Abstract Background: Curcumin, as a lipid-lowering drug, has been reported to be effective in the treatment of breast cancer. However, the underlying molecular mechanisms have not been completely investigated. Methods: MTT assay was used to determine the effect of curcumin on survival rate of MCF-7 cells. The effects of curcumin on tumor growth were observed in animal models of breast cancer. The positive reactions of Caspase-1, IL-1β and IL-18 were detected by immunohistochemistry. LC3, p62, CTSB, ASC, Pro-Caspase-1, GSDMD, NLRP3, Caspase-1, GSDMD-N, IL-1β and IL-18 were determined by Western blot in vitro and vivo. The release of extracellular IL-1β and IL-18 was determined by ELISA. LDH release was measured. The expression level of CTSB in cytoplasm were determined by immunofluorescence assay. Cell proliferation, cell migration and tube formation assays were used to determine the abilities of cells. In this study, NLRP3 inflammasome inhibitor MCC950, cathepsin B inhibitor CA-074 ME and autophagy inhibitor 3-MA were used to act on cells to investigate the role of NLRP3 inflammasome, cathepsin B and autophagy in curcumin-induced pyroptosis of MCF-7 breast cancer cells. Results: In mouse model of breast cancer, we observed that curcumin treatment significantly induced cell autophagy and pyroptosis. In human breast cancer MCF-7 cells, we found that curcumin induced pyroptotic cell death was dependent on the activation of NLRP3/Caspase-1/GSDMD signaling pathway, which was CTSB-dependent. In addition, curcumin-induced cell autophagy caused lysosomal rupture and CTSB release. Furthermore, NLRP3 inhibitor (MCC950) significantly suppressed curcumin-induced pyroptosis, as well as CTSB inhibitor (CA074 Me) and autophagy inhibitor (3-MA). Besides, we also found that curcumin suppressed cell proliferation, cell migration and tube formation, which could be reversed by inhibitors. Conclusions: In summary, our results demonstrated that curcumin induced MCF-7 cell pyroptosis by the activation of autophagy/CTSB/NLRP3/Caspase-1/GSDMD signaling pathway. These findings offer novel insights into the potential molecular mechanisms of curcumin in treatment of breast cancer.
Dexterous in-hand manipulation for a multi-fingered anthropomorphic hand is extremely difficult because of the high-dimensional state and action spaces, rich contact patterns between the fingers and objects. Even though deep reinforcement learning has made moderate progress and demonstrated its strong potential for manipulation, it is still faced with certain challenges, such as large-scale data collection and high sample complexity. Especially, for some slight change scenes, it always needs to re-collect vast amounts of data and carry out numerous iterations of fine-tuning. Remarkably, humans can quickly transfer learned manipulation skills to different scenarios with little supervision. Inspired by human flexible transfer learning capability, we propose a novel dexterous in-hand manipulation progressive transfer learning framework (PTL) based on efficiently utilizing the collected trajectories and the source-trained dynamics model. This framework adopts progressive neural networks for dynamics model transfer learning on samples selected by a new samples selection method based on dynamics properties, rewards and scores of the trajectories. Experimental results on contact-rich anthropomorphic hand manipulation tasks show that our method can efficiently and effectively learn in-hand manipulation skills with a few online attempts and adjustment learning under the new scene. Compared to learning from scratch, our method can reduce training time costs by 95%.
Rationale Short‐chain fatty acids (SCFAs) are associated with intestinal microbiota and diseases in humans. SCFAs have a low response in mass spectrometry, and in order to increase sensitivity, reduce sample consumption, shorten analysis time, and simplify sample preparation steps, a derivatization method was developed. Methods We converted seven SCFAs into amide derivatives with 4‐aminomethylquinoline. The reaction occurred for 20 min at room temperature. The analytes were separated on a reversed‐phase C18 column and quantitated in the positive ion electrospray ionization mode using multiple reaction monitoring. Acetic acid‐d 4 was used as the stable‐isotope‐labeled surrogate analyte for acetic acid in the working solutions, while the other stable‐isotope‐labeled standards were used as internal standards (ISs). Results Method validation showed that the intra‐day and inter‐day precision of quantitation for the seven SCFAs over the whole concentration range was ≤3.8% ( n = 6). The quantitation accuracy ranged from 85.5% to 104.3% ( n = 6). Most important, the collected feces were vortexed immediately with ethanol. Conclusions This study provides a new derivatization method for a precise, accurate, and rapid quantitation of SCFAs in human feces using ultra‐performance liquid chromatography/tandem mass spectrometry. This method successfully determined the concentration of SCFAs in human feces and could assist in the exploration of intestinal microbiota and diseases.
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