Focal adhesion kinase (FAK) is a central component of focal adhesions that regulate cancer cell proliferation and migration. Here, we studied the effects of FAK inhibition in glioblastoma (GBM), a fast growing brain tumor that has a poor prognosis. Treating GBM cells with the FAK inhibitor PF-573228 induced a proliferative arrest and increased cell size. PF-573228 also reduced the growth of GBM neurospheres.
These effects were associated with increased p27/CDKN1B levels and β-galactosidase activity, compatible with acquisition of senescence. Interestingly, FAK inhibition repressed the expression of the autophagy cargo receptor p62/SQSTM-1. Moreover, depleting p62 in GBM cells also induced a senescent-like phenotype through transcriptional upregulation of p27.
Our results indicate that FAK inhibition arrests GBM cell proliferation, resulting in cell senescence, and pinpoint p62 as being key to this process. These findings highlight the possible therapeutic value of targeting FAK in GBM.
Topical Application of A New Herbal Complex, NI-01, Ameliorates House Dust Mite-Induced Atopic Dermatitis in NC/Nga Mice
Atopic dermatitis (AD) is a chronic inflammatory skin disease characterized by pruritus and cutaneous dry skin. Here, we investigated whether topical application of NI-01 composed of six herbal medicines has a therapeutic effect on AD in vivo. Twelve marker compounds of NI-01 were analyzed by high-performance liquid chromatography with a photodiode array detector for quality control.
To induce AD, house dust mite extract was applied to the shaved dorsal skin and ear surfaces of NC/Nga mice twice a week for 6 weeks. NI-01 (1, 2, or 4 mg/mouse) was applied daily to the site for experiment periods. The coefficient of determination of each compound showed good linearity (≥ 0.9999).
The recovery rate of the 12 marker components was 96.77%-105.17%; intra and interday precision and repeatability were ≤ 1.40%. Topical application of NI-01 reduced house dust mite induced AD symptoms. The increased expressions of interleukin-4 and intercellular adhesion molecule-1 caused by house dust mites were markedly suppressed in NI-01-treated mice. Corticosterone levels significantly decreased, whereas serotonin levels increased with NI-01 application.
These results suggest that NI-01 alleviates AD symptoms by inhibiting infiltration of inflammatory cells, thereby decreasing AD-related stress. NI-01 could be beneficial for the treatment of AD-like skin diseases.
A Polyhedral Oligomeric Silsesquioxane (POSS)-Incorporated Gelatin Hydrogel Promotes Angiogenesis During Vascularized Bone Regeneration
Many approaches have been made toward develop scaffolds with good biocompatibility and appreciable physicochemical properties to facilitate stem celladhesion, osteogenic differentiation and vascularization in tissue engineering. Nowadays, vascularization is a main bottleneck in tissue engineering strategies that needed to be overcome and innovated.
Herein, we construct a series of polyhedral oligomeric silsesquioxane modified porous gelatin hydrogels with different POSS concentrations from 0 to 5 wt %, defined as X% POSS hydrogels (X = 0, 1, 2, 3, 4, 5), to support vascularized bone repair.
The introduction of POSS into gelatin effectively promoted adhesive protein adsorption and Integrin α5β1 expression, subsequently leading to enhanced adhesion of both rat bone marrow mesenchymal stem cells (rBMSCs) and human umbilical vein endothelial cells (HUVECs). In vitro experiments further demonstrated that POSS-containing hybrid hydrogels more effectively support the angiogenic tube and network formation in HUVECs than the 0% POSS hydrogel.
Besides, POSS-containing hybrid hydrogels showed desirable performance as a sustained release system of vascular endothelial growth factor (VEGF) and bone morphogenetic protein (BMP-2), and they further accelerated vascular network establishment and the formation of new bone in defect regions.
When hydrogels were implanted into rat calvarial defects of critical-sized in vivo, the VEGF/BMP-2 coupled 3% POSS group gained higher blood vessel volume in the bone defect regions (5.49 ± 0.35 mm3) than the 3% POSS group (3.12 ± 0.20 mm3) and the 0% POSS group (1.57 ± 0.25 mm3), suggesting that the 3% POSS hydrogel with VEGF/BMP-2 would expedite vascularization.
Based on these evaluations, our results indicated that the POSS-incorporated gelatin hydrogel would provide a promising bone graft scheme in potential clinical application of large bone defect repair.