Attempted Diastereoselective Preparation and Chiroptical Properties of (2S)-1-(3-Mercapto-2-Methyl-1-Oxopropyl)-L-Proline (Captopril) and Some Congeners

CD and 13C-NMRstudy of the eonformational properties of (2S)-1-(3-mercapto-2-methyl-1-oxopropyl)-L-proline (captopril, 1), and its congeners 2-5, 8, 9 is reported. 13C-NMRdata (in DMSO-d6) reveal an E/Z (cis/trans) ratio of ea. (15-30) : (70-85) for the N-acetyl-prolines 1, 5, 10, and for N-acetyl-L-proline. CD data indicate practically identical conformations for the ring systems of 8 and 9. Attempted diastereoselective cyclization of the sodium salt of 7 or the free thioacid into 8 and 9 resulted in low chemical yields (-30%) and low diastereoselectivity, favouring formation of the »wrong- diastereomer 9 in small excess (-20%)

Effect of vascular endothelial growth factor gene therapy on post-traumatic peripheral nerve regeneration and denervation-related muscle atrophy

Functional recovery after peripheral nerve injury depends on both improvement of nerve regeneration and prevention of denervation-related skeletal muscle atrophy. To reach these goals, in this study we overexpressed vascular endothelial growth factor (VEGF) by means of local gene transfer with adeno-associated virus (AAV). Local gene transfer in the regenerating peripheral nerve was obtained by reconstructing a 1-cm-long rat median nerve defect using a vein segment filled with skeletal muscle fibers that have been previously injected with either AAV2-VEGF or AAV2-LacZ, and the morphofunctional outcome of nerve regeneration was assessed 3 months after surgery. Surprisingly, results showed that overexpression of VEGF in the muscle-vein-combined guide led to a worse nerve regeneration in comparison with AAV-LacZ controls. Local gene transfer in the denervated muscle was obtained by direct injection of either AAV2-VEGF or AAV2-LacZ in the flexor digitorum sublimis muscle after median nerve transection and results showed a significantly lower progression of muscle atrophy in AAV2-VEGF-treated muscles in comparison with muscles treated with AAV2-LacZ. Altogether, our results suggest that local delivery of VEGF by AAV2-VEGF-injected transplanted muscle fibers do not represent a rational approach to promote axonal regeneration along a venous nerve guide. By contrast, AAV2-VEGF direct local injection in denervated skeletal muscle significantly attenuates denervation-related atrophy, thus representing a promising strategy for improving the outcome of post-traumatic neuromuscular recovery after nerve injury and repair

Paracrine effect of regulatory T cells promotes cardiomyocyte proliferation during pregnancy and after myocardial infarction

Cardiomyocyte proliferation stops at birth when the heart is no longer exposed to maternal blood and, likewise, to regulatory T cells (Tregs) that are expanded to promote maternal tolerance towards the fetus. Here, we report a role of Tregs in promoting cardiomyocyte proliferation. Treg-conditioned medium promotes cardiomyocyte proliferation, similar to the serum from pregnant animals. Proliferative cardiomyocytes are detected in the heart of pregnant mothers, and Treg depletion during pregnancy decreases both maternal and fetal cardiomyocyte proliferation. Treg depletion after myocardial infarction results in depressed cardiac function, massive inflammation, and scarce collagen deposition. In contrast, Treg injection reduces infarct size, preserves contractility, and increases the number of proliferating cardiomyocytes. The overexpression of six factors secreted by Tregs (Cst7, Tnfsf11, Il33, Fgl2, Matn2, and Igf2) reproduces the therapeutic effect. In conclusion, Tregs promote fetal and maternal cardiomyocyte proliferation in a paracrine manner and improve the outcome of myocardial infarction

A microRNA program regulates the balance between cardiomyocyte hyperplasia and hypertrophy and stimulates cardiac regeneration

