Curcumin inhibits viability and promotes apoptosis by modulating miR-17/caspase-9 pathway in colorectal cancer

Purpose: To investigate the mechanism of curcumin effect on colorectal cancer cells. Methods: The miR-17-5p and caspase-9 were measured using quantitative real time polymerase chain reaction (qRT-PCR) and western blotting in colorectal cancer tissues or cells with or without curcumin treatment. The binding sites between miR-17-5p and caspase-9 were predicted by TargetScan and verified by luciferase assay. The miR-17-5p mimics were transfected into colorectal cells to determine its effects. The overexpressing miR-17-5p mimics and a caspase-9 plasmid were co-transfected into colorectal cells to explore the underlying mechanism. In addition, an in vivo experiment was performed in a mouse model after injection of HCT116 cells to determine the role of curcumin. Results: MiR-17-5p was upregulated in colorectal cancer tissues and cells. Curcumin treatment inhibits viability and induces apoptosis of colorectal cancer cells. MiR-17-5p inhibits viability and induces apoptosis of colorectal cancer cells by regulating the expression of caspase-9. Mechanism studies showed that curcumin induced colorectal cell apoptosis by regulation of caspase-9 expression via miR17-5p. Finally, the animal results demonstrated the anti-tumor activity of curcumin in vivo. Conclusion: The findings of this study indicate that curcumin suppresses cell apoptosis and induce cell viability by regulating miR-17-5p and caspase-9 in colorectal cancer

Arabinogalactan Proteins Are the Possible Extracellular Molecules for Binding Exogenous Cerium(III) in the Acidic Environment Outside Plant Cells

Rare earth elements [REE(III)] increasingly accumulate in the atmosphere and can be absorbed by plant leaves. Our previous study showed that after treatment of REE(III) on plant, REE(III) is first bound by some extracellular molecules of plant cells, and then the endocytosis of leaf cells will be initiated, which terminates the endocytic inertia of leaf cells. Identifying the extracellular molecules for binding REE(III) is the crucial first step to elucidate the mechanism of REE(III) initiating the endocytosis in leaf cells. Unfortunately, the molecules are unknown. Here, cerium(III) [Ce(III)] and Arabidopsis served as a representative of REE(III) and plants, respectively. By using interdisciplinary methods such as confocal laser scanning microscopy, immune-Au and fluorescent labeling, transmission electron microscope (TEM), X-ray photoelectron spectroscopy (XPS), ultraviolet-visible spectroscopy, circular dichroism spectroscopy, fluorescent spectrometry and molecular dynamics simulation, we obtained two important discoveries: first, the arabinogalactan proteins (AGP) inside leaf cells were sensitively increased in protein expression and recruited onto the plasma membrane; second, to verify whether AGP can bind to Ce(III) in the acidic environment outside leaf cells, by choosing fasciclin-like AGP11 (AtFLA11) as a representative of AGP, we found that Ce(III) can form stable [Ce(H2O)7](III)-AtFLA11 complexes with an apparent binding constant of 1.44 × 10−6 in simulated acidic environment outside leaf cells, in which the secondary and tertiary structure of AtFLA11 was changed. The structural change in AtFLA11 and the interaction between AtFLA11 and Ce(III) were enhanced with increasing the concentration of Ce(III). Therefore, AtFLA11 can serve as Lewis bases to coordinately bind to Ce(III), which broke traditional chemical principle. The results confirmed that AGP can be the possible extracellular molecules for binding to exogenous Ce(III) outside leaf cells, and provided references for elucidating the mechanism of REE(III) initiating the endocytosis in leaf cells

Teleconnections among tipping elements in the Earth system

Tipping elements are components of the Earth system that may shift abruptly and irreversibly from one state to another at specific thresholds. It is not well understood to what degree tipping of one system can influence other regions or tipping elements. Here, we propose a climate network approach to analyse the global impacts of a prominent tipping element, the Amazon Rainforest Area (ARA). We find that the ARA exhibits strong correlations with regions such as the Tibetan Plateau (TP) and West Antarctic ice sheet. Models show that the identified teleconnection propagation path between the ARA and the TP is robust under climate change. In addition, we detect that TP snow cover extent has been losing stability since 2008. We further uncover that various climate extremes between the ARA and the TP are synchronized under climate change. Our framework highlights that tipping elements can be linked and also the potential predictability of cascading tipping dynamics.Peer reviewe

Teleconnections among tipping elements in the Earth system

Tipping elements are components of the Earth system that may shift abruptly and irreversibly from one state to another at specific thresholds. It is not well understood to what degree tipping of one system can influence other regions or tipping elements. Here, we propose a climate network approach to analyse the global impacts of a prominent tipping element, the Amazon Rainforest Area (ARA). We find that the ARA exhibits strong correlations with regions such as the Tibetan Plateau (TP) and West Antarctic ice sheet. Models show that the identified teleconnection propagation path between the ARA and the TP is robust under climate change. In addition, we detect that TP snow cover extent has been losing stability since 2008. We further uncover that various climate extremes between the ARA and the TP are synchronized under climate change. Our framework highlights that tipping elements can be linked and also the potential predictability of cascading tipping dynamics

Downregulating Notch counteracts KrasG12D-induced ERK activation and oxidative phosphorylation in myeloproliferative neoplasm.

The Notch signaling pathway contributes to the pathogenesis of a wide spectrum of human cancers, including hematopoietic malignancies. Its functions are highly dependent on the specific cellular context. Gain-of-function NOTCH1 mutations are prevalent in human T-cell leukemia, while loss of Notch signaling is reported in myeloid leukemias. Here, we report a novel oncogenic function of Notch signaling in oncogenic Kras-induced myeloproliferative neoplasm (MPN). We find that downregulation of Notch signaling in hematopoietic cells via DNMAML expression or Pofut1 deletion significantly blocks MPN development in KrasG12D mice in a cell-autonomous manner. Further mechanistic studies indicate that inhibition of Notch signaling upregulates Dusp1, a dual phosphatase that inactivates p-ERK, and downregulates cytokine-evoked ERK activation in KrasG12D cells. Moreover, mitochondrial metabolism is greatly enhanced in KrasG12D cells but significantly reprogrammed by DNMAML close to that in control cells. Consequently, cell proliferation and expanded myeloid compartment in KrasG12D mice are significantly reduced. Consistent with these findings, combined inhibition of the MEK/ERK pathway and mitochondrial oxidative phosphorylation effectively inhibited the growth of human and mouse leukemia cells in vitro. Our study provides a strong rational to target both ERK signaling and aberrant metabolism in oncogenic Ras-driven myeloid leukemia