Notch2 Signaling Sensitizes Endothelial Cells to Apoptosis by Negatively Regulating the Key Protective Molecule Survivin

BACKGROUND: Notch signaling pathway controls key functions in vascular and endothelial cells (ECs) where Notch4 plays a major role. However, little is known about the contribution of other Notch receptors. This study investigated regulation of Notch2 and further examined its implication in EC dysfunction. METHODOLOGY/PRINCIPAL FINDINGS: Here, we provide evidence for a novel link between Notch and TNF signaling, where Notch2 is upregulated and activated in response to TNF. Forced expression of Notch2 intracellular domain in cultured ECs promotes apoptosis and allows the significant downregulation of several cell-death-related transcripts in a dose-dependent manner. In particular, activation of Notch2 led to a rapid decrease in survivin mRNA and protein expression, while survivin upregulation was obtained by the selective knockdown of Notch2 in ECs, indicating that survivin expression is controlled at the Notch level. Moreover, Notch2 silencing and ectopic expression of survivin, but not XIAP or Bcl2, rescued ECs from TNF and Notch2-mediated apoptosis, respectively. CONCLUSIONS/SIGNIFICANCE: In conclusion, TNF signaling activates Notch2 that sensitizes ECs to apoptosis via modulation of the key apoptosis regulator survivin. Overall, our findings also indicate that specific Notch receptors control distinct functions in vascular cells and inflammatory cytokines contribute to this specificity

Mannose-modified hyaluronic acid nanocapsules for the targeting of tumor-associated macrophages

Tumor-associated macrophages (TAMs), a class of immune cells that play a key role in tumor immunosuppression, are recognized as important targets to improve cancer prognosis and treatment. Consequently, the engineering of drug delivery nanocarriers that can reach TAMs has acquired special relevance. This work describes the development and biological evaluation of a panel of hyaluronic acid (HA) nanocapsules (NCs), with different compositions and prepared by different techniques, designed to target macrophages. The results showed that plain HA NCs did not significantly influence the polarization of M0 and M2-like macrophages towards an M1-like pro-inflammatory phenotype; however, the chemical functionalization of HA with mannose (HA-Man) led to a significant increase of NCs uptake by M2 macrophages in vitro and to an improved biodistribution in a MN/MNCA1 fibrosarcoma mouse model with high infiltration of TAMs. These functionalized HA-Man NCs showed a higher accumulation in the tumor compared to non-modified HA NCs. Finally, the pre-administration of the liposomal liver occupying agent Nanoprimer™ further increased the accumulation of the HA-Man NCs in the tumor. This work highlights the promise shown by the HA-Man NCs to target TAMs and thus provides new options for the development of nanomedicine and immunotherapy-based cancer treatmentsOpen Access funding provided thanks to the CRUE-CSIC agreement with Springer Nature. This work was supported by the 2^2-INTRATARGET project (A20/00028) funded by the ISCIII under the umbrella of the ERA NET EuroNanoMed GA N 723770 of the EU Horizon 2020 Research and Innovation Programme. This work was also supported by the Xunta de Galicia (ED431C 2018/30, and “Centro singular de investigación de Galicia” accreditation 2019 − 2022, ED431G2019/03), and the European Union (European Regional Development Fund-ERDF)S

Covalent functionalization of decellularized tissues accelerates endothelialization

[EN] In the field of tissue regeneration, the lack of a stable endothelial lining may affect the hemocompatibility of both synthetic and biological replacements. These drawbacks might be prevented by specific biomaterial functionalization to induce selective endothelial cell (EC) adhesion. Decellularized bovine pericardia and porcine aortas were selectively functionalized with a REDV tetrapeptide at 10(-5) M and 10(-6) M working concentrations. The scaffold-bound peptide was quantified and REDV potential EC adhesion enhancement was evaluated in vitro by static seeding of human umbilical vein ECs. The viable cells and MTS production were statistically higher in functionalized tissues than in control. Scaffold histoarchitecture, geometrical features, and mechanical properties were unaffected by peptide anchoring. The selective immobilization of REDV was effective in accelerating ECs adhesion while promoting proliferation in functionalized decellularized tissues intended for blood-contacting applications.JLGR acknowledges financial support from the Spanish State Research Agency (AEI) through the PID2019-106099RB-C41/AEI/10.13039/501100011033 project. CIBER-BBN is an initiative funded by the VI National R&D&I Plan 2008-2011, Iniciativa Ingenio 2010, Consolider Program. CIBER Actions are financed by the Instituto de Salud Carlos III with assistance from the European Regional Development Fund.Dal Sasso, E.; Zamuner, A.; Filippi, A.; Romanato, F.; Palmosi, T.; Vedovelli, L.; Gregori, D.... (2021). Covalent functionalization of decellularized tissues accelerates endothelialization. Bioactive materials. 6(11):3851-3864. https://doi.org/10.1016/j.bioactmat.2021.04.003S3851386461