Myocardial regeneration is restricted to early postnatal life, when mammalian cardiomyocytes still retain the ability to proliferate. The molecular cues that induce cell cycle arrest of neonatal cardiomyocytes towards terminally differentiated adult heart muscle cells remain obscure. Here we report that the miR-106b~25 cluster is higher expressed in the early postnatal myocardium and decreases in expression towards adulthood, especially under conditions of overload, and orchestrates the transition of cardiomyocyte hyperplasia towards cell cycle arrest and hypertrophy by virtue of its targetome. In line, gene delivery of miR-106b~25 to the mouse heart provokes cardiomyocyte proliferation by targeting a network of negative cell cycle regulators including E2f5, Cdkn1c, Ccne1 and Wee1. Conversely, gene-targeted miR-106b~25 null mice display spontaneous hypertrophic remodeling and exaggerated remodeling to overload by derepression of the prohypertrophic transcription factors Hand2 and Mef2d. Taking advantage of the regulatory function of miR-106b~25 on cardiomyocyte hyperplasia and hypertrophy, viral gene delivery of miR-106b~25 provokes nearly complete regeneration of the adult myocardium after ischemic injury. Our data demonstrate that exploitation of conserved molecular programs can enhance the regenerative capacity of the injured heart.E.D. is supported by a VENI award 916-150-16 from the Netherlands Organization for Health Research and Development (ZonMW), an EMBO Long-term Fellowship (EMBO ALTF 848-2013) and a FP7 Marie Curie Intra-European Fellowship (Project number 627539). V.S.P. was funded by a fellowship from the FCT/ Ministério da Ciência, Tec-nologia e Inovação SFRH/BD/111799/2015. P.D.C.M. is an Established Investigator of the Dutch Heart Foundation. L.D.W. acknowledges support from the Dutch CardioVascular Alliance (ARENA-PRIME). L.D.W. was further supported by grant 311549 from the European Research Council (ERC), a VICI award 918-156-47 from the Dutch Research Council and Marie Sklodowska-Curie grant agreement no. 813716 (TRAIN-HEART)

Genetic Basis of Myocarditis: Myth or Reality?

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Raman spectroscopic study of bioactive silica based glasses: The role of the alkali/alkali earth ratio on the non-bridging oxygen/bridging oxygen (NBO/BO) ratio

Raman spectra of bioactive glasses of the Na2O-K2O-MgO-CaO-B2O3-P2O5-SiO2 to be used in bone reconstruction systems have been collected from samples with three different concentrations of alkali and alkali earth elements. Compositions were chosen with a constant total amount of modifiers and formers, with only minor changes among the formers. The ratio of Non-Bridging Oxygens (NBO/BO) has been obtained from the Raman spectra and reported as a function of the alkali/alkali earth ratio, showing a linear increase. Dissolution tests indicate also a linear dependence of the amount of Na+, K+ and Ca++ ions leached in water has been obtained, thus demonstrating the sensitivity of the method, given that the changes from one glass composition tyo the other are of the order of some points in percentage among the glass modifiers

Rabbit pilot study on the resorbability of three-dimensional bioactive glass fibre scaffolds

Bioactive glass composed of Na2O\u2013K2O\u2013MgO\u2013CaO\u2013B2O3\u2013P2O5\u2013SiO2 is used in this study to manufacture three-dimensional glass fibre scaffolds for a synthetic bone filler material for the treatment of bone defects. The glass is characterized by a large working range, which is the temperature interval at which forming of glass can take place. A preliminary in vivo study on New Zealand skeletally mature rabbits tibia is reported here. Bone defects were prepared in the medial surfaces of the diaphyses of the tibia. For the first time melt derived three-dimensional bioactive glass fibre constructs were used to fill the cavities. The different implants investigated here were a scaffold with a porosity of 45\u201350%, scaffold with a porosity of 55\u201360% and morsels with a porosity of 55\u201360%. The implanted bone substitutes were dissected after 6 months and evaluated by histological and synchrotron radiation micro tomography analysis. PerioGlas and empty defects were used as positive and negative controls, respectively. The result was that the surgically created tibial defects were healed and new bone formation was found in the medullary cavities. Despite the intrinsic limitations of a pilot study, the preliminary results indicate that in 6 months the glass fibre scaffolds are completely resorbed and that the osteoconductive properties of the filling material are strictly correlated with the structural and morphological characteristics of the bone substitute