Notch signaling pathway is evolutionarily conserved in mammals, which plays an important role in cell development and differentiation. In recent years, increasing evidence has shown that aberrant ...activation of Notch is associated with tumor process. Aberrant activation of Notch signaling pathway has been found in many different solid tumors can induce cell proliferation, metastasis and epithelial-mesenchymal transition. Notch receptor and its ligand are both single transmembrane protein, and Notch is activated when it binds to the Notch ligand of neighbor cells. The signal transduction of Notch signaling pathway is only between cells that are in contact with each other, which is independent of second messengers. Thus, Notch needs to cross talk with other signaling pathways, including PI3K/AKT, NF-κB, integrin and miRNAs, to precisely regulate cell fate. In this review, we summarize the roles of Notch signaling pathway in tumor metastasis and its regulatory mechanisms and discuss the current treatment strategies targeting Notch signal pathway.
Type 2 diabetes mellitus (T2DM) is a metabolic disease primarily characterized by insulin resistance (IR) and insufficient insulin secretion. The unfolded protein response (UPR) overactivation ...induced by endoplasmic reticulum stress (ERS) appears to play a key role in this process, although the exact pathogenesis of T2DM is not fully understood. Studies have demonstrated that appropriate exercise can regulate ERS in the heart, liver, pancreas, skeletal muscle, and other body tissues leading to an improvement in diabetes and its complications. However, the exact mechanism remains unclear. By analyzing the relationship between ERS, T2DM pathology, and exercise intervention, this review concludes that exercise can increase insulin sensitivity, inhibit IR, promote insulin secretion and alleviate T2DM by regulating ERS. This paper specifically reviews the signaling pathways by which ERS induces diabetes, the mechanisms of exercise regulation of ERS in diabetes, and the varying effects of different types of exercise on diabetes improvement through ERS mechanisms. Physical exercise is an effective non-pharmacological intervention for T2DM. Thus, further exploration of how exercise regulates ERS in diabetes could refine "precision exercise medicine" for diabetes and identify new drug targets.
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•Endoplasmic reticulum stress is involved in the occurrence and development of type 2 diabetes.•Exercise can improve diabetes by regulating endoplasmic reticulum stress.•Different types of exercise have varying effects on regulating diabetes.
The aberrant activation of Notch-1 signaling pathway has been proven to be associated with the development and progression of cancers. However, the specific roles and the underlying mechanisms of ...Notch-1 signaling pathway on the malignant behaviors of breast cancer are poorly understood. In this study, using multiple cellular and molecular approaches, we demonstrated that activation of Notch-1 signaling pathway promoted the malignant behaviors of MDA-MB-231 cells such as increased cell proliferation, colony formation, adhesion, migration, and invasion, and inhibited apoptosis; whereas deactivation of this signaling pathway led to the reversal of the aforementioned malignant cellular behaviors. Furthermore, we found that activation of Notch-1 signaling pathway triggered the activation of NF-κB signaling pathway and up-regulated the expression of NF-κB target genes including MMP-2/-9, VEGF, Survivin, Bcl-xL, and Cyclin D1. These results suggest that Notch-1 signaling pathway play important roles in promoting the malignant phenotype of breast cancer, which may be mediated partly through the activation of NF-κB signaling pathway. Our results further suggest that targeting Notch-1 signaling pathway may become a newer approach to halt the progression of breast cancer.
Encapsulated gas microbubbles are well known as ultrasound contrast agents for medical ultrasound imaging. Nonetheless, not only do these microbubbles help to image, but they can also be used as ...drug/gene carriers. The microbubbles as drug/gene carriers have an average size less than that of red blood cells, i.e. they are capable of penetrating even into the small blood capillaries and releasing drug and genes under the action of ultrasound field. The application of ultrasound and microbubbles to targeted drug and gene delivery has been the subject of intense experimental research. Under exposure of sufficiently high-amplitude ultrasound, these targeted microbubbles would rupture, spewing drugs or genes, which are contained in its encapsulating layer, to targeted cells or tissues. Recently, targeting ligands are attached to the surface of the microbubbles (i.e. targeted-microbubbles), which have been widely used in cardiovascular system and tumor diagnosis and therapy. In this paper, the characterization of novel targeted ultrasonic contrast agents or microbubbles and their potential applications in drug delivery or gene therapy are reviewed.
