PRDX6 inhibits hepatic stellate cells activation and fibrosis via promoting MANF secretion.

Hepatic fibrosis is a chronic inflammatory process with hepatic stellate cells (HSCs) activation. Peroxiredoxin 6 (PRDX6), a multifunctional protein, was reported to protect against liver injury induced by ischemia/reperfusion and high-fat diet. However, the effect of PRDX6 on hepatic fibrosis remains unclear. Male Sprague-Dawley rats were treated with carbon tetrachloride (CCl4) for 4-8 weeks to induce hepatic fibrosis. Here, we found that PRDX6 was mainly expressed in hepatocytes and significantly upregulated in CCl4-induced liver fibrosis. To clarify the impact of PRDX6 in hepatic fibrosis, we constructed a PRDX6 knockout (PRDX6-/-) rat model by using CRISPR/Cas9 method. We found that PRDX6 deficiency accelerated CCl4-induced liver fibrosis. Furthermore, we found that PRDX6 knockout promoted α-SMA expression in normal and fibrotic conditions, especially in hepatic fibrosis. PRDX6 knockout significantly upregulated Col1α1 and Col3α1 in fibrotic tissues. To explore the underlying mechanisms, we identified mesencephalic astrocyte-derived neurotrophic factor (MANF), a suppressor for hepatic fibrosis and NF-κB pathway, as an interacting protein of PRDX6. PRDX6 promoted MANF secretion by binding to the C-terminus of MANF, which did not depend on its peroxidase and PLA2 activities. Similarly, MANF increased PRDX6 protein level and promoted its secretion. Additionally, PRDX6 knockout increased p65 level either in cytoplasm or nuclei in HSCs under fibrotic condition. In conclusion, PRDX6 is an effective inhibitor for hepatic fibrosis through a non-enzymic dependent interacting with MANF, which will offer a potential target for hepatic fibrosis therapy.

Lactoferrin modified graphene oxide iron oxide nanocomposite for glioma-targeted drug delivery.

Targeting delivery of drugs in a specific manner represents a potential powerful technology in gliomas. Herein, we prepared a multifunctional targeted delivery system based on graphene oxide (GO) that contains a molecular bio-targeting ligand and superparamagnetic iron oxide nanoparticles on the surface of GO for magnetic targeting. Superparamagnetic Fe3O4 nanoparticles was loaded on the surface of GO via chemical precipitation method to form GO@Fe3O4 nanocomposites. Lactoferrin (Lf), an iron-transporting serum glycoprotein that binds to receptors overexpressed at the surface of glioma cells and vascular endothelial cell of the blood brain barrier, was chosen as the targeted ligand to construct the targeted delivery system Lf@GO@Fe3O4 through EDC/NHS chemistry. With the confirmation of TEM, DLS and VSM, the resulting Lf@GO@Fe3O4 had a size distribution of 200-1000nm and exhibited a superparamagnetic behavior. The nano delivery system had a high loading capacity and exhibited a pH-dependent release behavior. Compared with free DOX and DOX@GO@Fe3O4, Lf@GO@Fe3O4@DOX displayed greater intracellular delivery efficiency and stronger cytotoxicity against C6 glioma cells. The results demonstrated the potential utility of Lf conjugated GO@Fe3O4 nanocomposites for therapeutic application in the treatment of gliomas.