ABSTRACT
Macrophage as a crucial component of innate immunity, plays an important role in inflammation and infection immunity. Notch signal pathway is a highly conserved pathway, which regulates cellular fate and participates in numerous pathological processes. At present, a lot of literature has confirmed the role of Notch signaling in regulating the differentiation, activation and metabolism of macrophage during inflammation and infection. This review focuses on how Notch signaling promotes macrophage pro-inflammatory and anti-infective immune function in different inflammatory and infectious diseases. In this regulation, Notch signaling interact with TLR signaling in macrophages or inflammatory-related cytokines including IL-6, IL-12, and TNF-α. Additionally, the potential application and challenges of Notch signaling as a therapeutic target against inflammation and infectious diseases are also discussed.
Subject(s)
Humans , Signal Transduction , Macrophages , Cytokines/metabolism , Inflammation/metabolism , Communicable Diseases , Receptors, Notch/metabolismABSTRACT
BACKGROUND: LincRNAs have been revealed to be tightly associated with various tumorigeneses and cancer development, but the roles of specific lincRNA on tumor-related angiogenesis was hardly studied. Here, we aimed to investigate whether linc-OIP5 in breast cancer cells affects the angiogenesis of HUVECs and whether the linc-OIP5 regulations are involved in angiogenesis-related Notch and Hippo signaling pathways. METHODS: A trans-well system co-cultured HUVECs with linc-OIP5 knockdown breast cancer cell MDA-MB-231 was utilized to study the proliferation, migration and tube formation abilities of HUVECs and alterations of related signaling indicators in breast cancer cells and their conditioned medium through a series of cell and molecular experiments. RESULTS: Overexpressed linc-OIP5, YAP1, and JAG1 were found in breast cancer cell lines MCF7 and MDA-MB-231 and the expression levels of YAP1 and JAG1 were proportional to the breast cancer tissue grades. MDA-MB-231 cells with linc-OIP5 knockdown led to weakened proliferation, migration, and tube formation capacity of co-cultured HUVECs. Besides, linc-OIP5 knockdown in co-cultured MDA-MB-231 cells showed downregulated YAP1 and JAG1 expression, combined with a reduced JAG1 level in conditioned medium. Furthermore, a disrupted DLL4/Notch/NRP1 signaling in co-cultured HUVECs were also discovered under this condition. CONCLUSION: Hence, linc-OIP5 in MDA-MB-231 breast cancer cells may act on the upstream of the YAP1/Notch/NRP1 signaling circuit to affect proliferation, migration, and tube formation of co-cultured HUVECs in a non-cellular direct contact way through JAG1 in conditioned medium. These findings at least partially provide a new angiogenic signaling circuit in breast cancers and suggest linc-OIP5 could be considered as a therapeutic target in angiogenesis of breast cancers.
Subject(s)
Humans , Female , Transcription Factors/metabolism , Breast Neoplasms/pathology , Neuropilin-1/metabolism , Adaptor Proteins, Signal Transducing/metabolism , Receptors, Notch/metabolism , Tumor Microenvironment , Human Umbilical Vein Endothelial Cells/cytology , Breast Neoplasms/metabolism , Immunohistochemistry , Signal Transduction , Blotting, Western , Reverse Transcriptase Polymerase Chain Reaction , Cell Line, Tumor , Real-Time Polymerase Chain ReactionABSTRACT
Notch signaling is an evolutionarily ancient, highly conserved pathway important for deciding cell fate, cellular development, differentiation, proliferation, apoptosis, adhesion, and epithelial-to-mesenchymal transition. Notch signaling is also critical in mammalian cardiogenesis, as mutations in this signaling pathway are linked to human congenital heart disease. Furthermore, Notch signaling can repair myocardial injury by promoting myocardial regeneration, protecting ischemic myocardium, inducing angiogenesis, and negatively regulating cardiac fibroblast-myofibroblast transformation. This review provides an update on the known roles of Notch signaling in the mammalian heart. The goal is to assist in developing strategies to influence Notch signaling and optimize myocardial injury repair.
Subject(s)
Animals , Humans , Heart Diseases/metabolism , Myocardium/metabolism , Receptors, Notch/metabolism , Signal Transduction/physiology , Apoptosis/physiology , Cell Differentiation/physiology , Heart Diseases/physiopathology , Ischemic Preconditioning, Myocardial , Mammals , Regeneration/physiologyABSTRACT
The Notch signaling pathway plays an important role in development and physiology. In Drosophila, Notch is activated by its Delta or Serrate ligands, depending in part on the sugar modifications present in its extracellular domain. O-fucosyltransferase-1 (OFUT1) performs the first glycosylation step in this process, O-fucosylating various EGF repeats at the Notch extracellular domain. Besides its O-fucosyltransferase activity, OFUT1 also behaves as a chaperone during Notch synthesis and is able to down regulate Notch by enhancing its endocytosis and degradation. We have reevaluated the roles that O-fucosylation and the synthesis of GDP-fucose play in the regulation of Notch protein stability. Using mutants and the UAS/Gal4 system, we modified in developing tissues the amount of GDP-mannose-deshydratase (GMD), the first enzyme in the synthesis of GDP-fucose. Our results show that GMD activity, and likely the levels of GDP-fucose and O-fucosylation, are essential to stabilize the Notch protein. Notch degradation observed under low GMD expression is absolutely dependent on OFUT1 and this is also observed in Notch Abruptex mutants, which have mutations in some potential O-fucosylated EGF domains. We propose that the GDP-fucose/OFUT1 balance determines the ability of OFUT1 to endocytose and degrade Notch in a manner that is independent of the residues affected by Abruptex mutations in Notch EGF domains.
