosahedral units or to additional metal atoms

Synthesis and characterization of ternary clusters containing the [As16]10– anion, [MM'As16]4– (M = Nb or Ta; M' = Cu or Ag)

The [Nb@As8]3– anion was first isolated from solution in 1986, and a number of isostructural [M@Pn8]n− clusters (M = Nb, Cr, or Mo; Pn = As or Sb; n = 2 or 3) have since been reported. We show here how anions of this class can be used as synthetic precursors that, in combination with sources of low-valent late transition metals (Cu and Ag), generate ternary polyarsenide cluster anions with unprecedented structural motifs. Chain type [MM′As16]4– (M = Nb or Ta; M′ = Cu or Ag) units are found in compounds 2–5. These clusters contain a nortricyclane-like As7 cage and a [M@As8] crown, linked by a single As atom, and represent a fusion of two quite distinct branches of polyarsenide chemistry. Our analysis of the electronic structure confirms that the cluster retains many of the features of the component units. Electrospray ionization mass spectrometry reveals a series of smaller component ions containing 8–12 As atoms, the density functional theory-computed structures of which can be understood in terms of the pseudoelement concept. This work not only presents a new type of coordination mode for As clusters but also offers a point of entry for the rational design of multinary arsenic-based materials