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Nouvelles approches thérapeutiques pour réduire les réponses au stress associées aux dysfonctions cérébrovasculaires et réparatrices en situation diabétique par des principes actifs vectorisés

Abstract : Diabetes is a major health issue worldwide. It is characterized by hyperglycemia, insulin resistance and is associated with many microvascular and macrovascular complications. In diabetic conditions, methylglyoxal (MGO) levels are increased. MGO is a major precursor of advanced glycation end products (AGE) formation and it induces cellular oxidative stress, inflammation and endoplasmic reticulum (ER) stress. These cellular stresses play a crucial role in endothelial and blood brain barrier (BBB) dysfunctions and also delay the wound healing. My thesis objective was to improve the drug delivery of a plant derived compound (Curcumin). Curcumin has several beneficial properties such as antioxidant and anti-inflammatory properties but its effects are limited due to its hydrophobic nature. Nanovectors such as High Density Lipoprotein (HDL) or micelles may help to improve the delivery of curcumin. Curcumin vectorized by HDL or micelles were evaluated in two different models: in vitro brain endothelial cell protection from methylglyoxal and in vivo tail regeneration in Zebra fish. Curcumin loaded rHDL nanoparticles (Cur-rHDLs) were prepared by mixing HDL and curcumin briefly followed by ultracentrifugation. Amount of curcumin loaded was quantified by LC-MS/MS analysis. Brain endothelial cells (Bend3), were pre-treated with rHDL, curcumin and Cur-rHDLs for 1h before co-incubating with MGO. Cur-rHDLs showed a protective effect by reducing the cytotoxicity, reactive oxygen species (ROS) production, ER stress, and chromatin condensation induced by MGO. It also improved the endothelial cell integrity impaired by MGO. Cur-rHDLs showed a synergistic effect compared to curcumin or rHDL alone. Curcumin loaded carrageenan polysaccharide micelles (Cur-micelles) were prepared by using oligocarrageenan (digested carrageenan) copolymerized with polycaprolactone. Curcumin was loaded by acetone volatilization method. Cur-micelles were characterized by nuclear magnetic resonance analysis and dynamic light scattering analysis. On the Zebrafish tail amputation model, Cur-micelles increased macrophages and neutrophils recruitment to the site of tail injuryand had a positive impact on the tail regeneration by increasing the tail regenerative area. Curmicelles also showed a synergistic effect compared to curcumin or micelles alone. These studies show the potential beneficial effects of Cur-rHDLs and Cur-micelles on MGO stimulated endothelial cells and on zebrafish tail regeneration, respectively. They open new research perspectives to further investigate and understand the mechanisms that can be used to develop therapeutics for diabetic vascular complications.
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Submitted on : Monday, May 23, 2022 - 8:31:05 AM
Last modification on : Wednesday, May 25, 2022 - 3:34:34 AM

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2022LARE0005_SS_NARRA.pdf
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  • HAL Id : tel-03675252, version 1

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Sai Sandhya Narra. Nouvelles approches thérapeutiques pour réduire les réponses au stress associées aux dysfonctions cérébrovasculaires et réparatrices en situation diabétique par des principes actifs vectorisés. Biochimie, Biologie Moléculaire. Université de la Réunion; Central University of Tamil Nadu (Inde), 2022. Français. ⟨NNT : 2022LARE0005⟩. ⟨tel-03675252⟩

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