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Regulation of Growth of Airway Smooth Muscle by Second Messenger Systems
Published in Alastair G. Stewart, AIRWAY WALL REMODELLING in ASTHMA, 2020
Few investigators have examined the role of PtdIns 3-kinase activation in modulating human ASM cell proliferation. A recent study examined whether PtdIns 3-kinase mediated ASM cell growth or modulated calcium transientsinduced by contractile agonists. Thrombin-induced increases in cytosolic calcium were examined in fura-2-loaded cells pretreated with wortmannin, a PtdIns 3-kinase inhibitor.57 As shown in Figure 3A, inhibition of PtdIns 3-kinase did not alter calcium transients induced by thrombin.57 In parallel experiments, confluent ASM cells that were growth arrested for 24 h were pretreated with wortmannin and then stimulated with thrombin or EGF. DNA synthesis was then measured by [3H]-thymidine incorporation. In a dose-dependent manner, wortmannin inhibited thrombin and EGF-induced DNA synthesis as shown in Figure 3B. Wortmannin had no effect on basal levels of [3H]-thymidine incorporation as compared with cells treated with diluent alone. If wortmannin was added 6 h after the cells were stimulated with mitogens, then wortmannin did not inhibit cell proliferation. These data suggest that PtdIns 3-kinase may mediate early signaling events that modulate myocyte growth. Taken together, these studies indicate that PtdIns 3-kinase activation may play an important role in modulating ASM cell proliferation induced by growth factors and contractile agonists.
Integrins, Integrin Regulators, and the Extracellular Matrix
Published in Bruce S. Bochner, Adhesion Molecules in Allergic Disease, 2020
Stephen W. Hunt, Sirid-Aimée Kellermann, Yoji Shimizu
Third, the fungal metabolite wortmannin, a relatively specific inhibitor of PI 3-K, can inhibit inside-out signaling mediated by several different integrin regulators. Wortmannin was initially found to inhibit αIIbβ3-dependent aggregation of platelets induced by thrombin (71). In recent studies, human CD2 and a CD2 chimeric receptor containing the CD28 cytoplasmic domain (CD2/28) were expressed in HL-60 cells, which express β1 integrins that can be rapidly up-regulated by PMA treatment. Stimulation of CD2 or CD2/28 resulted in rapid increases in β1 integrin-mediated adhesion that could be completely inhibited by wortmannin (70,72). The relevance of these findings for our understanding of integrin regulator function on human T cells is suggested by the fact that wortmannin can also inhibit CD2- and CD28-dependent up-regulation of β1 integrin function in peripheral T cells (70 and T. Zell, J. L. Mobley, and Y. Shimizu, unpublished data).
Herbal Products in Antihypertensive Therapy
Published in Dilip Ghosh, Pulok K. Mukherjee, Natural Medicines, 2019
Fernão C. Braga, Steyner F. Côrtes
We evaluated the vasodilator effect induced by an ethanolic extract from mangaba leaves in ex vivo preparations. In rat aortic rings, the extract produced a concentration-dependent vasodilatation (pIC50 = 5.6 ± 0.1), which was completely abolished in endothelium-denuded vessels (Ferreira et al. 2007a). The effect was abolished by l-NAME, but not by atropine or indomethacin. The vasodilator effect was dramatically reduced in the presence of wortmannin, an inhibitor of phosphatidylinositol 3-kinase (PI3K). Based on these findings, we could conclude that the ethanolic extract from mangaba leaves induces a NO- and endothelium-dependent vasodilatation in rat aortic preparations, likely by a mechanism dependent on the activation of PI3K.
