The blood-brain barrier (BBB) severely blocks the intracranial accumulation of most systemic drugs. Inspired by the contribution of the bacterial outer membrane to Escherichia coli K1 (EC-K1) binding to and invasion of BBB endothelial cells in bacterial meningitis, utilization of the BBB invasion ability of the EC-K1 outer membrane for brain-targeted drug delivery and construction of a biomimetic self-assembled nanoparticle with a surface featuring a lipopolysaccharide-free EC-K1 outer membrane are proposed. BBB penetration of biomimetic nanoparticles is demonstrated to occur through the transcellular vesicle transport pathway, which is at least partially dependent on internalization, endosomal escape, and transcytosis mediated by the interactions between outer membrane protein A and gp96 on BBB endothelial cells. This biomimetic nanoengineering strategy endows the loaded drugs with prolonged circulation, intracranial interstitial distribution, and extremely high biocompatibility. Based on the critical roles of gp96 in cancer biology, this strategy reveals enormous potential for delivering therapeutics to treat gp96-overexpressing intracranial malignancies.
Receptor‐mediated vesicular transport has been extensively developed to penetrate the blood‐brain barrier (BBB) and has emerged as a class of powerful brain‐targeting delivery technologies. However, commonly used BBB receptors such as transferrin receptor and low‐density lipoprotein receptor‐related protein 1, are also expressed in normal brain parenchymal cells and can cause drug distribution in normal brain tissues and subsequent neuroinflammation and cognitive impairment. Here, the endoplasmic reticulum residing protein GRP94 is found upregulated and relocated to the cell membrane of both BBB endothelial cells and brain metastatic breast cancer cells (BMBCCs) by preclinical and clinical investigations. Inspired by that Escherichia coli penetrates the BBB via the binding of its outer membrane proteins with GRP94, avirulent DH5α outer membrane protein‐coated nanocapsules (Omp@NCs) are developed to cross the BBB, avert normal brain cells, and target BMBCCs via recognizing GRP94. Embelin (EMB)‐loaded Omp@EMB specifically reduce neuroserpin in BMBCCs, which inhibits vascular cooption growth and induces apoptosis of BMBCCs by restoring plasmin. Omp@EMB plus anti‐angiogenic therapy prolongs the survival of mice with brain metastases. This platform holds the translational potential to maximize therapeutic effects on GRP94‐positive brain diseases.
The morphological and vascular characteristics of the optic nerve head (ONH) of normal guinea pigs have not been fully recognized. Therefore, we aimed to investigate them using optical coherence tomography (OCT) and optical coherence tomography angiography (OCTA). We measured the refractive error, axial length, and intraocular pressure (IOP) and performed OCT and OCTA of the ONH of 3- and 4-week-old tricolour guinea pigs. A total of 208 right eyes from 208 normal guinea pigs were examined. The refractive error (both myopic and hyperopic) of the 3-week group was significantly higher than that of the 4-week group (p < 0.001), the IOP of the 3-week group was significantly lower than that of the 4-week group (p = 0.014), and the circumpapillary retinal nerve fibre layer (cpRNFL) of the 3-week group was significantly thicker than that of the 4-week group (p = 0.048). There were no significant differences in the average vessel area, vascular density, total number of junctions, total vessel length, total number of endpoints, and vascular diameter between the two groups. However, an age-adjusted linear regression analysis revealed that the total vessel length was positively associated with the cpRNFL thickness (p = 0.024) and negatively associated with IOP (p = 0.016). This is the first report on morphological and vascular characteristics of the ONH in normal guinea pigs based on in vivo OCT and OCTA imaging and quantification of ONH parameters. These results may contribute to further research on myopia using guinea pig models.
Skp2 participates in the regulation of cell growth cycle and promotes the growth of tumor cells. It was speculated that miR-590-5p could regulate the expression of Skp2 and have therapeutic effects on malignant melanin. In this study, the expression of Skp2 was detected by qRT-PCR and Western blot (WB), and the targeted binding between miR-590-5p and Skp2 was verified by dual luciferase reporting assay. Subsequently, cell proliferation activity was detected by CCK8, cell invasion was detected by Transwell, and cell apoptosis was detected by mitochondrial membrane potential assay. The results indicate that Skp2 is highly expressed in melanoma cells and inhibits the proliferation and invasion of melanoma cells. However, miR-590-5p can bind to Skp2 in a targeted manner. miR-590-5p is underexpressed in melanoma cells, and its overexpression can inhibit Skp2 expression and proliferation and invasion of melanoma cells. Our results showed that miR-590-5p could inhibit melanoma cell development by targeting Skp2. This study provides more therapeutic targets for the treatment of melanoma.
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