Catenin/CTNNB1 is critical for leukemia initiation or the stem cell capacity of several hematological malignancies. This review focuses on a general evaluation of -catenin function in normal T-cell development and T-cell acute lymphoblastic leukemia (T-ALL). The integration of the existing literature offers a state-of-the-art dissection of the complexity of -catenin function in leukemia initiation and maintenance in both Notch-dependent and independent contexts. In addition, -catenin mutations are screened for in T-ALL primary samples, and it is found that they are rare and with little clinical relevance. Transcriptional analysis of Wnt family members (Ctnnb1, Axin2, Tcf7, and Lef1) and Myc in different publicly available T-ALL cohorts indicates that the expression of these genes may correlate with T-ALL subtypes and/or therapy outcomes.
High-density lipoproteins (HDL) undergo adverse remodeling and loss of function in the presence of comorbidities. We assessed the potential of lipid-lowering approaches (diet and rosuvastatin) to rescue hypercholesterolemia-induced HDL dysfunction. Hypercholesterolemia was induced in 32 pigs for 10 days. Then, they randomly received one of the 30-day interventions: (I) hypercholesterolemic (HC) diet; (II) HC diet + rosuvastatin; (III) normocholesterolemic (NC) diet; (IV) NC diet + rosuvastatin. We determined cholesterol efflux capacity (CEC), antioxidant potential, HDL particle number, HDL apolipoprotein content, LDL oxidation, and lipid levels. Hypercholesterolemia time-dependently impaired HDL function (−62% CEC, −11% antioxidant index (AOI); p < 0.01), increased HDL particles numbers 2.8-fold (p < 0.0001), reduced HDL-bound APOM (−23%; p < 0.0001), and increased LDL oxidation 1.7-fold (p < 0.0001). These parameters remained unchanged in animals on HC diet alone up to day 40, while AOI deteriorated up to day 25 (−30%). The switch to NC diet reversed HDL dysfunction, restored apolipoprotein M content and particle numbers, and normalized cholesterol levels at day 40. Rosuvastatin improved HDL, AOI, and apolipoprotein M content. Apolipoprotein A-I and apolipoprotein C-III remained unchanged. Lowering LDL-C levels with a low-fat diet rescues HDL CEC and antioxidant potential, while the addition of rosuvastatin enhances HDL antioxidant capacity in a pig model of hypercholesterolemia. Both strategies restore HDL-bound apolipoprotein M content.
Increasing evidence has cast doubt over the HDL-cholesterol hypothesis. The complexity of the HDL particle and its proven susceptibility to remodel has paved the way for intense molecular investigation. This state-of-the-art review discusses the molecular changes in HDL particles that help to explain the failure of large clinical trials intending to interfere with HDL metabolism, and details the chemical modifications and compositional changes in HDL-forming components, as well as miRNA cargo, that render HDL particles ineffective. Finally, the paper discusses the challenges that need to be overcome to shed a light of hope on HDL-targeted approaches.
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