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Notch signaling in spermatogenesis and male (in)fertility
Published in Rajender Singh, Molecular Signaling in Spermatogenesis and Male Infertility, 2019
Mahitha Sahadevan, Pradeep G. Kumar
Notch signaling is a highly conserved juxtacrine signaling pathway, which was genetically identified 10 decades ago. This pathway plays a vital role in determining the fate of cells, based on spatiotemporal expression of its ligand and receptor. It regulates various cellular processes, like embryogenesis; maintenance of stem cell population, proliferation and differentiation; cell fate specification (by lateral inhibition/inductive signaling); pattern formation; and apoptosis (9,14–16). At the same time, dysfunction in any gear of this pathway, such as gain/loss of function, leads to various developmental blemishes and adult pathological conditions such as T-cell acute lymphoblastic leukemia, Alagille syndrome, spondylocostal dystoses and multiple sclerosis (2,15,17,18).
Reproduction
Published in Frank J. Dye, Human Life Before Birth, 2019
In addition to cells communicating over relatively long distances, for example, by nerve impulses and neurotransmitters of the nervous system or by hormones of the endocrine system, cells may communicate over shorter distances. Cell communication over shorter distances occurs by paracrine, juxtacrine, or autocrine signaling. If a cell has receptors for signal molecules it itself produces, this is called autocrine signaling, a relatively rare kind of signaling, but exemplified by the cytotrophoblast cells of the placenta, which make and secrete platelet-derived growth factor (PDGF), the receptors for which are found on the very same cells, this results in the explosive growth of the cytotrophoblast, which is instrumental in the implantation of the embryo into the lining of the uterus, whereby a pregnancy is initiated. If the signaling molecules are embedded in the plasma membranes of the cells producing them, and the receptors for them are embedded in the plasma membranes of neighboring cells, then juxtacrine signaling is occurring. If the cells making and secreting the signaling molecules attach to receptors of nearby cells, then paracrine signaling is occurring.
Airway Wall Remodelling in the Pathogenesis of Asthma: Cytokine Expression in the Airways
Published in Alastair G. Stewart, AIRWAY WALL REMODELLING in ASTHMA, 2020
Peter Bradding, Anthony E. Redington, Stephen T. Holgate
A further level of complexity is added by the fact that, once released, many cytokines do not remain in the soluble phase but bind in a specific fashion to components of the extracellular matrix (ECM) and that these interactions can profoundly alter the biologic properties of the cytokines. For example, heparan sulphate proteoglycans (HSPGs) are ubiquitous components of the ECM which are located predominantly in basement membranes and on the surfaces of many cells. These molecules are capable of binding many cytokines including the haematopoietic growth factors interleukin 3 (IL-3) and granulocyte/macrophage colony-stimulating factor (GM-CSF),15,16 members of the chemokine family such as IL-8,17 and the potent fibrogenic and angiogenic cytokine, basic fibroblast growth factor (bFGF).18,19 In the case of IL-8 this interaction serves to increase the activity of the cytokine as a neutrophil activator,17 presumably by facilitating its precise spatial orientation when presented to the target cell. On the other hand, in the case of bFGF its interaction with basement membrane HSPGs is believed to create an extracellular reservoir of cytokine which can be released in response to specific stimuli.18,20,21 Presentation of cytokines as cell surface molecules is also important in the process of juxtacrine signalling,22 whereas in the case of bFGF this cytokine must first bind to cell surface HSPGs in order to be presented to its high-affinity receptors.23 The role that cytokine–matrix interactions play in cytokine biology has received relatively little attention, and their significance is likely to become increasingly evident with further research. The recognition of their importance also draws attention to the need to exert caution when interpreting measurement of quantities of “free” cytokine in a biologic fluid, as these may not provide a true reflection of its biologic activity. Ideally, when studying cytokine expression, evidence of mRNA and protein synthesis, together with cytokine release and biologic activity, should all be investigated.
