Discovery of Clinical Candidate GLPG3970: A Potent and Selective Dual SIK2/SIK3 Inhibitor for the Treatment of Autoimmune and Inflammatory Diseases.

The salt-inducible kinases (SIKs) SIK1, SIK2, and SIK3 belong to the adenosine monophosphate-activated protein kinase (AMPK) family of serine/threonine kinases. SIK inhibition represents a new therapeutic approach modulating pro-inflammatory and immunoregulatory pathways that holds potential for the treatment of inflammatory diseases. Here, we describe the identification of GLPG3970 (), a first-in-class dual SIK2/SIK3 inhibitor with selectivity against SIK1 (IC of 282.

Stability and Function of Extracellular Vesicles Derived from Immortalized Human Corneal Stromal Stem Cells: A Proof of Concept Study.

With significant advancement and development of extracellular vesicle (EV)-based therapies, there is a growing need to understand how their storage affects their physical and functional characteristics. EVs were isolated from the conditioned medium of a corneal stromal stem cell line (imCSSC) using Total Exosome isolation kit (TEI) and ultracentrifugation (UC) combined protocol. Purified EVs were stored at 4°C, - 80°C, room temperature (RT) after lyophilization with or without trehalose for 4 weeks.

Generation of Functional Immortalized Human Corneal Stromal Stem Cells.

In addition to their therapeutic potential in regenerative medicine, human corneal stromal stem cells (CSSCs) could serve as a powerful tool for drug discovery and development. Variations from different donors, their isolation method, and their limited life span in culture hinder the utility of primary human CSSCs. To address these limitations, this study aims to establish and characterize immortalized CSSC lines (imCSSC) generated from primary human CSSCs.

Bioprinting of dual ECM scaffolds encapsulating limbal stem/progenitor cells in active and quiescent statuses.

Limbal stem cell deficiency and corneal disorders are among the top global threats for human vision. Emerging therapies that integrate stem cell transplantation with engineered hydrogel scaffolds for biological and mechanical support are becoming a rising trend in the field. However, methods for high-throughput fabrication of hydrogel scaffolds, as well as knowledge of the interaction between limbal stem/progenitor cells (LSCs) and the surrounding extracellular matrix (ECM) are still much needed.

Therapeutic Potential of Extracellular Vesicles for the Treatment of Corneal Injuries and Scars.

Infection, trauma, and chemical exposure of the ocular surface can severely damage the cornea, resulting in visually significant stromal scars. Current medical treatments are ineffective in mitigating corneal scarring, and corneal transplantation is the only therapy able to restore vision in these eyes. However, because of a severe shortage of corneal tissues, risks of blinding complications associated with corneal transplants, and a higher rate of graft failure in these eyes, an effective and deliverable alternative therapy for the prevention and treatment of corneal scarring remains a significant unmet medical need globally.

Evaluation of Cryopreservation Media for the Preservation of Human Corneal Stromal Stem Cells.

Human corneal stromal stem cells (CSSCs) have gained increasing attention in the treatment of corneal stromal scars. In view of this, the preparation and storage of CSSCs are critical to maintaining the regenerative potential of CSSCs. The goal of the study was to investigate the human serum (HS) concentration in the cryomedia that could best preserve CSSCs.

Differentiation Capacity of Human Mesenchymal Stem Cells into Keratocyte Lineage.

Purpose: Mesenchymal stem cells (MSCs) have been extensively studied for their capacity to enhance wound healing and represent a promising research field for generating cell therapies for corneal scars. In the present study, we investigated MSCs from different tissues and their potential to differentiate toward corneal keratocytes.

Methods: Adipose-derived stem cells, bone marrow MSCs, umbilical cord stem cells, and corneal stromal stem cells (CSSCs) were characterized by their expression of surface markers CD105, CD90, and CD73, and their multilineage differentiation capacity into adipocytes, osteoblasts, and chondrocytes.

Mesenchymal Stem Cells Reduce Corneal Fibrosis and Inflammation via Extracellular Vesicle-Mediated Delivery of miRNA.

