Xingang Liu

Abnormal cholesterol metabolism is an established feature of Alzheimer's disease (AD). Cerebrospinal fluid (CSF) is the fluid surrounding the central nervous system, and the protein and lipid content alterations in the CSF could be biomarkers for degenerative changes in the brain. The laboratory diagnosis of AD is limited to the analysis of three biomarkers in CSF: Aβ42, total tau, and phospho-tau. The purpose of this analysis is to systematically analyze the available data describing the biomarkers of cholesterol and its metabolites in the CSF of subjects with AD. MEDLINE, EMBASE, and the Cochrane Central database were systematically queried to collect studies that have evaluated the markers of cholesterol and its metabolites in the CSF of subjects with mild cognitive impairment (MCI) or AD and age-matched controls. Analysis of the published data shows that the levels of cholesterol are increased in MCI subjects; 24-hydroxycholesterol and 27-hydroxycholesterol are elevated in AD and MCI subjects compared to controls. There is a significant dysfunction of cholesterol metabolism in the CSF of AD subjects. This analysis indicates that in addition to the available biomarkers in the CSF, such as Aβ42, total tau, and phospho-tau, 24-hydroxycholesterol, 27-hydroxycholesterol, and cholesterol appear to be sensitive biomarkers for the evaluation of MCI and AD.

The structural variability data of drug transporter (DT) are key for research on precision medicine and rational drug use. However, these valuable data are not sufficiently covered by the available databases. In this study, a major update of VARIDT (a database previously constructed to provide DTs' variability data) was thus described. First, the experimentally resolved structures of all DTs reported in the original VARIDT were discovered from PubMed and Protein Data Bank. Second, the structural variability data of each DT were collected by literature review, which included: (a) mutation-induced spatial variations in folded state, (b) difference among DT structures of human and model organisms, (c) outward/inward-facing DT conformations and (d) xenobiotics-driven alterations in the 3D complexes. Third, for those DTs without experimentally resolved structural variabilities, homology modeling was further applied as well-established protocol to enrich such valuable data. As a result, 145 mutation-induced spatial variations of 42 DTs, 1622 inter-species structures originating from 292 DTs, 118 outward/inward-facing conformations belonging to 59 DTs, and 822 xenobiotics-regulated structures in complex with 57 DTs were updated to VARIDT (https://idrblab.org/varidt/ and http://varidt.idrblab.net/). All in all, the newly collected structural variabilities will be indispensable for explaining drug sensitivity/selectivity, bridging preclinical research with clinical trial, revealing the mechanism underlying drug-drug interaction, and so on.

Protein-nanoparticle interactions are important in biomedical applications of nanoparticles and for growing biosafety concerns about nanomaterials. In this study, the interactions of four plasma proteins, human serum albumin (HSA), myoglobin (MB), hemoglobin (HB), and trypsin (TRP), with Au and Ag nanoparticles were investigated by FT-IR spectroscopy. The secondary structure of thio-proteins changed with time during incubation with Au and Ag nanoparticles, but the secondary structures of non-thio-proteins remained unchanged. The incubation time for structural changes depended on the sulfur-metal bond energy; the stronger the sulfur-metal energy, the less the time needed. H/D exchange experiments revealed that protein-NP complexes with thio-proteins were less dynamic than free proteins. No measurable dynamic differences were found between free non-thio-proteins and the protein-Au (or Ag) nanoparticle complex. Therefore, the impact of covalent bonds on the protein structure is greater than that of the electrostatic force.

Receptor-mediated delivery of hydrophobic antitumor drugs is of great interest in chemotherapy of tumors such as glioma. Specific expression of interleukin-13 (IL-13) receptor has been characterized in glioma. In this work, a specific peptide corresponding to the residues within IL-13 protein, designated as IP, was exploited, for the first time, as a glioma-targeting ligand. IP was conjugated to mesoporous silica nanoparticles (MSN) via bifunctional polyethyleneglycol (PEG), constructing the vector MSN–PEG–IP. The successful synthesis of MSN–PEG–IP was demonstrated via Fourier transform infrared spectroscopy. The transmission electron microscopy result showed that the size of MSN–PEG–IP was about 160 nm with an average pore diameter of around 2.6 nm. The cellular uptake of doxorubicin (DOX)-loading IP-modified system (MSN–PEG–IP/DOX) was concentration-dependent in glioma U251 cells. IP modification could significantly enhance the cellular uptake of the drug delivery system in U251 cells but not in normal astrocyte 1800 cells, compared to unmodified counterparts. This effect was further verified by cytotoxicity analysis. Furthermore, the intracellular trafficking result indicated that the loaded DOX was mostly accumulated in nuclei, even at very short incubation time (5 min). All the results suggested that IP could be applied as a special glioma-targeting ligand, and MSN–PEG–IP is a potential vector for delivering hydrophobic chemotherapeutic drugs to IL-13 receptor-overexpressed tumors.