Noninvasive imaging of cell necrosis can provide an early evaluation of tumor response to treatments. Here, we aimed to design and synthesize a novel diindole-based magnetic resonance imaging (MRI) contrast agent (Gd-bis-DOTA-diindolylmethane, Gd-DIM) for assessment of tumor response to therapy at an early stage.
Procedures
The oil-water partition coefficient (Log P) and relaxivity of Gd-DIM were determined in vitro. Then, its necrosis avidity was examined in necrotic cells in vitro and in rat models with microwave ablation-induced muscle necrosis (MAMN) and ischemia reperfusion-induced liver necrosis (IRLN) by MRI. Visualization of tumor necrosis induced by combretastatin A-4 disodium phosphate (CA4P) was evaluated in rats bearing W256 orthotopic liver tumor by MRI. Finally, DNA binding assay was performed to explore the possible necrosis-avidity mechanism of Gd-DIM.
Results
The Log P value and T1 relaxivity of Gd-DIM is ??2.15?±?0.01 and 6.61 mM?1 s?1, respectively. Gd-DIM showed predominant necrosis avidity in vitro and in vivo. Clear visualization of the tumor necrosis induced by CA4P was achieved at 60 min after administration of Gd-DIM. DNA binding study indicated that the necrosis-avidity mechanism of Gd-DIM may be due to its binding to exposed DNA in necrotic cells.
Conclusion
Gd-DIM may serve as a promising necrosis-avid MRI contrast agent for early assessment of tumor response to therapy.
This study aimed to investigate the effects of paeoniflorin, the main active ingredient of the medicinal plant Paeonia lactiflora Pall., on the permeability of endothelial cells induced by lipopolysaccharide (LPS) and the underlying mechanisms. Human umbilical vein endothelial cells (HUVECs) were stimulated by LPS. Extravasated FITC-dextran reflecting permeability was assessed by multimode microplate reader, and the migration of bis-carboxyethyl-carboxyfluorescein acetoxy-methyl-labeled human acute monocytic leukemia cell line and leukemia cell line cells through HUVECs were analyzed by fluorescence microscopy. The phosphorylations of phosphatidylinositol 3-kinase (PI3K)/Akt, protein kinase C (PKC), and cofilin in HUVECs were assessed by western blotting, and the F-actin level was detected by laser scanning confocal microscopy. After LPS stimulation, inflammatory endothelial cells exhibited significantly increased permeability. Paeoniflorin (10, 30, and 100 μM) inhibited dextran extravasation and leukocyte migration through HUVECs induced by LPS in a concentration-dependent manner. Moreover, paeoniflorin was able to suppress the phosphorylations of PI3K/Akt, PKC, and cofilin, as well as F-actin reorganization in HUVECs induced by LPS. These findings revealed that paeoniflorin partly blocked LPS-induced endothelium permeability, supporting a new explanation for its anti-inflammatory effects. 相似文献