Mesenchymal stem cells from corneal stromal stem cells (CSSC) prevent fibrotic scarring and stimulate regeneration of transparent stromal tissue after corneal wounding in mice. These effects rely on the ability of CSSC to block neutrophil infiltration into the damaged cornea. The current study investigated the hypothesis that tissue regeneration by CSSC is mediated by secreted extracellular vesicles (EVs).

Context and social perceptions of blood donation in donors found positive for human immunodeficiency virus in France.

Background: In France, information collected during postdonation interviews showed that a majority of human immunodeficiency virus (HIV)-infected donors were not eligible to donate as per donor selection criteria. In the interest of blood safety, this study aimed to explore the mechanisms of noncompliance with blood donor selection criteria, notably the permanent deferral of men who have sex with men (MSM).

Study Design And Methods: Semistructured individual interviews were conducted with 32 blood donors found positive for HIV between mid-2011 and 2014.

Theory versus practice, bacteriological efficiency versus personal habits: A bacteriological and user acceptability evaluation of filtering tools for people who inject drugs.

Introduction And Aims: People who inject drugs (PWID) are exposed to associated viral, bacterial and fungal risks. These risks can be reduced by filtration. Large disparities in the quality of filtration exist between the various available filters.

Bmi1 Loss in the Organ of Corti Results in p16ink4a Upregulation and Reduced Cell Proliferation of Otic Progenitors In Vitro.

The mature mammalian organ of Corti does not regenerate spontaneously after injury, mainly due to the absence of cell proliferation and the depletion of otic progenitors with age. The polycomb gene B lymphoma Mo-MLV insertion region 1 homolog (Bmi1) promotes proliferation and cell cycle progression in several stem cell populations. The cell cycle inhibitor p16ink4a has been previously identified as a downstream target of Bmi1.

Optimized Conditions for Passerini-Smiles Reactions and Applications to Benzoxazinone Syntheses.

Initial conditions disclosed for the Passerini-Smiles reaction are associated with a lack of efficiency that has prevented chemists from using it since its discovery. We wish to report herein our thorough study in the development of new experimental conditions for this coupling between electron-poor phenols, isocyanides, and carbonyl derivatives. These new conditions have been applied to several synthetic strategies towards benzoxazinones.

Correction: Formal [3+2] cycloaddition of Ugi adducts towards pyrrolines.

Correction for 'Formal [3+2] cycloaddition of Ugi adducts towards pyrrolines' by Abdelbari Ben Abdessalem et al., Chem. Commun.

Passerini/Tsuji-Trost strategies towards achieving lactams and cyclopentane derivatives.

The Passerini reaction of α,β-unsaturated aldehydes affords suitable substrates for the Tsuji-Trost reaction with various carbon based-nucleophiles. The resulting α,β-unsaturated amides may be cyclized to lactams or converted into cyclopentane derivatives if bis-nucleophiles are used in the Tsuji-Trost step.

Formal [3+2] cycloaddition of Ugi adducts towards pyrrolines.

Ugi adducts derived from aromatic aldehydes may be converted to pyrrolines via addition of Michael acceptors under microwave irradiation. The reaction may proceed via unusual formation of azomethine ylides followed by a [3+2] cycloaddition using Michael acceptors.

Metal-free aerobic oxidation of benzazole derivatives.

2-Benzyl benzothiazoles and benzimidazoles are easily oxidized under air and basic conditions to give the corresponding ketones in good yields. The use of palladium acetate as a catalyst has little effect and even gives, in some cases, much lower yields.

Ugi post-condensation copper-triggered oxidative cascade towards pyrazoles.

Pyrazolidinones were prepared in a two-step sequence starting from α-hydrazonocarboxylic acids. After a four-component Ugi coupling, the resulting hydrazone was engaged in a copper triggered [3 + 2] cycloaddition/aerobic oxidation cascade.

Unconventional oxazole formation from isocyanides.

The coupling of an acyl chloride with an isocyanide affords 2,5-disubstituted oxazoles under mild basic conditions instead of 4,5-disubstituted derivatives when using Schöllkopf conditions (butyllithium); this reaction constitutes a remarkable example of a base-induced chemoselective process in isocyanide chemistry.