Exploring the boundaries of vinylogous Mukaiyama aldol processes: stereoselective access to polyunsaturated homoallylic alcohols

Catalytic enantioselective vinylogous aldol reactions using extended enolates are of prominent value in synthetic organic chemistry. Here, we report our advances in the development of enantioselective bis-vinylogous and hyper-vinylogous Mukaiyama aldol reactions between a series of polyenylsilyloxy furans or polyenylsilyoxy indoles and aromatic aldehydes, realized by use of the enabling catalyst combination of silicon tetrachloride and Denmark’s chiral bis-phosphoramide base (R,R)-I. Several crucial issues such as the remote site-, enantio- and geometrical selectivity of the reaction will be highlighted, ultimately focusing on one main question: how far can we push the limits of the vinylogous reactivity transmittal?</i

Unlocking Access to Enantiopure Fused Uracils by Chemodivergent [4+2] Cross‐Cycloadditions: DFT‐Supported Homo‐Synergistic Organocatalytic Approach

The discovery of chemical methods enabling the construction of carbocycle‐fused uracils which embody a three‐dimensional and functional‐group‐rich architecture is a useful tool in medicinal chemistry oriented synthesis. In this work, an unprecedented amine‐catalyzed [4+2] cross‐cycloaddition is documented; it involves remotely enolizable 6‐methyluracil‐5‐carbaldehydes and β‐aryl enals, and chemoselectively produces two novel bicyclic and tricyclic fused uracil chemotypes in good yields with a maximum level of enantiocontrol. In‐depth mechanistic investigations and control experiments support an intriguing homo‐synergistic organocatalytic approach, where the same amine organocatalyst concomitantly engages both aldehyde partners in a stepwise eliminative [4+2] cycloaddition, whose vinylogous iminium ion intermediate product may diverge—depending upon conditions—to either bicyclic targets by hydrolysis or tricyclic products by a second homo‐synergistic trienamine‐mediated stepwise [4+2] cycloaddition

Nintedanib-Containing Dual Conjugates Targeting αVβ6 Integrin and Tyrosine Kinase Receptors as Potential Antifibrotic Agents

αVβ6 Integrin plays a fundamental role in the activation of transforming growth factor-β (TGF-β), the major profibrotic mediator; for this reason, αVβ6 ligands have recently been forwarded to clinical phases for the therapy of fibrotic diseases. Herein, we report the synthesis and in vitro biological evaluation as antifibrotic agents of three new covalent conjugates, constituted by c(AmpLRGDL), an αVβ6 integrin-recognizing small cyclopeptide, and nintedanib, a tyrosine kinase inhibitor approved for idiopathic pulmonary fibrosis (IPF) treatment. One of these conjugates recapitulates optimal in vitro antifibrotic properties of the two active units. The integrin ligand portion within the conjugate plays a role in inhibiting profibrotic stimuli, potentiating the nintedanib effect and favoring the selective uptake of the conjugate in cells overexpressing αVβ6 integrin. These results may open a new perspective on the development of dual conjugates in the targeted therapy of IPF

Direct vinylogous Michael addition of prochiral 3-alkylideneoxindoles to nitroolefins

3-Alkylidene-2-oxindoles represent a simple, yet enabling subfamily of indole alkaloids, and their ability to react as electron-poor acceptors has largely been investigated. In contrast, their utility as pronucleophilic synthons remains elusive. In this context, the present describes the successful execution of the direct, organocatalytic asymmetric Michael addition of prochiral 3-alkylideneoxindoles to nitroolefins

Carpal tunnel syndrome in cardiac amyloidosis: implications for early diagnosis and prognostic role across the spectrum of aetiologies

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Le urolitine del metabotipo ‘A’ potenziano il profilo antinfiammatorio dei macrofagi M2

Background. Gli ellagitannini (ET), polifenoli presenti nel melograno, una volta ingeriti vengono metabolizzati dal microbiota intestinale a urolitine (Uro), a cui si ascrivono proprietà antinfiammatorie e antiossidanti nell’aterosclerosi. In relazione ai tipi di Uro prodotte, si distinguono due metabotipi, A (Uro A) e B (Uro A, IsoUro A, Uro B e Uro C). I macrofagi sono cellule chiave nell’infiammazione e nell’aterosclerosi, e, pertanto, eccellenti candidati come bersagli dell’azione delle urolitine. Scopo. Valutare l’effetto di dosi fisiologiche di Uro, che mimano i metabotipi, sul trascrittoma di macrofagi umani. Metodi. I monociti sono stati isolati da buffy coat di donatori sani e stimolati per indurre la polarizzazione M1 o M2, in presenza o in assenza di differenti combinazioni di Uro, corrispondenti ai metabotipi A e B. Le alterazioni a livello di trascrittoma sono state rilevate mediante tecnica microarray a genoma intero. Risultati. Il trascrittoma dei macrofagi M1 è stato solo minimamente influenzato dai metabotipi. Al contrario, le Uro del metabotipo A, modificano profondamente l’impronta trascrittomica degli M2, smorzando i processi di adesione focale e di migrazione transendoteliale e amplificando i meccanismi antisenescenza, mediante l’espressione dei geni implicati nell’attività lisosomiale e delle vie di riparazione del DNA. Nel metabotipo B, le modifiche del trascrittoma degli M2 sono molto contenute, e includono la repressione della via del segnale associata alla diapedesi. Conclusioni. Questi dati suggeriscono che le Uro del metabotipo A sono eccellenti candidate al ruolo di sostanze naturali a effetto netto antiaterogenico, attraverso l’esaltazione del ruolo antinfiammatorio dei macrofagi M2. Un ruolo analogo, ma quantitativamente molto minore, potrebbe essere svolto anche dalle urolitine del metabotipo B. Studio finanziato dal MIUR, Programma SIR2014 (RBSI14LHMB)

