ABSTRACT
METHODS: Immunohistochemical staining, sequencing, and genetic analysis of liver cancer tissues were performed. The antitumor efficacy of single-agent or combination treatment was measured by cell counting kit-8 assay and colony formation assays. Their antiproliferative and apoptosis activity is evaluated by cell cycle analyses and wound healing assays. The DNA-related proteins were also measured by Western blotting and immunohistochemical staining. The HepG2 xenograft model was used to detect the effects of lenvatinib-alisertib on the antitumor activity. RESULTS: AURKA was found to be upregulated in HCC tissues (77.3%, 17/22). Combined alisertib and lenvatinib treatment significantly enhanced the inhibition of proliferation and migration in HepG2 and Hep3B cell lines compared to single-agent treatments (all Ps < 0.01). Alisertib alone or in combination with lenvatinib demonstrated a significant increase in the percentage of super-G2 cells (lenvatinib 1 µM vs. lenvatinib 1 µM + alisertib 0.1 µM 8.84 ± 0.84 vs. 34.0 ± 1.54, P < 0.001). Discontinuous spindles and missegregated chromosomes in HCC cells treated with alisertib in combination with lenvatinib were observed. We further revealed that combined treatment inhibited the expression of DNA damage pathway proteins compared to those of single-agent treatments. In nude mice, combined administration of alisertib combined with lenvatinib significantly enhanced the suppression of tumor growth and induced apoptosis (all Ps < 0.01). CONCLUSIONS: Our findings provide evidence for the possible use of alisertib in combination with lenvatinib in the treatment of HCC for better therapeutic outcomes.
Subject(s)
Antineoplastic Agents/therapeutic use , Azepines/therapeutic use , Carcinoma, Hepatocellular/drug therapy , DNA Damage , Liver Neoplasms/drug therapy , Phenylurea Compounds/therapeutic use , Pyrimidines/therapeutic use , Quinolines/therapeutic use , Animals , Antineoplastic Agents/pharmacology , Apoptosis/drug effects , Aurora Kinase A/metabolism , Carcinoma, Hepatocellular/pathology , Cell Death/drug effects , Cell Proliferation/drug effects , Female , Liver Neoplasms/pathology , Mice, Inbred BALB C , Mice, Nude , Models, Biological , Neoplasm Metastasis , Signal Transduction/drug effects , Up-RegulationABSTRACT
Owing to the high morbidity and mortality of cardiovascular diseases resulting from atherosclerosis, developing specific noninvasive diagnostic methods to distinguish vulnerable atherosclerotic plaques becomes urgent and mandatory. Herein, scavenger receptors AI (SR-AI), a secreted biomarker associated with foam macrophages, was selected as a target for identifying vulnerable plaques. A dual-modality imaging probe (PP1-Au@GSH@Gd NCs) was constructed by covalently attaching a peptidic SR-AI ligand, PP1 to gadolinium-integrated gold nanoclusters, which exhibited remarkably improved fluorescence signal and longitudinal relaxivity with highly loaded Au and Gd species. In vitro cellular binding studies showed preferential affinity of PP1-Au@GSH@Gd NCs to activated macrophages in SR-AI-dependent manner. In vivo MR/fluorescence images presented robust and prolonged plaque contrast enhancement in established ApoE-/- mice models thanks to favorable targeting efficacy of PP1-Au@GSH@Gd NCs. Collectively, the noninvasive MR/fluorescence molecular imaging strategy with PP1-Au@GSH@Gd NCs holds great promise for precise clinical diagnosis of vulnerable plaques.
Subject(s)
Gold/chemistry , Magnetic Resonance Imaging , Metal Nanoparticles/chemistry , Particle Size , Plaque, Atherosclerotic/diagnostic imaging , Receptors, Scavenger/metabolism , Animals , Aorta/diagnostic imaging , Aorta/drug effects , Aorta/pathology , Apolipoproteins E/deficiency , Apolipoproteins E/metabolism , Carotid Arteries/diagnostic imaging , Carotid Arteries/drug effects , Carotid Arteries/pathology , Cell Death/drug effects , Fluorescence , Gadolinium/chemistry , Macrophage Activation/drug effects , Metal Nanoparticles/ultrastructure , Mice , Mice, Inbred C57BL , Plaque, Atherosclerotic/pathology , Pyrazoles/pharmacology , Pyrimidines/pharmacology , RAW 264.7 Cells , Tissue DistributionABSTRACT
By changing -COOH content in poly(acrylic acid-co-methacryloxypropyl trimethoxy silane (poly(AA-co-γ-MPS)), a series of PVA/SiO(2) cation exchange membranes are prepared from sol-gel process of poly(AA-co-γ-MPS) in presence of poly(vinyl alcohol) (PVA). The membranes have the initial decomposition temperature (IDT) values of 236-274 °C. The tensile strength (TS) ranges from 17.4 MPa to 44.4 MPa. The dimensional stability in length (DS-length) is in the range of 10%-25%, and the DS-area is in the range of 21%-56% in 65 °C water. The water content (W(R)) ranges from 61.2% to 81.7%, the ion exchange capacity (IEC) ranges from 1.69 mmol/g to 1.90 mmol/g. Effects of -COOH content on diffusion dialysis (DD) performance also are investigated for their potential applications. The membranes are tested for recovering NaOH from the mixture of NaOH/Na(2)WO(4) at 25 - 45 °C. The dialysis coefficients of NaOH (U(OH)) are in the range of 0.006-0.032 m/h, which are higher than those of the previous membranes (U(OH): 0.0015 m/h, at 25 °C). The selectivity (S) can reach up to 36.2. The DD performances have been correlated with the membrane structure, especially the continuous arrangement of -COOH in poly(AA-co-γ-MPS) chain.
