Vitamina D in Nefrologia Clinica: nuove evidenze e nuovi dubbi

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Intervista a Diego Brancaccio

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Phosphate overload accelerates vascular aging in uremic patients

Vascular calcification is a very common event in atients affected by diabetes and chronic kidney disease (CKD). Recently, it has been well documented that abnormalities in mineral and bone metabolism in CKD patients are associated with increased morbidity and mortality. Elevated serum phosphate and calcium-phosphate product levels play an important role in the pathogenesis of vascular mineralization in uremic patients and also appear to be associated with increased cardiovascular mortality. Together with classical passive precipitation of calcium-phosphate in soft tissues, during the last decade it has been demonstrated that inorganic phosphate may cause extraskeletal calcification directly through a real “ossification” of the tunica media in the vasculature of CKD patients. Therefore, control of phosphate retention is now an even more crucial target of treatment in patients affected by chronic kidney disease

DOTA-Derivatives of Octreotide Dicarba-Analogs with High Affinity for Somatostatin sst2,5 Receptors

In vivo somatostatin receptor scintigraphy is a valuable method for the visualization of human endocrine tumors and their metastases. In fact, peptide ligands of somatostatin receptors (sst's) conjugated with chelating agents are in clinical use. We have recently developed octreotide dicarba-analogs, which show interesting binding profiles at sst's. In this context, it was mandatory to explore the possibility that our analogs could maintain their activity also upon conjugation with DOTA. In this paper, we report and discuss the synthesis, binding affinity and conformational preferences of three DOTA-conjugated dicarba-analogs of octreotide. Interestingly, two conjugated analogs exhibited nanomolar affinities on sst(2) and sst(5) somatostatin receptor subtypes

Urantide Conformation and Interaction with the Urotensin-II Receptor

Urotensin II (U-II) is a disulfide bridged peptide hormone identified as the ligand of a G protein-coupled receptor. Human U-II (H-Glu-Thr-Pro-Asp-c[Cys-Phe-Trp-Lys-Tyr-Cys]-Val-OH) has been described as the most potent vasoconstrictor compound identified to date. We have previously identified the compound termed urantide (H-Asp-c[Pen-Phe-DTrp-Orn-Tyr-Cys]-Val-OH), which is the most potent UT receptor (UTR) antagonist described to date. Urantide may have potential clinical value in the treatment of atherosclerosis. In the present study, we studied the conformational preferences of urantide in DPC micelles and developed a urantide/UTR interaction model. This model can help the design of novel peptides and small molecules as UTR antagonists

ISMuLT Guidelines for muscle injuries

Muscle injuries are frequent in high demand sports. No guidelines are available in the scientific literature. ISMuLT, the "Italian Society of Muscles, Ligaments and Tendons", in line with its multidisciplinary mission, is proud to cover this gap

The enzymatic processing of α-dystroglycan by MMP-2 is controlled by two anchoring sites distinct from the active site

Dystroglycan (DG) is a membrane receptor, belonging to the dystrophin-glycoprotein complex (DGC) and formed by two subunits, α-dystroglycan (α-DG) and β-dystroglycan (β -DG). The C-terminal domain of α-DG and the N-terminal extracellular domain of β -DG are connected, providing a link between the extracellular matrix and the cytosol. Under pathological conditions, such as cancer and muscular dystrophies, DG may be the target of metalloproteinases MMP-2 and MMP-9, contributing to disease progression. Previously, we reported that the C-terminal domain α-DG (483-628) domain is particularly susceptible to the catalytic activity of MMP-2; here we show that the α-DG 621-628 region is required to carry out its complete digestion, suggesting that this portion may represent a MMP-2 anchoring site. Following this observation, we synthesized an α-DG based-peptide, spanning the (613-651) C-terminal region. The analysis of the kinetic and thermodynamic parameters of the whole and the isolated catalytic domain of MMP-2 (cdMMP-2) has shown its inhibitory properties, indicating the presence of (at least) two binding sites for the peptide, both located within the catalytic domain, only one of the two being topologically distinct from the catalytic active groove. However, the different behavior between whole MMP-2 and cdMMP-2 envisages the occurrence of an additional binding site for the peptide on the hemopexin-like domain of MMP-2. Interestingly, mass spectrometry analysis has shown that α-DG (613-651) peptide is cleavable even though it is a very poor substrate of MMP-2, a feature that renders this molecule a promising template for developing a selective MMP-2 inhibitor

Muscle injuries: a brief guide to classification and management

Muscle injuries are frequent in athletes. Despite their high incidence, advances in clinical diagnostic criteria and imaging, their optimal management and rehabilitation strategies are still debated in literature. Furthermore, reinjury rate is high after a muscle lesion, and an improper treatment or an early return to sports can increase the rate of reinjury and complications. Most muscle injuries are managed conservatively with excellent results, and surgery is normally advocated only for larger tears. This article reviews the current literature to provide physicians and rehabilitation specialists with the necessary basic tools to diagnose, classify and to treat muscle injuries. Based on anatomy, biomechanics, and imaging features of muscle injury, the use of a recently reported new classification system is also advocated

Interaction of peptides and small molecules with biological targets

During my PhD course, I focused my attention on the conformational analysis of peptides that interact with GPCR and ligand-receptor interactions from NMR spectroscopy with possible application to cytotoxic agents binding to DNA. In particular, I investigated the conformational behaviour of peptide analogues of Urotensin, Melanocortin and Somatostatin in water solution and membrane mimetic environment (SDS and DPC micelles). Another research field was the NMR-based screening as potent technique for the identification of small molecules that interact with macromolecule targets. Several methods based on the ligand observation have been proposed in the literature, among these WaterLOGSY (water-ligand observed via gradient spectroscopy), and STD-NMR (saturation transfer difference) experiments. I applied these NMR techniques for the evaluation of the DNA interactions of a new series of thiophen-naphthoquinones with interesting cytotoxic activity