Notch Jagged1 Research Articles

Evaluation of Newly Designed Blister Packs for Easier Handling to Prevent Pill Dropping.

BackgroundBlister packs with paperboard backing, which is useful for displaying instructions and information, are the most popular type of packaging for osteoporosis drugs in Japan. However, the main users of drugs are the aged, who often find blister packs difficult to open or drop their pills during opening. In this study, we compared different types of blister packs in terms of usability and handling.MethodsWe conducted a subjective and objective study to compare commonly used blister packs with newly designed ones that have a jagged notch designed to hold a pill temporarily and a perforated line that enables the pack to be held easily in one hand. Regarding subjective data, packaging and sensory tests were performed. The participants in the sensory test were healthy older adults and patients with rheumatoid arthritis (RA). We also measured the pinch power of all participants.ResultsA comparison of several items, including opening status, prevention of pill dropping, and understanding of the instructions, using a numerical rating scale revealed no significant differences between ordinary (type A) and newly designed (type B) packaging. However, the scores for type B were the same or better than those for type A for every evaluation item. In addition, more than 85% of the participants reported preferring to use type B. More than 80% of the participants in both groups reported dropping pills using type A, which seemed to be related to their preference for type B. In the evaluation by the examiner (objective study), all participants could successfully remove their pills without dropping using type B, including those in the RA group who had difficulty handling packages.ConclusionThese findings suggest that the new type of blister pack assessed in this study (type B) is preferable among older and shows promise for a universal design.

Vimentin regulates Notch signaling strength and arterial remodeling in response to hemodynamic stress

The intermediate filament (IF) cytoskeleton has been proposed to regulate morphogenic processes by integrating the cell fate signaling machinery with mechanical cues. Signaling between endothelial cells (ECs) and vascular smooth muscle cells (VSMCs) through the Notch pathway regulates arterial remodeling in response to changes in blood flow. Here we show that the IF-protein vimentin regulates Notch signaling strength and arterial remodeling in response to hemodynamic forces. Vimentin is important for Notch transactivation by ECs and vimentin knockout mice (VimKO) display disrupted VSMC differentiation and adverse remodeling in aortic explants and in vivo. Shear stress increases Jagged1 levels and Notch activation in a vimentin-dependent manner. Shear stress induces phosphorylation of vimentin at serine 38 and phosphorylated vimentin interacts with Jagged1 and increases Notch activation potential. Reduced Jagged1-Notch transactivation strength disrupts lateral signal induction through the arterial wall leading to adverse remodeling. Taken together we demonstrate that vimentin forms a central part of a mechanochemical transduction pathway that regulates multilayer communication and structural homeostasis of the arterial wall.

Mechanosensitivity of Jagged–Notch signaling can induce a switch-type behavior in vascular homeostasis

Hemodynamic forces and Notch signaling are both known as key regulators of arterial remodeling and homeostasis. However, how these two factors integrate in vascular morphogenesis and homeostasis is unclear. Here, we combined experiments and modeling to evaluate the impact of the integration of mechanics and Notch signaling on vascular homeostasis. Vascular smooth muscle cells (VSMCs) were cyclically stretched on flexible membranes, as quantified via video tracking, demonstrating that the expression of Jagged1, Notch3, and target genes was down-regulated with strain. The data were incorporated in a computational framework of Notch signaling in the vascular wall, where the mechanical load was defined by the vascular geometry and blood pressure. Upon increasing wall thickness, the model predicted a switch-type behavior of the Notch signaling state with a steep transition of synthetic toward contractile VSMCs at a certain transition thickness. These thicknesses varied per investigated arterial location and were in good agreement with human anatomical data, thereby suggesting that the Notch response to hemodynamics plays an important role in the establishment of vascular homeostasis.

Notch Signaling in T Helper Cell Subsets: Instructor or Unbiased Amplifier?

For protection against pathogens, it is essential that naïve CD4+ T cells differentiate into specific effector T helper (Th) cell subsets following activation by antigen presented by dendritic cells (DCs). Next to T cell receptor and cytokine signals, membrane-bound Notch ligands have an important role in orchestrating Th cell differentiation. Several studies provided evidence that DC activation is accompanied by surface expression of Notch ligands. Intriguingly, DCs that express the delta-like or Jagged Notch ligands gain the capacity to instruct Th1 or Th2 cell polarization, respectively. However, in contrast to this model it has also been hypothesized that Notch signaling acts as a general amplifier of Th cell responses rather than an instructive director of specific T cell fates. In this alternative model, Notch enhances proliferation, cytokine production, and anti-apoptotic signals or promotes co-stimulatory signals in T cells. An instructive role for Notch ligand expressing DCs in the induction of Th cell differentiation is further challenged by evidence for the involvement of Notch signaling in differentiation of Th9, Th17, regulatory T cells, and follicular Th cells. In this review, we will discuss the two opposing models, referred to as the “instructive” and the “unbiased amplifier” model. We highlight both the function of different Notch receptors on CD4+ T cells and the impact of Notch ligands on antigen-presenting cells.