Subject(s)
Animals , Drosophila Proteins/metabolism , Drosophila melanogaster/genetics , Fucosyltransferases/metabolism , Guanosine Diphosphate Fucose/metabolism , Guanosine Diphosphate Mannose/metabolism , Receptors, Notch/metabolism , Wings, Animal/metabolism , Alleles , Drosophila Proteins/genetics , Drosophila melanogaster/anatomy & histology , Drosophila melanogaster/metabolism , Endocytosis/genetics , Fucosyltransferases/genetics , Guanosine Diphosphate Fucose/genetics , Guanosine Diphosphate Mannose/genetics , Immunohistochemistry , In Situ Hybridization , Intracellular Signaling Peptides and Proteins/genetics , Mutant Proteins/genetics , Mutant Proteins/metabolism , Mutation/genetics , Phenotype , Reverse Transcriptase Polymerase Chain Reaction , Receptors, Notch/genetics , Signal Transduction , Wings, Animal/anatomy & histologyABSTRACT
Objective: To investigate the molecular mechanism underlying the differentiation of human umbilical cord-derived mesenchymal stem cells (hUCMSCs) into myocardial cells induced by 5-azacytidine (5-aza), and to explore the expression and significance of DLL4-Notch signaling in this process. Materials and Methods: hUCMSCs were isolated and purified from the umbilical cords of normal or cesarean term deliveries under sterile conditions. After treatment with 5-aza for 24 h, hUCMSCs was continued to culture, the expression of GATA4 and NKx2.5 at 4 weeks after induction, DLL4 and Notch1 mRNA at 1d, 3d, 5d, 7d after induction were detected. The expression of cardiac troponin I (cTnI) after 4 weeks was determined by immunocytochemistry. Results: hUCMSCs treated with 5-aza were stained positively for cTnI 4 weeks after induction. The expression of Notch1 and DLL4 mRNA in the 5-aza-induced group was stable and significantly higher than that in the control group (mean Ct value for the Notch1 gene: 0.51 ± 0.21 in the 5-aza-induced group vs. 7.85 ± 0.35 in the control group; mean Ct value for the DLL4 gene: 1.60 ± 0.49 in the 5-aza-induced group vs. 12.42 ± 0.73 in the control group). Similar results were observed for Nkx2.5 and GATA4 genes. The expressions of Nkx2.5 and GATA4 mRNA in the 5-aza group were 4.72 ± 0.58 and 3.76 ± 0.06 times higher than that in the control group, respectively, with statistical significance. Conclusions: hUCMSCs can be differentiated into myocardial cells by 5-aza induction in vitro. 5-Aza may affect this process by regulating the expression of GATA4 and Nkx2.5 genes. The DLL4-Notch signal pathway may be involved in this process.
Subject(s)
Azacitidine/metabolism , Cell Differentiation/drug effects , GATA4 Transcription Factor/metabolism , Homeodomain Proteins/metabolism , Humans , Mesenchymal Stem Cells/metabolism , Myocytes, Cardiac/cytology , Myocytes, Cardiac/drug effects , Receptor, Notch1/metabolism , Receptors, Notch/metabolism , Signal Transduction/drug effects , Transcription Factors/metabolism , Umbilical Cord/cytologyABSTRACT
Juxtacrine signaling is intercellular communication, in which the receptor of the signal (typically a protein) as well as the ligand (also typically a protein, responsible for the activation of the receptor) are anchored in the plasma membranes, so that in this type of signaling the activation of the receptor depends on direct contact between the membranes of the cells involved. Juxtacrine signaling is present in many important cellular events of several organisms, especially in the development process. We propose a generic formal model (a modeling framework) for juxtacrine signaling systems that is a class of discrete dynamic systems. It possesses desirable characteristics in a good modeling framework, such as: a) structural similarity with biological models, b) capacity of operating in different scales of time, and c) capacity of explicitly treating both the events and molecular elements that occur in the membrane, and those that occur in the intracellular environment and that are involved in the juxtacrine signaling process. We have implemented this framework and used it to develop a new three-level discrete model for the neurogenic network and its participation in neuroblast segregation. This paper presents the details of this framework and its current status.