Publicaciones > Kopytina et al

Front Pharmacol. 2022 Aug 16;13:868374. doi: 10.3389/fphar.2022.868374. eCollection 2022. PubMed 36052133

Steviol glycosides as an alternative osmotic agent for peritoneal dialysis fluid.

Valeria Kopytina¹, Lucía Pascual-Antón¹, Nora Toggweiler², Eva-María Arriero-País¹, Lisa Strahl², Patricia Albar-Vizcaíno³, David Sucunza⁴, Juan J Vaquero⁴, Sonja Steppan⁵, Dorothea Piecha⁵, Manuel López-Cabrera¹, Guadalupe-Tirma González-Mateo¹

1. Department of Immunology, Molecular Biology Research Center Severo Ochoa (CBMSO), Spanish National Research Council (CSIC), Madrid, Spain.  2. Fresenius Medical Care Deutschland GmbH, Frankfurter, St. Wendel, Germany.  3. Department of Nephrology, IdiPAZ Research Institute, La Paz University Hospital, Madrid, Spain.  4. Department of Organic and Inorganic Chemistry, Faculty of Pharmacy, University of Alcalá (IRYCIS), Madrid, Spain.  5. Fresenius Medical Care Deutschland GmbH, St. Wendel, Germany.

Keywords: biocompatibility; chronic inflammation; dialysis solutions; fibrosis; osmotic agents; peritoneal dialysis (PD)

Abstract

Background: Peritoneal dialysis (PD) is a renal replacement technique that requires repeated exposure of the peritoneum to hyperosmolar PD fluids (PDFs). Unfortunately, it promotes alterations of the peritoneal membrane (PM) that affects its functionality, including mesothelial-mesenchymal transition (MMT) of mesothelial cells (MCs), inflammation, angiogenesis, and fibrosis. Glucose is the most used osmotic agent, but it is known to be at least partially responsible, together with its degradation products (GDP), for those changes. Therefore, there is a need for more biocompatible osmotic agents to better maintain the PM. Herein we evaluated the biocompatibility of Steviol glycosides (SG)-based fluids. Methods: The ultrafiltration and transport capacities of SG-containing and glucose-based fluids were analyzed using artificial membranes and an in vivo mouse model, respectively. To investigate the biocompatibility of the fluids, Met-5A and human omental peritoneal MCs (HOMCs) were exposed in vitro to different types of glucose-based PDFs (conventional 4.25% glucose solution with high-GDP level and biocompatible 2.3% glucose solution with low-GDP level), SG-based fluids or treated with TGF-β1. Mice submitted to surgery of intraperitoneal catheter insertion were treated for 40 days with SG- or glucose-based fluids. Peritoneal tissues were collected to determine thickness, MMT, angiogenesis, as well as peritoneal washings to analyze inflammation. Results: Dialysis membrane experiments demonstrated that SG-based fluids at 1.5%, 1%, and 0.75% had a similar trend in weight gain, based on curve slope, as glucose-based fluids. Analyzing transport capacity in vivo, 1% and 0.75% SG-based fluid-exposed nephrectomized mice extracted a similar amount of urea as the glucose 2.3% group. In vitro, PDF with high-glucose (4.25%) and high-GDP content induced mesenchymal markers and angiogenic factors (Snail1, Fibronectin, VEGF-A, FGF-2) and downregulates the epithelial marker E-Cadherin. In contrast, exposition to low-glucose-based fluids with low-GDP content or SG-based fluids showed higher viability and had less MMT. In vivo, SG-based fluids preserved MC monolayer, induced less PM thickness, angiogenesis, leukocyte infiltration, inflammatory cytokines release, and MMT compared with glucose-based fluids. Conclusion: SG showed better biocompatibility as an osmotic agent than glucose in vitro and in vivo, therefore, it could alternatively substitute glucose in PDF.

Publicaciones > Altarejos et al

Eur. J. Org. Chem. 2022; e202200521. doi:10.1002/ejoc.202200521

Synthesis of Tri- and Tetrasubstituted Alkenyl Boronates from Alkynes

Julia Altarejos, Antonio Valero, Rubén Manzano, Javier Carreras

Palabras clave: alkenyl boronates; alkynes; metal catalysis; metal-free; synthetic methods

Resumen

The synthesis of organoboron compounds have attracted the attention of the synthetic community. In particular, molecules with C(sp2)-B bonds enable the transformation to new C?C or C-heteroatom bonds by well-established methodologies. Alkenyl boronates have the possibility for further conversion of the boron moiety or functionalization of the double bond. This review gives an overview on the recent methodologies for the selective preparation of the challenging highly substituted alkenyl boronates from alkynes.

Publicaciones > García-Marín et al

J Comput Aided Mol Des. 2022 Aug;36(8):575-589. doi: 10.1007/s10822-022-00466-1. PubMed 35869378

Insight into the mechanism of molecular recognition between human Integrin-Linked Kinase and Cpd22 and its implication at atomic level.

Javier García-Marín^1, a, Diego Rodríguez-Puyol^2, b, Juan J Vaquero^3, c

1. Departamento de Química Orgánica y Química Inorgánica, Instituto de Investigación Química Andrés M. del Río (IQAR), Universidad de Alcalá (IRYCIS), Alcalá de Henares, 28805, Madrid, Spain.  2. Departamento de Química Biológica y Estructural, Centro de Investigaciones Biológicas, CIB-CSIC, C/Ramiro de Maeztu 9, 28040, Madrid, Spain.  3. Department of Chemistry, University of Bath, Claverton Down, Bath, BA2 7AX, UK.

a. javier.garciamarin@uah.es  b. javier.garciamarin@uah.es  c. javier.garciamarin@uah.es

Keywords: Cpd22; ILK; Integrin-linked kinase; Molecular dynamics; PELE; Pseudokinase

Abstract

Pseudokinases have received increasing attention over the past decade because of their role in different physiological phenomena. Although pseudokinases lack several active-site residues, thereby hindering their catalytic activity, recent discoveries have shown that these proteins can play a role in intracellular signaling thanks to their non-catalytic functions. Integrin-linked kinase (ILK) was discovered more than two decades ago and was subsequently validated as a promising target for neoplastic diseases. Since then, only a few small-molecule inhibitors have been described, with the V-shaped pyrazole Cpd22 being the most interesting and characterized. However, little is known about its detailed mechanism of action at atomic level. In this study, using a combination of computational chemistry methods including PELE calculations, docking, molecular dynamics and experimental surface plasmon resonance, we were able to prove the direct binding of this molecule to ILK, thus providing the basis of its molecular recognition by the protein and the effect over its architecture. Our breakthroughs show that Cpd22 binding stabilizes the ILK domain by binding to the pseudo-active site in a similar way to the ATP, possibly modulating its scaffolding properties as pseudokinase. Moreover, our results explain the experimental observations obtained during Cpd22 development, thus paving the way to the development of new chemical probes and potential drugs.