Broadening the scope of high structural dimensionality nanomaterials using pyridine-based curcuminoids

This work has received funding from the European Research Council (ERC) under the European Union's Horizon 2020 R&D programme (ERC-724981). We also acknowledge the Spanish Government, Ministerio de Ciencia e Innovacion (projects CTQ2017-83632, CTQ2015-68370-P, PGC2018-098630-B-I00, MAT2016-77852-C2-1-R, CTQ2016-75150-R, PGC2018-098630B-I00, PGC2018-102047-B-I00 and Ramon y Cajal grant RYC-2017-22910) and the Generalitat de Catalunya for the grant 2017SGR1277. The work at the University of Chile was supported by ANID, Fondecyt Regular Project 1201962 and 1161775 (M. S.). C. D., N. A.-A., A. L.-P., A. G.-C., and L. R.-C. acknowledge the financial support through the "Severo Ochoa" program for Centres of Excellence in R&D (SEV-2015-0496) under the FUNMAT-FIP-2016 fellowship. Some of the experiments were performed at the XALOC46 and NCD-SWEET beamlines of the ALBA synchrotron with the support of ALBA staff and at the Advanced Light Source (ALS) synchrotron. The Advanced Light Source is supported by the Director, Office of Science, Office of Basic Energy Sciences of the U.S. Department of Energy under contract no. DE-AC0205CH11231. This work (L. R.-C.) has been done in the framework of the doctoral program "Chemistry" of the Universitat Autonoma de Barcelona.We present a new heteroditopic ligand (3pyCCMoid) that contains the typical skeleton of a curcuminoid (CCMoid) decorated with two 3-pyridyl groups. The coordination of 3pyCCMoid with Zn-II centres results in a set of novel coordination polymers (CPs) that display different architectures and dimensionalities (from 1D to 3D). Our work analyses how synthetic methods and slight changes in the reaction conditions affect the formation of the final materials. Great efforts have been devoted toward understanding the coordination entities that provide high dimensional systems, with emphasis on the characterization of 2D materials, including analyses of different types of substrates, stability and exfoliation in water. Here, we foresee the great use of CCMoids in the field of CPs and emphasize 3pyCCMoid as a new-born linker.European Research Council (ERC) ERC-724981Spanish Government CTQ2017-83632 CTQ2015-68370-P PGC2018-098630-B-I00 MAT2016-77852-C2-1-R CTQ2016-75150-R PGC2018-098630B-I00 PGC2018-102047-B-I00Spanish Government, Ministerio de Ciencia e Innovacion (Ramon y Cajal grant) RYC-2017-22910Generalitat de Catalunya 2017SGR1277ANID, Fondecyt Regular Project 1201962 1161775"Severo Ochoa" program for Centres of Excellence in R&D under the FUNMAT-FIP-2016 fellowship SEV-2015-0496United States Department of Energy (DOE) DE-AC0205CH1123

Translational engagement of LPA1_{1} receptor in skin fibrosis: from dermal fibroblasts of patients with scleroderma to Tsk1 mouse

BACKGROUND AND PURPOSE: Genetic deletion and pharmacological studies suggest a role for lysophosphatidic acid receptor-1 (LPA$_{1}$ receptor) in fibrosis. We investigated the therapeutic potential in systemic sclerosis (SSc) of a new orally active selective LPA$_{1}$ receptor antagonist using dermal fibroblasts from patients and animal model of skin fibrosis. EXPERIMENTAL APPROACH: Dermal fibroblast and skin biopsies from SSs patients were used. Myofibroblast differentiation, gene expression and cytokine secretion were measured following LPA and/or SAR100842 treatment. Therapeutic effect of SAR100842 was assessed in the tight skin mouse model-1 (Tsk1). KEY RESULTS: SAR100842 is equipotent against various LPA isoforms. SSc dermal fibroblasts and skin biopsies expressed high levels of LPA$_{1}$ receptor. The LPA functional response (Ca$^{2+}$ ) in SSc dermal fibroblasts was fully antagonized with SAR100842. LPA induced myofibroblast differentiation in SSc dermal and IPF lung fibroblasts and the secretion of inflammatory markers and activated Wnt markers. Results from SSc dermal fibroblasts mirror those obtained in a mouse Tsk1 model of skin fibrosis. Using a therapeutic protocol, SAR100842 consistently reversed dermal thickening, inhibited myofibroblast differentiation and reduced skin collagen content. Inflammatory and Wnt pathway markers were also inhibited by SAR100842 in the skin of Tsk1 mice. CONCLUSION: The effects of SAR100842 on LPA -induced inflammation and on mechanisms linked to fibrosis like myofibroblast differentiation and Wnt pathway activation indicate that LPA$_{1}$ receptor activation plays a key role in skin fibrosis. Our results support the therapeutic potential of LPA$_{1}$ receptor antagonists in systemic sclerosis