NOTCH decoys that selectively block DLL/NOTCH or JAG/NOTCH disrupt angiogenesis by unique mechanisms to inhibit tumor growth.

A proangiogenic role for Jagged (JAG)-dependent activation of NOTCH signaling in the endothelium has yet to be described. Using proteins that encoded different NOTCH1 EGF-like repeats, we identified unique regions of Delta-like ligand (DLL)-class and JAG-class ligand-receptor interactions, and developed NOTCH decoys that function as ligand-specific NOTCH inhibitors. N110-24 decoy blocked JAG1/JAG2-mediated NOTCH1 signaling, angiogenic sprouting in vitro, and retinal angiogenesis, demonstrating that JAG-dependent NOTCH signal activation promotes angiogenesis. In tumors, N110-24 decoy reduced angiogenic sprouting, vessel perfusion, pericyte coverage, and tumor growth. JAG-NOTCH signaling uniquely inhibited expression of antiangiogenic soluble (s) VEGFR1/sFLT1. N11-13 decoy interfered with DLL1-DLL4-mediated NOTCH1 signaling and caused endothelial hypersprouting in vitro, in retinal angiogenesis, and in tumors. Thus, blockade of JAG- or DLL-mediated NOTCH signaling inhibits angiogenesis by distinct mechanisms. JAG-NOTCH signaling positively regulates angiogenesis by suppressing sVEGFR1-sFLT1 and promoting mural-endothelial cell interactions. Blockade of JAG-class ligands represents a novel, viable therapeutic approach to block tumor angiogenesis and growth. This is the first report identifying unique regions of the NOTCH1 extracellular domain that interact with JAG-class and DLL-class ligands. Using this knowledge, we developed therapeutic agents that block JAG-dependent NOTCH signaling and demonstrate for the first time that JAG blockade inhibits experimental tumor growth by targeting tumor angiogenesis.

Non-allergenic factors from pollen modulate T helper cell instructing notch ligands on dendritic cells

Background Pollen allergens are delivered to epithelial surfaces of the upper respiratory tract in conjunction with multiple endogenous adjuvants. We previously demonstrated pollen-mediated modulation of cytokine and chemokine production of dendritic cells, contributing to a Th2-dominated micromilieu. As T helper cell differentiation not only depends on dendritic cell-derived cytokines but also on cell-cell-contact mediated mechanisms, we studied the expression of notch ligands and myeloid differentiation primary response protein 88 (MyD88) in dendritic cells matured in the presence of aqueous birch pollen extracts and pollen-associated E1-phytoprostanes.Methods Human monocyte-derived dendritic cells were stimulated with aqueous birch pollen extracts in the absence or presence of lipopolysaccharide, and mRNA expression levels of notch ligands delta-1 and −4, jagged-1 and −2 and of myd88 were determined. Regulation of Delta-4 and MyD88 by aqueous pollen extracts was assessed on protein level. The contribution of notch signaling to T helper cell differentiation was analyzed in allogeneic T cell stimulation assays.Results In immature dendritic cells, stimulation with pollen extracts resulted in an induction of both delta and jagged notch ligands. The lipopolysaccharide-induced up-regulation of delta-1 and −4 and of myd88 was decreased by aqueous pollen extracts, whereas jagged expression was induced. Reduction of Delta-4 and MyD88 by aqueous pollen extracts was confirmed on protein level. The Th2-skewing activity was contained in a fraction of aqueous pollen extracts enriched for molecules <3 kDa and was distinct from the previously identified E1-phytoprostanes. Reduction of notch signaling in dendritic cells matured in the presence aqueous pollen extract leads to inhibition of IL-10 and to induction of IL-5 production in naïve T cells differentiated by these dendritic cells.Conclusions Pollen derived, non-allergenic factors reduce the dendritic cell’s expression of Th1 instructing Delta-like notch ligands and of MyD88, thereby promoting Th2 skewing of T helper cell responses.

