Two-Membrane Hybrid Nanobiomimetic Delivery System for Targeted Autophagy Inhibition of Activated Hepatic Stellate Cells To Synergistically Treat Liver Fibrosis.

Liver fibrosis is one of the most common and highly prevalent chronic liver diseases caused by multiple pathogenic factors, and there is still no effective therapeutic drugs up to now. The activated hepatic stellate cells (aHSCs) are the main executor in liver fibrosis, and the autophagy plays a key role in the proliferation and differentiation of aHSCs, which promotes the development of liver fibrosis. However, autophagy has the opposite effect on the different kinds of liver cells in the development of liver fibrosis, and the clinical treatment has been limited by the poor selectivity and inefficient drug delivery to aHSCs. Therefore, in this study, a liposome (Lip) and exosome (Exo) two-membrane hybrid nanobiomimetic delivery system HCQ@VA-Lip-Exo was designed, which was modified by vitamin A (VA) to target the aHSCs and carried the autophagy inhibitor hydroxychloroquine (HCQ). The experimental results in vitro and in vivo revealed that the constructed aHSC-targeted hybrid delivery system HCQ@VA-Lip-Exo combined with the benefits of HCQ and exosomes derived from bone marrow mesenchymal stem cells. HCQ@VA-Lip-Exo had good aHSC-targeted delivery ability, effective autophagy inhibition, and synergistical anti-liver fibrosis performance, thus reducing the production and deposition of the extracellular matrix to inhibit the liver fibrosis. This combined strategy provided a potential idea for the construction and clinical application of a two-membrane hybrid delivery system as an effective targeted therapy of liver fibrosis.

Glucagon-like peptide-1 cleavage product GLP-1(9-36) reduces neuroinflammation from stroke via the activation of insulin-like growth factor 1 receptor in astrocytes.

Glucagon-like peptide-1 (GLP-1) is an endogenous gut hormone and a key regulator in maintaining glucose homeostasis by stimulating insulin secretion. Its natural cleavage product GLP-1 (9-36), which was formerly considered a "bio-inactive" metabolite mainly due to its low affinity for GLP-1 receptor, possesses unique properties such as cardiovascular protection. Little is known about the effects and mechanisms of GLP-1 (9-36) in cerebral ischemia and reperfusion injury. Here, we report that systemic application of GLP-1 (9-36) in adult mice facilitated functional recovery and reduced infarct volume, astrogliosis, and neuronal apoptosis following middle cerebral artery occlusion and reperfusion. Interestingly, these effects were still observed in GLP-1 receptor knockout (Glp-1rKO) mice but were partially reversed in insulin-like growth factor 1 (IGF-1) receptor knockdown (Igf-1rKD) mice. Primary astrocytes were cultured and subjected to oxygen-glucose deprivation/reoxygenation (OGD/R), and enzyme-linked immunosorbent assay indicated that GLP-1 (9-36) pretreatment reduces tumor necrosis factor-α, interleukin (IL)-1ß, and IL-6 levels. This effect was not diminished in Glp-1rKO astrocytes but was reversed in Igf-1rKO astrocytes, emphasizing that the anti-inflammatory effect of GLP-1 (9-36) in astrocytes is independent of GLP-1 receptor signaling and is instead mediated by IGF-1 receptor. Immunoprecipitation experiments showed that GLP-1 (9-36) directly interacts with IGF-1 receptor in astrocytes. Western blot data indicated that GLP-1 (9-36) activates IGF-1 receptor and downstream PI3K-AKT pathway in astrocytes upon OGD/R injury, which was abrogated by preincubation with IGF-1 receptor autophosphorylation inhibitor picropodophyllin. Thus, our findings suggest that GLP-1 (9-36) improved stroke outcome by reducing inflammation in astrocytes via interaction with IGF-1 receptor.