Depletion of Vasohibin 1 Speeds Contraction and Relaxation in Failing Human Cardiomyocytes

International audienceRationale: Impaired myocardial relaxation is an intractable feature of several heart failure (HF) causes. In human HF, detyrosinated microtubules stiffen cardiomyocytes and impair relaxation. Yet the identity of detyrosinating enzymes have remained ambiguous, hindering mechanistic study and therapeutic development.Objective: We aimed to determine if the recently identified complex of VASH1/2 (vasohibin 1/2) and SVBP (small vasohibin binding protein) is an active detyrosinase in cardiomyocytes and if genetic inhibition of VASH-SVBP is sufficient to lower stiffness and improve contractility in HF.Methods and results: Transcriptional profiling revealed that VASH1 transcript is >10-fold more abundant than VASH2 in human hearts. Using short hairpin RNAs (shRNAs) against VASH1, VASH2, and SVBP, we showed that both VASH1- and VASH2-SVBP complexes function as tubulin carboxypeptidases in cardiomyocytes, with a predominant role for VASH1. We also generated a catalytically dead version of the tyrosinating enzyme TTL (TTL-E331Q) to separate the microtubule depolymerizing effects of TTL from its enzymatic activity. Assays of microtubule stability revealed that both TTL and TTL-E331Q depolymerize microtubules, while VASH1 and SVBP depletion reduce detyrosination independent of depolymerization. We next probed effects on human cardiomyocyte contractility. Contractile kinetics were slowed in HF, with dramatically slowed relaxation in cardiomyocytes from patients with HF with preserved ejection fraction. Knockdown of VASH1 conferred subtle kinetic improvements in nonfailing cardiomyocytes, while markedly improving kinetics in failing cardiomyocytes. Further, TTL, but not TTL-E331Q, robustly sped relaxation. Simultaneous measurements of calcium transients and contractility demonstrated that VASH1 depletion speeds kinetics independent from alterations to calcium cycling. Finally, atomic force microscopy confirmed that VASH1 depletion reduces the stiffness of failing human cardiomyocytes.Conclusions: VASH-SVBP complexes are active tubulin carboxypeptidases in cardiomyocytes. Inhibition of VASH1 or activation of TTL is sufficient to lower stiffness and speed relaxation in cardiomyocytes from patients with HF, supporting further pursuit of detyrosination as a therapeutic target for diastolic dysfunction

Exploring the fate of inhaled monoclonal antibody in the lung parenchyma by microdialysis

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PCSK9 Modulates the Secretion But Not the Cellular Uptake of Lipoprotein(a) Ex Vivo: An Effect Blunted by Alirocumab.

International audienceTo elucidate how the proprotein convertase subtilisin kexin type 9 (PCSK9) inhibitor alirocumab modulates lipoprotein(a) [Lp(a)] plasma levels, the authors performed a series of Lp(a) uptake studies in primary human hepatocytes and dermal fibroblasts and measured Lp(a) secretion from human hepatocytes. They found that Lp(a) cellular uptake occurred in a low-density lipoprotein receptor-independent manner. Neither PCSK9 nor alirocumab altered Lp(a) internalization. By contrast, the secretion of apolipoprotein (a) from human hepatocytes was sharply increased by PCSK9, an effect that was reversed by alirocumab. They propose that PCSK9 does not significantly modulate Lp(a) catabolism, but rather enhances the secretion of Lp(a) from liver cells

Lipoprotein(a) Cellular Uptake Ex Vivo and Hepatic Capture In Vivo Is Insensitive to PCSK9 Inhibition With Alirocumab

International audienceLipoprotein(a) (Lp[a]) is the most common genetically inherited risk factor for cardiovascular disease. Many aspects of Lp(a) metabolism remain unknown. We assessed the uptake of fluorescent Lp(a) in primary human lymphocytes as well as Lp(a) hepatic capture in a mouse model in which endogenous hepatocytes have been ablated and replaced with human ones. Modulation of LDLR expression with the PCSK9 inhibitor alirocumab did not alter the cellular or the hepatic uptake of Lp(a), demonstrating that the LDL receptor is not a major route for Lp(a) plasma clearance. These results have clinical implications because they underpin why statins are not efficient at reducing Lp(a). (C) 2020 The Authors. Published by Elsevier on behalf of the American College of Cardiology Foundation