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Fei Xu Ming‐Liang Ye Yu‐Peng Zhang Wen‐Jie Li Meng‐Ting Li Hai‐Zhou Wang Xiao Qiu Yan Xu Jin‐Wen Yin Qian Hu Wan‐Hui Wei Ying Chang Lan Liu Qiu Zhao 《Cancer science》2020,111(5):1528-1541
Resistance to chemotherapy is a major challenge for the treatment of patients with colorectal cancer (CRC). Previous studies have found that microRNAs (miRNAs) play key roles in drug resistance; however, the role of miRNA‐373‐3p (miR‐375‐3p) in CRC remains unclear. The current study aimed to explore the potential function of miR‐375‐3p in 5‐fluorouracil (5‐FU) resistance. MicroRNA‐375‐3p was found to be widely downregulated in human CRC cell lines and tissues and to promote the sensitivity of CRC cells to 5‐FU by inducing colon cancer cell apoptosis and cycle arrest and by inhibiting cell growth, migration, and invasion in vitro. Thymidylate synthase (TYMS) was found to be a direct target of miR‐375‐3p, and TYMS knockdown exerted similar effects as miR‐375‐3p overexpression on the CRC cellular response to 5‐FU. Lipid‐coated calcium carbonate nanoparticles (NPs) were designed to cotransport 5‐FU and miR‐375‐3p into cells efficiently and rapidly and to release the drugs in a weakly acidic tumor microenvironment. The therapeutic effect of combined miR‐375 + 5‐FU/NPs was significantly higher than that of the individual treatments in mouse s.c. xenografts derived from HCT116 cells. Our results suggest that restoring miR‐375‐3p levels could be a future novel therapeutic strategy to enhance chemosensitivity to 5‐FU. 相似文献
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《药学学报(英文版)》2020,10(7):1294-1308
A great challenge in multi-targeting drug discovery is to identify drug-like lead compounds with therapeutic advantages over single target inhibitors and drug combinations. Inspired by our previous efforts in designing antitumor evodiamine derivatives, herein selective histone deacetylase 1 (HDAC1) and topoisomerase 2 (TOP2) dual inhibitors were successfully identified, which showed potent in vitro and in vivo antitumor potency. Particularly, compound 30a was orally active and possessed excellent in vivo antitumor activity in the HCT116 xenograft model (TGI = 75.2%, 150 mg/kg, p.o.) without significant toxicity, which was more potent than HDAC inhibitor vorinostat, TOP inhibitor evodiamine and their combination. Taken together, this study highlights the therapeutic advantages of evodiamine-based HDAC1/TOP2 dual inhibitors and provides valuable leads for the development of novel multi-targeting antitumor agents. 相似文献
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The specific role of postsynaptic activity for the generation of a functional magnetic resonance imaging (fMRI) response was determined by a simultaneous measurement of generated field excitatory postsynaptic potentials (fEPSPs) and blood oxygen level-dependent (BOLD) response in the rat hippocampal CA1 region during electrical stimulation of the contralateral CA3 region. The stimulation electrode was placed either in the left CA3a/b or CA3c, causing the preferentially basal or apical dendrites of the pyramidal cells in the right CA1 to be activated. Consecutive stimulations with low-intensity stimulation trains (i.e., 16 pulses for 8 seconds) resulted in clear postsynaptic responses of CA1 pyramidal cells, but in no significant BOLD responses. In contrast, consecutive high-intensity stimulation trains resulted in stronger postsynaptic responses that came along with minor (during stimulation of the left CA3a/b) or substantial (during stimulation of the left CA3c) spiking activity of the CA1 pyramidal cells, and resulted in the generation of significant BOLD responses in the left and right hippocampus. Correlating the electrophysiologic parameters of CA1 pyramidal cell activity (fEPSP and spiking activity) with the resultant BOLD response revealed no positive correlation. Consequently, postsynaptic activity of pyramidal cells, the most abundant neurons in the CA1, is not directly linked to the measured BOLD response. 相似文献