Epidermal growth factor receptor ligands: targets for optimizing treatment of metastatic colorectal cancer
Published in Growth Factors, 2019
Siavash Foroughi, Jeanne Tie, Peter Gibbs, Antony Wilks Burgess
In mouse embryonic cells, ADAM17, also known as Tumour-Necrosis Factor-α converting enzyme (TACE), is the main sheddase for EREG, TGF-α, AREG, HB-EGF, and the neuregulins, however, it is unclear if ADAM19 also plays a role in neuregulin processing (Horiuchi et al. 2005; Kurohara et al. 2004). ADAM10 appears to be responsible for the shedding and activation of EGF and BTC (Sahin et al. 2004). Although juxtacrine signaling by membrane-bound EGFR ligands, such as TGF-α, has been observed (Anklesaria et al. 1990), metalloprotease activity is required for autocrine and paracrine signaling to occur (Gee and Knowlden 2003). Metalloprotease-dependent EGFR-family signaling can be disrupted by protease inhibitors, eloquently demonstrated using the metalloprotease inhibitor Batimastat (BB-94) (Dong et al. 1999). This inhibitor blocks EGFR-dependent cell proliferation and migration of human mammary epithelial cells, i.e. the growth of primary tumors and the migration of cells into metastatic sites. Cell proliferation was inhibited in direct proportion to the inhibition of EGF release and the consequential signaling, however, the inhibition of autocrine ligand stimulated proliferation and migration by the protease inhibitors is rescued by exogenous EGF (Dong et al. 1999).
Exosomes as drug carriers for clinical application
Published in Artificial Cells, Nanomedicine, and Biotechnology, 2018
Cuixia Di, Qianjing Zhang, Yupei Wang, Fang Wang, Yuhong Chen, Lu Gan, Rong Zhou, Chao Sun, Hongyan Li, Xuetian Zhang, Hongying Yang, Hong Zhang
Tumor cells can produce anti-radiation effects through hypoxia, tumor cell genetic heterogeneity and DNA repair, et al. After irradiation, tumor cells can secrete exosomes and affect the surrounding cells to produce radiotherapy tolerance [55]. Khan et al. [56] reported that radiotherapy can induce the increase of the exosomes containing apoptosis inhibitory factor secretion from tumor cells, by which can increase the survival rate of tumor cells and result in radiotherapy tolerance. Soon after, Arscott et al. [57] suggested that exosomes derived from irradiated cells enhanced the migration of recipient cells, and their molecular profiling revealed an abundance of molecules related to signaling pathways important for cell migration, their further studies indicated that radiation influences exosome abundance, specifically alters their molecular composition, and on uptake, promotes a migratory phenotype, due to which tumor cells produce radiotherapy tolerance. In addition, Boelens et al. [58] found that stromal and breast cancer cells utilize paracrine and juxtacrine signaling to drive chemotherapy and radiation resistance, in which the paracrine antiviral and juxtacrine NOTCH3 pathways converge as STAT1 facilitates transcriptional responses to NOTCH3 and expands therapy-resistant tumor-initiating cells, and further primary human and/or mouse breast cancer analysis support the role of antiviral/NOTCH3 pathways in NOTCH signaling and stroma-mediated resistance.
Reconstructing human pancreatic islet architectures using computational optimization
Published in Islets, 2020
Gerardo J. Félix-Martínez, Aurelio N. Mata, J. Rafael Godínez-Fernández
At the single-cell level, pancreatic α, β and δ-cells rely on the generation of an electrical activity pattern for the secretion of glucagon, insulin and somatostatin, respectively, although it has been shown recently that Ca2+ plays a relevant role in δ-cells independently of the electrical activity.11 The stimulus-secreting processes in the α, β and δ-cells can be found in recent works on the subject (see for instance refs.8,12–17). At a higher level of organization (i.e. islets), pancreatic cells communicate via direct electrical coupling through gap-junctions (between β cells and β and δ cells),18,19 as well as paracrine, autocrine and juxtacrine signaling.20–23 These interactions between cells depend on the number, distribution and organization of the α, β and δ-cells within the islets.2,24,25 Several factors are involved in the formation, development and organization of pancreatic islets. For instance, it has been shown that factors such as the hepatocyte nuclear factor 626 and Nkx2.2,27,28 as well as the mTOR pathway29 and the Roundabout receptors30 have an important role for the spatial organization of cells within the islet. It is also known that the architecture of pancreatic islets is disrupted in type 2 diabetes in rodents, non-human primates and humans,31–33 including a decrease in β-cell mass in people living with type 2 diabetes2,32,33 and the formation of amyloid deposits within the islets.34–36 In addition to the functional implications of a loss of β-cell mass (i.e. impaired insulin secretion), it is reasonable to hypothesize that alterations of the islet architecture also affect the interactions between cells within the pancreatic islets.