The Production and Application of Hydrogels for Wound Management: A Review

Wound treatment has increased in importance in the wound care sector due to the pervasiveness of chronic wounds in the high-risk population including, but not limited to, geriatric population, immunocompromised and obese patients. Furthermore, the number of people diagnosed with diabetes is rapidly growing. According to the World Health Organization (WHO), the global diabetic occurrence has increased from 4.7 in 1980 to 8.5 in 2014. As diabetes becomes a common medical condition, it has also become one of the major causes of chronic wounds which require specialised care to address patients’ unique needs. Wound dressings play a vital role in the wound healing process as they protect the wound site from the external environment. They are also capable of interacting with the wound bed in order to facilitate and accelerate the healing process. Advanced dressings such as hydrogels are designed to maintain a moist environment at the site of application and due to high water content are ideal candidates for wound management. Hydrogels can be used for both exudating or dry necrotic wounds. Additionally, hydrogels also demonstrate other unique features such as softness, malleability and biocompatibility. Nowadays, advanced wound care products make up around 7.1 billion of the global market and their production is growing at an annual rate of 8.3 with the market projected to be worth 12.5 billion by 2022. The presented review focuses on novel hydrogel wound dressings, their main characteristics and their wound management applications. It also describes recent methodologies used for their production and the future potential developments

Etude de faisabilité de l'enquête European practice Assessment Cardio (prévention et gestion du risque cardiovasculaire en médecine générale)

Introduction Dans un contexte de morbi-mortalité cardiovasculaire encore élevée, l enquête EPA Cardio a pour but de comparer les performances en soins primaires et les caractéristiques des patients en Europe. Une étude de faisabilité est un préalable nécessaire à sa réalisation en France. Objectif Evaluer la faisabilité en France de l'enquête européenne EPA Cardio. Apporter des solutions aux problèmes rencontrés pour en faciliter la réalisation à l'échelle nationale. Méthode Notre étude était descriptive et menée par trois médecins généralistes volontaires. Trois groupes de patients étaient étudiés : maladie cardiovasculaire avérée (MCVA), haut risque cardiovasculaire (HRCV) et témoin (GT). L'étude était basée sur des questionnaires élaborés par une procédure Delphi et traduits préalablement en français. Ils renseignaient sur la performance clinique, des aspects organisationnels et l'engagement des cabinets dans les programmes de santé publique visant à améliorer la gestion du risque cardiovasculaire. Ils évaluaient aussi les facteurs de risque cardiovasculaire (régime alimentaire, tabagisme, exercice physique) des patients, leur observance et leur satisfaction vis-à-vis des soins prodigués. Résultats Le taux de réponse était supérieur à 90%. Les populations étaient homogènes. Le recrutement par les questionnaires était validé sur tous les items d évaluation. On dénombrait peu de données manquantes hormis pour l évaluation de l'utilité des conseils de prévention par les patients : l absence de réponse allait de 67 à 83% selon les items abordés. Des erreurs d inclusion ont été dénombrées : 7 AVC (19%) et 8 diabétiques (22%) dans le groupe MCVA, 4 diabétiques (10,5%) dans le groupe HRCV. Discussion - Conclusion Nous concluons à une bonne faisabilité prévisible de l étude en France. Une meilleure préparation des médecins a pour objectif une bonne adhésion à l'étude et un gain de temps pour une faisabilité de l étude nationale supérieure.PARIS6-Bibl. St Antoine CHU (751122104) / SudocSudocFranceF

Repopulation of intrahepatic bile ducts in engineered rat liver grafts

Engineered liver grafts for transplantation with sufficient hepatic function have been developed both in small and large animal models using the whole liver engineering approach. However, repopulation of the bile ducts in the whole liver scaffolds has not been addressed yet. In this study, we show the feasibility of repopulating the bile ducts in decellularized rat livers. Biliary epithelial cells were introduced into the bile ducts of the decellularized liver scaffolds with or without hepatocytes in the parenchymal space. The recellularized grafts were cultured under perfusion for up to 2 days and histological analysis revealed that the biliary epithelial cells formed duct-like structures, with the viable hepatocyte mass residing in the parenchymal space, in an arrangement highly comparable to the native tissue. The grafts were viable and functional as confirmed by both albumin and urea assay results and the gene expression analysis of biliary epithelial cells in recellularized liver grafts. This study provides the proof-of-concept results for rat liver grafts co-populated with parenchymal and biliary epithelial cells. </jats:p