Inhibitors of phosphoinositide 3-kinase (PI3K) and phosphoinositide 3-kinase-related protein kinase family (PIKK)
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2023
Xueqin Huang, Li You, Eugenie Nepovimova, Miroslav Psotka, David Malinak, Marian Valko, Ladislav Sivak, Jan Korabecny, Zbynek Heger, Vojtech Adam, Qinghua Wu, Kamil Kuca
In the past few years, PI3K and AKT have become the research objects of targeted cancer therapy due to their crucial roles in the PI3K/AKT/mTOR signalling cascade. At present, a variety of inhibitors have entered clinical research, and they have shown good prospects in clinical trials. Among them, five drugs targeting PI3K have been approved by the FDA for marketing. PIKK and PI3K are two related kinase families with identical origins and very similar kinase structural domains but distinct characteristics. Extensive research on these kinases has demonstrated that inhibiting PIKK family kinases is useful in overcoming resistance to cancer therapy, and so the design and implementation of PIKK inhibitors could be a novel technique for effective cancer and other illness treatment. LY294002, the first-generation PI3K inhibitor, may efficiently inhibit PI3K, mTOR, DNA-PK, and ATM. Wortmannin can inhibit all four isoforms of PI3K, as well as mTOR and DNA-PK. Due to their poor physicochemical properties or adverse effects, both inhibitors have been excluded from further biological evaluation and clinical trials. They are, however, useful chemical tools for the development of other PI3K and PIKK inhibitors. In recent years, as the understanding of PIKK family kinases has deepened, inhibitors related to DNA damage response and mTOR inhibitors have started to appear prevalently in the public spotlight. A broad number of ATM, ATR, DNA-PK, and mTOR inhibitors have entered clinical trials, but only mTOR has an authorised medication on the market.
Nonlinearities in the cellular response to ionizing radiation and the role of p53 therein
Published in International Journal of Radiation Biology, 2021
David Murray, Razmik Mirzayans
In reality, the use of such high doses can be misinformative, as was seen in a study where we were investigating the mechanism by which the drug wortmannin radiosensitizes human cells (Mirzayans et al. 2004). We found that a 1-h pretreatment with 20 μM wortmannin – a known inhibitor of key DDR proteins such ataxia telangiectasia mutated (ATM) and DNA-dependent protein kinase (DNA-PK) – inhibited DSB rejoining in normal fibroblasts exposed to a supra-lethal dose of γ-rays (40 Gy) when assayed by constant-field gel electrophoresis (Mirzayans et al. 2004), supporting the premise that its radiosensitizing effect might be caused by an inhibition of DSB repair proteins. However, this same concentration of wortmannin had little impact on DSB rejoining in fibroblasts exposed to lower doses of IR in the 5–20 Gy range. Clearly, in this cell background, the extrapolation of mechanisms implicated through the use of high/supra-lethal doses to biologically relevant lower doses was not warranted. Thankfully, this obstacle was eliminated with Bill Bonner’s seminal finding that γ-H2AX could provide an incredibly sensitive readout for IR-induced DSBs (Rogakou et al. 1998).
Cellular assays and applied technologies for characterisation of orally administered protein nanoparticles: a systematic review
Published in Journal of Drug Targeting, 2020
Chun Y. Wong, Hani. Al-Salami, Crispin R. Dass
Micropinocytosis and macropinocytosis are actin-independent and -dependent endocytotic mechanism respectively [124]. Particles that are larger than 1 μm usually internalise into cells via macropinocytosis [125]. There are a number of inhibitors including amiloride and dimethylamiloride that can be used to inhibit both macropinocytosis and micropinocytosis pathways [45,64,65]. In contrast, wortmannin is a specific inhibitor for micropinocytosis [76]. The cellular uptake of protein-loaded nanoparticles such as R8-CM-β-CD nanoparticles [64] could be blocked by amiloride due to inhibition of Na+/H+ exchange mechanism. In the meantime, wortmannin reduces 17–53% of protein-loaded nanoparticle uptake via micropinocytosis pathway, which includes FITC-INS/HTCC-LA4 nanoparticles [76] and FITC-INS/HTCCOA10 nanoparticles [76]. When the inhibitors failed to inhibit the uptake of protein-loaded nanoparticle, it would be an indication that the respective endocytotic pathway was irrelevant for cell internalisation [45]. Nevertheless, protein-loaded P22-modified nanoparticles could internalise into cells by amiloride treatment [119].