Combining PLGA microspheres loaded with Liver X receptor agonist GW3965 with a chitosan nerve conduit can promote the healing and regeneration of the wounded sciatic nerve.

Globally, peripheral nerve injury (PNI) is a common clinical issue. Successfully repairing severe PNIs has posed a major challenge for clinicians. GW3965 is a highly selective LXR agonist, and previous studies have demonstrated its positive protective effects in both central and peripheral nerve diseases. In this work, we examined the potential reparative effects of GW3965-loaded polylactic acid co-glycolic acid microspheres in conjunction with a chitosan nerve conduit for peripheral nerve damage. The experiment revealed that GW3965 promoted Schwann cell proliferation and neurotrophic factor release in vitro. In vivo experiments conducted on rats showed that GW3965 facilitated the restoration of motor function, promoted axon and myelin regeneration in the sciatic nerve, and enhanced the microenvironment of nerve regeneration. These results offer a novel therapeutic approach for the healing of nerve damage. Overall, this work provides valuable insights and presents a promising therapeutic strategy for addressing PNI.

Targeted delivery of LXR-agonists to atherosclerotic lesions mediated by polydiacetylene micelles.

We report the development of compact and stabilized micelles incorporating a synthetic LXR agonist prodrug for the passive targeting of atherosclerotic lesions and therapeutic intervention. In vivo studies showed that the nanohybrid micelles exhibited favorable pharmacokinetics/biodistribution and were able to upregulate, to some extent, LXR target genes with no alteration of lipid metabolism.

Juniper Berries Regulate Diabetes and Obesity Markers Through Modulating PPARα, PPARγ, and LXR: In Vitro and In Vivo Effects.

The berries of Juniperus communis have been traditionally used for therapeutic purposes. They have been reported to possess various pharmacological effects such as anti-inflammatory, hypoglycemic and hypolipidemic activities. In this study, a methanolic extract of J. communis berries (JB) was evaluated for its effects on peroxisome proliferator-activated receptors alpha and gamma (PPARα and PPARγ), liver X receptor (LXR), glucose uptake and lipid accumulation using various cellular systems. At a concentration of 25 µg/mL, JB caused 3.77-fold activation of PPARα, 10.90-fold activation of PPARγ, and 4.43-fold activation of LXR in hepatic cells. JB inhibited (11%) the adipogenic effect induced by rosiglitazone in adipocytes and increased glucose uptake (90%) in muscle cells. In high-fat diet (HFD) fed mice, JB at a dose of 25 mg/kg body weight exhibited a 21% decrease in body weight. Fasting glucose levels in mice treated with 12.5 mg/kg of JB were significantly decreased (39%) indicating its efficacy in regulating hyperglycemia and obesity induced by HFD thus ameliorating the symptoms of type 2 diabetes. A series of energy metabolic genes, including Sirt1 (2.00-fold) and RAF1 (2.04-fold), were upregulated by JB, while rosiglitazone regulated the hepatic PPARγ only. Phytochemical analysis of JB indicated presence of a number of flavonoids and biflavonoids which seem to be responsible for the observed activity. It was concluded that JB acted as a multiple agonist of PPARα, PPARγ and LXR without the undesired effect of adipogenesis and exhibited the property of enhancing glucose uptake. The regulation of PPARα, PPARγ and LXR seems to be through Sirt1 and RAF1. In vivo results confirmed the antidiabetic and antiobesity potential of JB and indicated its utility in metabolic disorder and type 2 diabetes.

Exploiting lipotoxicity for the treatment of liver cancer.

Metabolic alterations occur frequently in solid tumours, but metabolic cancer therapies are limited by the complexity and plasticity of metabolic networks. We could recently show that activation of the liver X receptor alpha (LXRα) and inhibition of a Raf-1-SCD1 protein complex induces an intracellular accumulation of saturated free fatty acids leading to lethal lipotoxicity in tumour cells and allows for an efficient treatment of liver carcinomas.

Peptide Amphiphile Supramolecular Nanostructures as a Targeted Therapy for Atherosclerosis.

The rising prevalence of cardiovascular disease worldwide necessitates novel therapeutic approaches to manage atherosclerosis. Intravenously administered nanostructures are a promising noninvasive approach to deliver therapeutics that reduce plaque burden. The drug liver X receptor agonist GW3965 (LXR) can reduce atherosclerosis by promoting cholesterol efflux from plaque but causes liver toxicity when administered systemically at effective doses, thus preventing its clinical use. The ability of peptide amphiphile nanofibers containing apolipoprotein A1-derived targeting peptide 4F to serve as nanocarriers for LXR delivery (ApoA1-LXR PA) in vivo is investigated here. These nanostructures are found to successfully target atherosclerotic lesions in a mouse model within 24 h of injection. After 8 weeks of intravenous administration, the nanostructures significantly reduce plaque burden in both male and female mice to a similar extent as LXR alone in comparison to saline-treated controls. Furthermore, they do not cause increased liver toxicity in comparison to LXR treatments, which may be related to more controlled release by the nanostructure. These findings demonstrate the potential of supramolecular nanostructures as safe, effective drug nanocarriers to manage atherosclerosis.