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Small-Molecule Targeted Therapies
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
Sonolisib (PX-866), derived from the natural product wortmannin (from Penicillium wortmannin), was developed by Oncothyreon, and is an inhibitor of the alpha, gamma, and delta isoforms of PI3K. Like wortmannin, sonolisib inhibits PI-3K by forming a covalent bond with the enzyme, and so is a non-reversible inhibitor. It also inhibits production of the secondary messenger signaling protein PIP3 (phosphatidylinositol-3,4,5-trisphosphate) which is involved in activation of the PI3K/Akt signaling pathway. Sonolisib reached Phase II clinical trials for the treatment of a number of cancer types including glioblastoma multiforme, melanoma, and prostate, non-small-cell lung and head and neck cancers. However, although well tolerated, its clinical activity was insufficient to warrant further progression.
Nontoxic RsDPLA As a Potent Antagonist of Toxic Lipopolysaccharide
Published in Helmut Brade, Steven M. Opal, Stefanie N. Vogel, David C. Morrison, Endotoxin in Health and Disease, 2020
Nilofer Qureshi, Bruce W. Jarvis, Kuni Takayama
These two complexes could interact with another transmembrane protein (this would be the signaling protein) and cause a dimerization of these proteins. We suggest that when the CD14-LPS complex associates with the signaling protein (this would constitute the third level of competitive binding), a strong signal is generated, which initiates the activation of the cell. This signaling protein could be one or more of the three classes of transmembrane receptors described by Bernard (70). We suggest that when CD14-RsDPLA associates with the signaling protein, only a weak signal is generated, which is not adequate to activate the cell. A similar mechanism was proposed by Davis et al. (71) for the activation of the ciliary neurotrophic factor receptor complex. An alternative mechanism might be proposed where CD 14 transfers the toxic LPS directly to the receptor (the signaling unit) to initiate signal transduction.
General Considerations for Labeling and Imaging of Cells
Published in Martin G. Pomper, Juri G. Gelovani, Benjamin Tsui, Kathleen Gabrielson, Richard Wahl, S. Sam Gambhir, Jeff Bulte, Raymond Gibson, William C. Eckelman, Molecular Imaging in Oncology, 2008
Once the target cells of interest to be tracked are decided, there are three different cellular locations in which exogenous signaling probes can accumulate in the cell—cell membrane, endosomes and lysosomes, or cytosol (Fig. 7). If endogenous signaling probes are employed, signaling protein can be localized at any parts of cells by changing the genetic sequences of either the signal peptide or the protein itself.
Mapping the human sperm proteome – novel insights into reproductive research
Published in Expert Review of Proteomics, 2023
Mika Alexia Miyazaki, Raquel Lozano Guilharducci, Paula Intasqui, Ricardo Pimenta Bertolla
During their journey through the female genital tract, sperm undergo functional changes in order to achieve successful fertilization. Among these processes, spermatozoa capacitation has been studied from a proteomics point of view to understand the protein pattern transition in this event. After capacitation medium (CAP) incubation, increased proteins mainly involved in fertilization, sperm motility, and energy production were observed. Between 11 proteins identified, 9 were decreased, such as AKAP3, AKAP4, ODF2, Phosphoglycerate kinase 2 (PGK2), and Radial spoke head 1 homolog (RSPH1), all of them involved in PKA-dependent signaling process and consequently in supporting sperm motility [55,70]. In order to catalyze the first ATP-generating step in the central metabolic pathway of glycolysis to promote = tail movement, PGK2 protein is necessary. Located mainly in the principal piece of the flagellum, in male Pgk2−/− mice, sperm function, and motility were found to be altered, what may be the reason for the low expression [82]. On the other hand, five proteins, mainly from signaling, protein degradation, and vesicular trafficking processes were increased [70]. Moreover, a study incubating sperm with increasing concentrations of sperm plasma membrane-associated proteins (SMAP) showed about 12 proteins associated with the sperm surface. Of these, 22% are associated with protein binding and 7% with endopeptidase inhibitor activity, and they can also affect tyrosine phosphorylation, which, in turn, affects sperm hyperactivated motility [83].
Preclinical studies of chimeric antigen receptor-modified natural killer cells in cancer immunotherapy: a review
Published in Expert Opinion on Biological Therapy, 2022
Mina Hosseini, Zahra Habibi, Narges Hosseini, Sina Abdoli, Nima Rezaei
FcεRIγ, the γ subunit of the high-affinity IgE receptor, is a signaling protein with one ITAM, which is structurally homologous to CD3ζ [46]. In a study by Fabian et al., a PD-L1 targeting CAR structure consisting of a PD-L1 binding scFv and FcεRIγ intracellular signaling domain was designed, by which haNK-cells were transduced. haNK-cells are genetically engineered NK-92 cells that express a high-affinity CD16 and endoplasmic reticulum-retained IL-2. PD-L1-targeted-haNK cells expressed considerable amounts of perforin and granzyme, exerted PD-L1-expression-dependent cytotoxic responses against cancer cell lines of 20 different types, and, in addition, lysed MDSCs upon co-culture with Peripheral-Blood Mononuclear Cells (PBMCs). Moreover, these cells were able to effectively traffic into tumor site, inhibiting tumor growth in vivo in several xenograft mice models [51]. Given the fact that FcRγ-deficient NK-cells have demonstrated memory-like phenotypes [52], CAR-NK-cells with FcεRIγ as the main signaling domain might demonstrate distinct features compared to CD3ζ-based cells, especially in terms of persistence, which could be investigated through future experiments.
Regulation of platelet numbers and sizes by signaling pathways
Published in Platelets, 2021
Jaturawat Pawinwongchai, Ponthip Mekchay, Nungruthai Nilsri, Nipan Israsena, Ponlapat Rojnuckarin
Protein samples were diluted with sample buffer and fluorescence master mix at the final concentration of 3 µg in 5 µl. The samples, blocking reagent, primary antibodies, secondary antibody and chemiluminescent substrate were pipetted into the plate. The instrument settings were stacking and separation at 375 V for 25 minutes, blocking for 5 minutes, incubating of primary and secondary antibodies for 30 minutes each and luminol-peroxide chemiluminescence detection for 15 minutes. Chemiluminescent signals were quantitated by the Compass for SW program. Activation of each molecule was expressed as a ratio of the phosphorylated to the total signaling protein. The values of ERK1 and ERK2 were combined. The samples were processed in triplicate and compared using the independent sample t-test (SPSS version 22) with a significant value of <0.05.