Specific delivery of NCEH1 plasmid
is a promising approach to boost
the cholesterol removal from lipid-laden macrophages for antiatherosclerosis.
Polyethylenimine (PEI) is one of the most efficient gene carriers
among nonviral vectors. However, the high transfection activity of
PEI is always accompanied by profound cytotoxicity. To tackle the
paradox between transfection efficiency and safety, we constructed
a novel ATP-responsive multifunctional supramolecular polymer by cross-linking
functionalized low-molecular-weight PEI via a boronic ester bond for
NCEH1 plasmid delivery. The supramolecular polymer could condense
NCEH1 plasmids to form stable nanosized polyplexes when the w/w ratios
of the polymer and gene were higher than 2. ATP-triggered degradation
of the polymer and pDNA release were characterized by a series of
studies, including 1H NMR, 31P NMR, XPS, agarose
gel electrophoresis, and ethidium bromide exclusion tests. In addition,
the changes in particle size and morphology were observed in the presence
of ATP. Interestingly, the supramolecular polymer showed broad spectrum
antioxidant activities by measuring the elimination rates of different
reactive oxygen species. In addition, the supramolecular polymer displayed
a high buffering capability and good cytocompatibility as demonstrated
by the results of the buffering capacity, a hemolysis assay, and a
cytotoxicity test. Importantly, it was revealed that the supramolecular
polymer/NCEH1 plasmid polyplex formulated at a w/w ratio of 20 was
most effective in enhancing cholesterol removal from lipid-laden macrophages
and reducing the accumulation of lipid droplets as evidenced by transfection
study, cholesterol efflux assay, and oil red O staining studies. Collectively,
the ATP-responsive multifunctional supramolecular polymer holds great
potential for safe and efficient gene delivery for antiatherosclerosis.
Licorice flavonoids (LCFs) are natural flavonoids isolated from Glycyrrhiza which are known to have anti-melanoma activities in vitro. However, the molecular mechanism of LCF anti-melanoma has not been fully understood. In this study, network pharmacology, 3D/2D-QSAR, molecular docking, and molecular dynamics (MD) simulation were used to explore the molecular mechanism of LCF anti-melanoma. First of all, we screened the key active components and targets of LCF anti-melanoma by network pharmacology. Then, the logIC50 values of the top 20 compounds were predicted by the 2D-QSAR pharmacophore model, and seven highly active compounds were screened successfully. An optimal 3D-QSAR pharmacophore model for predicting the activity of LCF compounds was established by the HipHop method. The effectiveness of the 3D-QSAR pharmacophore was verified by a training set of compounds with known activity, and the possible decisive therapeutic effect of the potency group was inferred. Finally, molecular docking and MD simulation were used to verify the effective pharmacophore. In conclusion, this study established the structure–activity relationship of LCF and provided theoretical guidance for the research of LCF anti-melanoma.
Platinum-based chemotherapy is the first-line treatment for small cell lung cancer (SCLC). However, due to patients developing a resistance to the drug, most experience relapse and their cancer can become untreatable. A large number of recent studies have found that platinum drug sensitivity of various cancers is affected by specific gene mutations, and so with this study, we attempted to find an effective genetic biomarker in SCLC patients that indicates their sensitivity to platinum-based drugs. To do this, we first analyzed whole exome sequencing (WES) and clinical data from two cohorts to find gene mutations related to the prognosis and to the platinum drug sensitivity of SCLC patients. The cohorts used were the Zhujiang cohort (N = 138) and the cohort reported by George et al. (N = 101). We then carried out gene set variation analysis (GSVA) and gene set enrichment analysis (GSEA) to investigate possible molecular mechanisms through which these gene mutations affect patient prognosis and platinum drug sensitivity. We found that for SCLC patients, CAMSAP1 mutation can activate anti-tumor immunity, mediate tumor cell apoptosis, inhibit epithelial-mesenchymal transition (EMT), improve prognosis, and improve platinum drug sensitivity, suggesting that CAMSAP1 mutation may be a potential biomarker indicating platinum drug sensitivity and patient prognosis in SCLC.
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