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Tumors are characterized by extracellular matrix (ECM) remodeling and stiffening. The importance of ECM stiffness in cancer is well known. However, the biomechanical behavior of tumor ...cells and the underlying mechanotransduction pathways remain unclear. Here, we used polyacrylamide (PAA) substrates to simulate tissue stiffness at different progress stages of breast cancer in vitro, and we observed that moderate substrate stiffness promoted breast cancer cell motility. The substrate stiffness directly activated integrin β1 and focal adhesion kinase (FAK), which accelerate focal adhesion (FA) maturation and induce the downstream cascades of intracellular signals of the RhoA/ROCK pathway. Interestingly, the differential regulatory mechanism between two ROCK isoforms (ROCK1 and ROCK2) in cell motility and mechanotransduction was clearly identified. ROCK1 phosphorylated the myosin regulatory light chain (MRLC) and facilitated the generation of traction force, while ROCK2 phosphorylated cofilin and regulated the cytoskeletal remodeling by suppressing F-actin depolymerization. The ROCK isoforms differentially regulated the pathways of RhoA/ROCK1/p-MLC and RhoA/ROCK2/p-cofilin in a coordinate fashion to modulate breast cancer cell motility in a substrate stiffness-dependent manner through integrin β1-activated FAK signaling. Our findings provide new insights into the mechanisms of matrix mechanical property-induced cancer cell migration and malignant behaviors.
Here, we examined the relationship between substrate stiffness and tumor cellular motility by using polyacrylamide (PAA) substrates to simulate the stages in vivo of breast cancer. The results elucidated the different regulatory roles between the two ROCK isoforms in cell motility and demonstrated that stiff substrate (38 kPa) mediated RhoA/ROCK1/p-MLC and RhoA/ROCK2/p-cofilin pathways through integrin β1-FAK activation and eventually promoted directional migration. Our discoveries would have significant implications in the understanding of the interaction between cancer cells and tumor microenvironments, and hence, it might provide new insights into the metastasis inhibition, which could be an adjuvant way of cancer therapy.
Catalytic/initiated cracking of endothermic hydrocarbon fuels is an effective technology for cooling a hypersonic aircraft with a high Mach number (over 5). Catalysts and initiators can promote fuel ...cracking at low temperatures, increase fuel conversion and the heat sink capacity, and suppress coke deposition, thereby reducing waste heat. Catalysts mainly include metal oxide catalysts, noble metal catalysts and metal nanoparticles, zeolite catalysts, nanozeolite catalysts, and coating catalysts. Moreover, initiators roughly include nitrogenous compounds, oxygenated compounds, and hyperbranched polymer initiators. In this review, we aim to summarize the catalysts and initiators for cracking endothermic hydrocarbon fuels and their mechanisms for promoting cracking. This review will facilitate the development of the synthesis and exploration of catalysts and initiators.
BACKGROUND AND PURPOSE Emodin 1,3,8‐trihydroxy‐6‐methylanthraquinone has been reported to exhibit vascular anti‐inflammatory properties. However, the corresponding mechanisms are not well understood. ...The present study was designed to explore the molecular target(s) of emodin in modifying lipopolysaccharide (LPS)‐associated signal transduction pathways in endothelial cells.
EXPERIMENTAL APPROACH Cultured primary human umbilical vein endothelial cells (HUVECs; passages 3–5) were pre‐incubated with emodin (1–50 µg·mL−1). LPS‐induced expression of pro‐inflammatory cytokines interleukin (IL)‐1β, IL‐6 and chemokines (IL‐8; CCL2/MCP‐1) were determined by reverse transcription‐PCR and elisa. Nuclear factor‐κB (NF‐κB) activation, inhibitor of κB (IκB)α degradation and Toll‐like receptor‐4 (TLR‐4) were detected by immunocytochemistry and Western blotting. Cholesterol depletion by methyl β‐cyclodextrin (MBCD), a specific cholesterol binding agent and cholesterol replenishment were further used to investigate the roles of lipid rafts in activation of HUVECs.