Regulatory T cells from patients with end-stage organ disease can be isolated, expanded and cryopreserved according good manufacturing practice improving their function

Background Here, we isolated, expanded and functionally characterized regulatory T cells (Tregs) from patients with end stage kidney and liver disease, waiting for kidney/liver transplantation (KT/LT), with the aim to establish a suitable method to obtain large numbers of immunomodulatory cells for adoptive immunotherapy post-transplantation. Methods We first established a preclinical protocol for expansion/isolation of Tregs from peripheral blood of LT/KT patients. We then scaled up and optimized such protocol according to good manufacturing practice (GMP) to obtain high numbers of purified Tregs which were phenotypically and functionally characterized in vitro and in vivo in a xenogeneic acute graft-versus-host disease (aGVHD) mouse model. Specifically, immunodepressed mice (NOD-SCID-gamma KO mice) received human effector T cells with or without GMP-produced Tregs to prevent the onset of xenogeneic GVHD. Results Our small scale Treg isolation/expansion protocol generated functional Tregs. Interestingly, cryopreservation/thawing did not impair phenotype/function and DNA methylation pattern of FOXP3 gene of the expanded Tregs. Fully functional Tregs were also isolated/expanded from KT and LT patients according to GMP. In the mouse model, GMP Tregs from LT or KT patient proved to be safe and show a trend toward reduced lethality of acute GVHD. Conclusions These data demonstrate that expanded/thawed GMP-Tregs from patients with end-stage organ disease are fully functional in vitro. Moreover, their infusion is safe and results in a trend toward reduced lethality of acute GVHD in vivo, further supporting Tregs-based adoptive immunotherapy in solid organ transplantation

Metodologías de Diseño para Sistemas Embebidos

Se presentan los aspectos relevantes de un proyecto de investigación y desarrollo abordado en el grupo Inca del Instituto Intia de la UNCPBA. Este proyecto fue oportunamente aprobado en el marco de los incentivos a la investigación y busca como objetivos generales el trabajo conjunto tendiente a desarrollar tecnologías para el manejo de dispositivos en sistemas embebidos. Conjuntamente se realiza la formación de varios de los integrantes quienes se encuentran realizando sus estudios de posgrado en temas afines al proyecto. El proyecto busca desarrollar tareas de investigación y desarrollo en temas relacionados a los sistemas embebidos, tanto en aspectos de software como de hardware. De este modo se busca desarrollar soluciones a problemas en áreas como visualización, optimización de sistemas operativos de tiempo real, sensores, etc. no solo desde el punto de vista algorítmico sino a partir de su implementación en sistemas de hardware programable como FPGAs.Eje: Procesamiento de Señales y Sistemas de Tiempo RealRed de Universidades con Carreras en Informática (RedUNCI

Metodologías de Diseño para Sistemas Embebidos

Se presentan los aspectos relevantes de un proyecto de investigación y desarrollo abordado en el grupo Inca del Instituto Intia de la UNCPBA. Este proyecto fue oportunamente aprobado en el marco de los incentivos a la investigación y busca como objetivos generales el trabajo conjunto tendiente a desarrollar tecnologías para el manejo de dispositivos en sistemas embebidos. Conjuntamente se realiza la formación de varios de los integrantes quienes se encuentran realizando sus estudios de posgrado en temas afines al proyecto. El proyecto busca desarrollar tareas de investigación y desarrollo en temas relacionados a los sistemas embebidos, tanto en aspectos de software como de hardware. De este modo se busca desarrollar soluciones a problemas en áreas como visualización, optimización de sistemas operativos de tiempo real, sensores, etc. no solo desde el punto de vista algorítmico sino a partir de su implementación en sistemas de hardware programable como FPGAs.Eje: Procesamiento de Señales y Sistemas de Tiempo RealRed de Universidades con Carreras en Informática (RedUNCI