Crosstalk between Jagged–Notch, Edn1, and Bmp signaling pathways patterns the dorsal–ventral axis of the vertebrate face

Crosstalk between Jagged–Notch, Edn1, and Bmp signaling pathways patterns the dorsal–ventral axis of the vertebrate face

Th2 Differentiation Is Unaffected by Jagged2 Expression on Dendritic Cells

Expression of the Jagged Notch ligands by dendritic cells (DCs) has been suggested to play a role in instructing Th2 responses. Supporting this hypothesis, we found that Jagged2 but not Jagged1 expression, correlates with the ability of DCs to induce Th2 responses. Jagged2 expression is up-regulated in response to the helminth soluble Schistosoma mansoni egg Ag, which conditions DCs to induce Th2 responses, and is markedly down-regulated following exposure to TLR agonists that generally promote Th1 responses. Conversely, Jagged1 expression is markedly induced by TLR ligation. Despite these correlations, suppression of expression of Jagged2 using retrovirally delivered small interfering RNA failed to affect the ability of DCs to induce Th2 cell differentiation either in vitro or in vivo. Moreover, retrovirally induced expression of Jagged2 did not enhance the ability of DCs to induce Th2 cell responses. Our data indicate that Jagged2 expression by DCs is not sufficient or required for Th2 cell differentiation.

Notch signals spread breast cancer

Cancer cells are more dangerous when they are on the move. Leong et al. (page 2935) now reveal that the Notch receptor sets cancer cells on this metastatic journey. Figure 1 Human breast cancer cells that overexpress Notch (green) lose E-cadherin (red) and metastasize. Breast cancer cells grow aggressively and enter the circulation when they stop expressing E-cadherin, which glues cells together. E-cadherin is suppressed by Notch signaling in some cell types during periods of development, when cells need to move around to form three-dimensional organs. Increased levels of Notch and its ligand Jagged are found in breast cancer patients who have malignant tumors and are therefore less likely to survive. Leong et al. now find that Notch activation by Jagged frees cancer cells by shutting off their E-cadherin glue. When Notch receptor levels were increased in E-cadherin–expressing human breast cancer cells, the cells turned on Slug—one of the several known transcriptional suppressors of E-cadherin. Slug levels were also increased in primary human breast cancers that had high levels of Jagged and Notch, suggesting that this Jagged–Notch–Slug pathway puts cancer cells on the road. How Notch receptors are ramped up in cancer cells is unknown. But the availability of patients' cell lines that overexpress Notch receptors and ligands allowed the authors to transplant mice with human breast tumors. Mice transplanted with cancer cells that lacked E-cadherin developed metastatic tumors. The tumor growth and metastasis was prevented when E-cadherin expression was enforced by blocking Notch signaling with soluble Notch receptors. Whether these Notch inhibitors also block metastasis of human cancers remains to be tested. Notch-mediated loss of E-cadherin also protected the cancer cells from apoptosis, which is normally triggered in cells that detach from their support structures. Metastasizing tumor cells that expressed Notch lacked caspase activity and thus survived the transit to new tumor sites. The team is now trying to understand how Notch blocks tumor cell apoptosis.

Jagged-mediated Notch signaling maintains proliferating neural progenitors and regulates cell diversity in the ventral spinal cord

Previous studies have shown that Delta-mediated Notch signaling regulates the number of early differentiating neurons. However, the role of Notch activation and Jagged-mediated signaling during late neurogenesis remains poorly defined. In the developing spinal cord of zebrafish, GABAergic Kolmer-Agduhr (KA'') cells and motor neurons (MN) emerge sequentially from their progenitors in the p3 domain. Jagged2 is expressed uniformly in the pMN domain during late neurogenesis where Olig2 is required for its expression. We suggest that Jagged2 interacts ventrally with progenitors in the adjacent p3 domain, where it has a critical role in the maintenance of proliferating neural progenitors and in preventing differentiation of these progenitors as GABAergic KA'' cells or secondary MN. This study identifies a critical role for Jagged-Notch signaling in the maintenance of proliferating neural precursors in a discrete compartment of the neural tube during the continuing growth and development of the vertebrate nervous system.

Regulation of T lymphopoiesis by Notch1 and Lunatic fringe–mediated competition for intrathymic niches

Notch1 activation regulates T lineage commitment and early T cell development. Fringe glycosyltransferases alter the sensitivity of Notch receptors to Delta-like versus Jagged Notch ligands, but their functions in T lymphopoiesis have not been defined. Here we show that developmental stage-specific expression of the glycosyltransferase lunatic fringe (Lfng) is required for coordination of the access of T cell progenitors to intrathymic niches that support Notch1-dependent phases of T cell development. Lfng-null progenitors generated few thymocytes in competitive assays, whereas Lfng overexpression converted thymocytes into 'supercompetitors' with enhanced binding of Delta-like ligands and blocked T lymphopoiesis from normal progenitors. We suggest that the ability of Lfng and Notch1 to control progenitor competition for limiting cortical niches is an important mechanism for the homeostatic regulation of thymus size.