JAK-STAT pathway: Testicular development, spermatogenesis and fertility
Rajender Singh in Molecular Signaling in Spermatogenesis and Male Infertility, 2019
Ligand molecules are the extracellular molecules that cannot cross the membrane but through ligand-receptor interaction have the potential to activate an intracellular cell signaling cascade. Initially, the JAK-STAT pathway was discovered by interferon (IFN)-induced intracellular signaling. But later, a large number of cytokines, interferons and growth hormones were known to induce JAK-STAT signaling. In mammals, these ligand molecules are classified into various families depending on their structural and functional characteristics (10) (Table 15.3). In Drosophila, Upd is the only known ligand molecule for inducing JAK-STAT signaling. The unpaired gene encodes a 47 kDa secretory glycoprotein, localized to an extracellular matrix (ECM) (16). While curating a Drosophila database, other Upd-like genes have also been identified, such as Upd2 (19) and Upd3 (17).
Finding a Target
Nathan Keighley in Miraculous Medicines and the Chemistry of Drug Design, 2020
Cell signalling processes allow the cells that make up multicellular organism to communicate with one another; be it their neighbours or distant cells elsewhere in the body. Any given cells may be exposed to hundreds of signals, not all of them relevant to its particular function. In order to perform their specific role in the body, each cell is programmed to respond to specific combinations of signalling molecules. Furthermore, different cells respond differently to the same chemical signals. This means that the behaviour of cells can be controlled in highly specific ways. These signalling molecules generate a response by binding to cell surface receptor proteins, which act as signal transducers, where the binding of the signalling ligand induces an intracellular response that alters the behaviour of the target cell. There are three known classes of cell surface receptor, defined by the mechanism of transduction used. Ion-channel-linked receptors are those involved in the rapid synaptic signalling between neurones during an action potential (nerve impulse), mediated by neurotransmitters. G-protein-linked receptors indirectly regulate the activities of target proteins bound separately to the plasma membrane, for example enzymes or channel proteins. The mediator for this process is called “G protein”, which binds to the receptor, and then upon binding of the signalling molecule to the receptor, becomes activated, and then departs to bind to, and activate, the target enzyme or channel protein. The third type of receptor are enzyme-linked receptors, which become activated by a signalling molecule and prompted into acting as an enzyme.
Cell Biology
C.S. Sureka, C. Armpilia in Radiation Biology for Medical Physicists, 2017
Due to their nature, cells communicate with their environment in several ways. The four important ways of cell signaling are (1) endocrine signaling (cells at a longer distance)—hormones are released into the circulatory system, which carries them to the target cell that contains receptors to receive signals; (2) paracrine signaling (nearby cells)—secretions from one cell have an effect only on cells in the immediate area; (3) neuronal signaling (cells at longer distance)—involves the transmission of signal molecules, called neurotransmitters, from a neuron over a small synaptic gap to the target cell; and (4) direct contact (cells in contact)—two cells in direct contact with each other can send signals across gap junctions (Figure 1.5).
Emerging molecular target antagonists for the treatment of biliary tract cancer
Published in Expert Opinion on Emerging Drugs, 2018
Pasquale Lombardi, Donatella Marino, Elisabetta Fenocchio, Giovanna Chilà, Massimo Aglietta, Francesco Leone
α-SMA positive CAFs are involved in cancer progression through production of matricellular proteins, growth factors, chemokines, and matrix metalloproteinases. Patients expressing high levels of α-SMA have poorer survival [93]. The desmoplastic matrix also allows the development of a niche fostering tumor spread rather than as a response to the anticancer treatments [94]. Transforming growth factor β (TGF- β) seems to be implicated in the generation of the niche. Indeed, preclinical models have demonstrated a reduction in fibrosis and tumor spread with TGF-β antagonist [95].CAFs produce numerous factors involved in autocrine and paracrine signaling that promote oncogenic processes like periostin, tenascin-c, thrombospandin 1, stromal cell-derived factor 1 (SDF-1), HGF and Wnt inducible signaling protein-1v (WISP1) [93]. These interact with cell signaling pathways. For example, periostin interacts with tenascin-C, HGF and SDF-1, which bind to their respective receptors, integrin, MET, and CXCR4 on CCA cells, leading to activation of the PIK3CA/AKT signaling pathway.
Improving cellular uptake of therapeutic entities through interaction with components of cell membrane
Published in Drug Delivery, 2019
Renshuai Zhang, Xiaofei Qin, Fandong Kong, Pengwei Chen, Guojun Pan
Proteins are the second major components of cell membranes and some of them can mediate cellular uptake termed also receptor-mediated uptake in general describing. In order to profound the understanding of key role of trans-membrane proteins in mediated drug delivery, they were divided into two categories, transporters and receptors in this review. For instance, some trans-membrane proteins are transporters that carry small molecules (e.g. glucose) into the cell. Some other proteins are known as receptors to mediate the cell signaling pathway for growth and proliferation. For transporters, they maintained the normal metabolism of cells via transferring necessary nutrients from the outside to the inside. Meanwhile, some transporters showed high affinity to ligand-drug conjugates and even ligand-drug carrier complexes. Thus, it provided an ideal opportunity for enhancing drug delivery and improving drug targeting. For receptors, they can be especially bound by natural ligands or monoclonal antibodies (mAbs), and thus mediated cellular signal or used in the treatment of disease. To date, lots of mAbs have been conjugated to small molecule drugs or drug carriers for drug delivery. Additionally, some transporters can also be targeted by mAbs, such as folate receptors (FR) which transport folate into cells, and meanwhile as antigens can specially bind anti-FR antibody. Importantly, covalent attachment of small molecule drugs or drug carriers to antibodies did not significantly influence their cell internalization, thus providing another delivery strategy utilizing interaction between antibody and membrane proteins.
Update on the proteomics of male infertility: A systematic review
Published in Arab Journal of Urology, 2018
Manesh Kumar Panner Selvam, Ashok Agarwal
New generation techniques, such as proteomics, are poised to help researchers identify the molecular aspects of spermatozoa that are affected in infertility conditions. The majority of protein biomolecules are involved in cell signalling pathways. Generally, spermatozoa are transcriptionally and translationally silent, so they depend on their proteins to carry out their biological functions [6]. Proteomics is an emerging tool that could potentially help identify protein alterations in spermatozoa and seminal plasma of male infertile patients [7]. Differential expression of sperm proteins in fertility compromised patients is an indicator of defective spermatogenesis, motility, capacitation, hyperactivation, acrosome reaction, and fertilisation processes at a molecular level.
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