KEY RESULTS Emodin inhibited, concentration‐dependently, the expression of LPS‐induced pro‐inflammatory cytokines (IL‐1β, IL‐6) and chemokines (IL‐8, CCL2) and, in parallel, inhibited NF‐κB activation and IκBα degradation in HUVECs. However, emodin did not inhibit the NF‐κB activation and IκBα degradation induced by IL‐1β. The cholesterol binding agent, MBCD, inhibited LPS‐induced NF‐κB activation in passaged HUVECs which also lack the LPS receptor, membrane CD14 (mCD14), showing that lipid rafts played a key role in LPS signalling in mCD14‐negative HUVECs. Moreover, emodin disrupted the formation of lipid rafts in cell membranes by depleting cholesterol.
CONCLUSIONS AND IMPLICATIONS Lipid rafts were crucial in facilitating inflammatory responses of mCD14‐negative HUVECs to LPS. Emodin disrupted lipid rafts through depleting cholesterol and, consequently, inhibited inflammatory responses in endothelial cells.
Cancer cells are subjected to fluid shear stress during passage through the venous and lymphatic system. Caveolin-1 (Cav-1), a principal structural component of caveolar membrane domains, contributes ...to cancer development but its mechanobiological roles under low shear stress (LSS) conditions remain largely unknown. Here, we identified Cav-1 is mechanosensitive to LSS exposure, and its activation-induced PI3K/Akt/mTOR signaling promotes motility, invadopodia formation and metastasis of breast carcinoma MDA-MB-231 cells. Application of LSS (1.8 and 4.0 dynes/cm2) to MDA-MB-231 cells significantly increased the cell motility, invadopodia formation, MT1-MMP expression, ECM degradation, and also induced a sustained activation of Cav-1 and PI3K/Akt/mTOR signaling cascades. Methyl-β-cyclodextrin-caused caveolae destruction markedly decreased LSS-induced activation of both Cav-1 and PI3K/Akt/mTOR, leading to suppress MT1-MMP expression, inhibit invadopodia formation and ECM degradation, suggesting that caveolae integrity also involved in metastasis. Immunocytochemical assay showed that LSS induces the Cav-1 clustering in lipid rafts and co-localization of Cav-1 and MT1-MMP on invadopodia. Immunofluorescence confocal analysis demonstrated that Cav-1 activation were required for the acquisition of a polarized phenotype in MDA-MB-231 cells. Finally, Cav-1 knockdown significantly suppressed tumor colonization in the lungs and distant metastases in animal models. Our findings highlight the importance of Cav-1 in hematogenous metastasis, and provide new insights into the underlying mechanisms of mechanotransduction induced by LSS.
Oil-tea tree (
) is the most important edible oil tree species in China with late-acting self-incompatibility (LSI) properties. The mechanism of LSI is uncertain, which seriously hinders the research ...on its genetic characteristics, construction of genetic map, selection of cross breeding parents and cultivar arrangement. To gain insights into the LSI mechanism, we performed cytological, transcriptomic, proteomic and metabolomic studies on self- and cross-pollinated pistils. The studies identified 166,591 transcripts, 6851 proteins and 6455 metabolites. Transcriptomic analysis revealed 1197 differentially expressed transcripts between self- and cross-pollinated pistils and 47 programmed cell death (PCD)-control transcripts. Trend analysis by Pearson correlation categorized nine trend graphs linked to 226 differentially expressed proteins and 38 differentially expressed metabolites. Functional enrichment analysis revealed that the LSI was closely associated with PCD-related genes, mitogen-activated protein kinase (MAPK) signaling pathway, plant hormone signal transduction, ATP-binding cassette (ABC) transporters and ubiquitin-mediated proteolysis. These particular trends in transcripts, proteins and metabolites suggested the involvement of PCD in LSI. The results provide a solid genetic foundation for elucidating the regulatory network of PCD-mediated self-incompatibility in
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