ABSTRACT
Alzheimer's disease (AD) and related dementias constitute an important global health challenge. Detailed understanding of the multiple molecular mechanisms underlying their pathogenesis constitutes a clue for the management of the disease. Kallikrein-related peptidases (KLKs), a lead family of serine proteases, have emerged as potential biomarkers and therapeutic targets in the context of AD and associated cognitive decline. Hence, KLKs were proposed to display multifaceted impacts influencing various aspects of neurodegeneration, including amyloid-beta aggregation, tau pathology, neuroinflammation, and synaptic dysfunction. We propose here a comprehensive survey to summarize recent findings, providing an overview of the main kallikreins implicated in AD pathophysiology namely KLK8, KLK6 and KLK7. We explore the interplay between KLKs and key AD molecular pathways, shedding light on their significance as potential biomarkers for early disease detection. We also discuss their pertinence as therapeutic targets for disease-modifying interventions to develop innovative therapeutic strategies aimed at halting or ameliorating the progression of AD and associated dementias.
ABSTRACT
Biocompatible and biodegradable polymers are widely used in the medical field. In some cases, the biopolymer is accompanied by an active drug, which is delivered locally in a controlled manner in order to improve the healing conditions. Poly([R,S]-3,3-dimethylmalic acid) (PDMMLA) is a synthetic amphiphilic biodegradable polymer, which unlike PLA, can be chemically modified to adapt hydrophilic/hydrophobic balance, degradation kinetics, and physicochemical and biological properties. It may contain a lateral alkyl group or a functional group for coupling bioactive molecules to release during its degradation. In this work, we realized the chemical grafting of paclitaxel (PTX), a microtubule stabilizing anti-cancer agent on PDMMLA derivatives bio-polyesters following a Steglich esterification protocol. 1D and 2D NMR analyses validated the reaction with 10% (using 0.1 equivalent) of PTX on the copolymer PDMMLAH40-co-Hex60 (PDMMLA 40/60) and a maximal PTX grafting rate of 55% on the homopolymer PDMMLAH (PDMMLA 100/0). In vitro adhesion and cytotoxicity assays were carried out on HUVEC cells with PDMMLA 40/60, PDMMLA-PTX 30/10/60 and PLA.
ABSTRACT
Atherosclerosis, in the ultimate stage of cardiovascular diseases, causes an obstruction of vessels leading to ischemia and finally to necrosis. To restore vascularization and tissue regeneration, stimulation of angiogenesis is necessary. Chemokines and microRNAs (miR) were studied as pro-angiogenic agents. We analysed the miR-126/CXCL12 axis and compared impacts of both miR-126-3p and miR-126-5p strands effects in CXCL12-induced angiogenesis. Indeed, the two strands of miR-126 were previously shown to be active but were never compared together in the same experimental conditions regarding their differential functions in angiogenesis. In this study, we analysed the 2D-angiogenesis and the migration assays in HUVEC in vitro and in rat's aortic rings ex vivo, both transfected with premiR-126-3p/-5p or antimiR-126-3p/-5p strands and stimulated with CXCL12. First, we showed that CXCL12 had pro-angiogenic effects in vitro and ex vivo associated with overexpression of miR-126-3p in HUVEC and rat's aortas. Second, we showed that 2D-angiogenesis and migration induced by CXCL12 was abolished in vitro and ex vivo after miR-126-3p inhibition. Finally, we observed that SPRED-1 (one of miR-126-3p targets) was inhibited after CXCL12 treatment in HUVEC leading to improvement of CXCL12 pro-angiogenic potential in vitro. Our results proved for the first time: 1-the role of CXCL12 in modulation of miR-126 expression; 2-the involvement of miR-126 in CXCL12 pro-angiogenic effects; 3-the involvement of SPRED-1 in angiogenesis induced by miR-126/CXCL12 axis.
