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Role of NF-κB in Macrophage Activation
Published in Helmut Brade, Steven M. Opal, Stefanie N. Vogel, David C. Morrison, Endotoxin in Health and Disease, 2020
Because the addition of purified PKC and ATP to cytosol (29) or to partially purified NF-κB–IκB complexes (3) can activate NF-κB, and because PMA, a potent activator of PKC, strongly activates NF-κB in 70Z/3 pre-B cells (30,31), PKC has been considered to mediate phosphorylation of IκB. Based on studies using the PKC inhibitor calphostin C, Lindholm et al. (32) showed the involvement of PKC in human T-cell lymphotropic virus type 1 Tax1-mediated activation of NF-κB in Tax1-transformed C81 cells and Tax1 stimulated murine pre-B cells. More recently, based on results of dominant negative experiments and direct expression experiments, PKCζ was shown to induce phosphorylation and inactivation of IκBα in vitro (33–36). The potential role of PKCε in NF-κB activation was suggested by PKC overexpression experiments with rat fibroblast (3Y1) (37) and human T-cell line (JH6.2) (38). However, Janosch et al. (39) showed that none of the recombinant, purified PKC isozymes α, β, γ, δ, ε, η and ζ were capable of phosphorylating recombinant IkκBα in vitro. Thus, whether phosphorylation of IκBα by PKC is solely responsible for the activation of NF-κB and what PKC isoenzymes are responsible for IκB a phosphorylation remain controversial.
Phosphoinositide Metabolism
Published in Enrique Pimentel, Handbook of Growth Factors, 2017
A number of exogenous inhibitors of protein kinase C have been described but many of them may be unspecific and their action mechanism is frequently unknown. Staurosporine, an alkaloid purified from Streptomyces actuosus, is a potent inhibitor of protein kinase C, but it may also inhibit protein kinase A and tyrosine kinases at similar concentrations. The 7-hydroxy derivative of staurosporine, UCN-10, is a more selective and potent inhibitor of protein kinase C activity. Calphostin C, isolated from the fungus Cladosporium cladosporioides, is potent and more selective for protein kinase C due to its interaction with the regulatory domain of the enzyme.211 The protein K252a, isolated from a microbe (Nocardipsis sp.), inhibits protein kinase C activity in vivo by competing with ATP.212 The application of protein kinase C inhibitors may contribute to the elucidation of the precise functions of the enzyme in normal and tumor cells. The discovery that sangivamycin, a purine nucleotide analog with antitumor activity, is an inhibitor of protein kinase C could open new possibilities for the design of antitumor compounds.213 However, protein kinase C inhibitors may have toxic effects on a number of metabolic processes. The study of mutant cell clones that lack functional protein kinase C molecules may give clues to make clearer the role of the enzyme in physiological processes occurring in different types of cells.214
Integrins as Signal Transducing Receptors
Published in Yoshikazu Takada, Integrins: The Biological Problems, 2017
In HeLa cells, PKC was found to be required for cell spreading and to be involved in an interesting regulatory circuit with arachidonic acid.31,32 The authors observed a rapid release of arachidonic acid, production of diacylglycerol, and translocation of PKC to the plasma membrane upon contact of HeLa cells with gelatin or collagen. These effects preceded cell spreading. Pharmacological inhibition of either arachidonic acid release, or of arachidonic acid metabolism through the lipoxygenase pathway, inhibited DAG production and cell spreading. Spreading could also be blocked by calphostin C, a specific PKC inhibitor. Finally, the inhibition of spreading by blockade of phospholipase A2 or the lipoxygenase could be reversed by exogenous activation of PKC with a phorbol ester. Taken together, these data suggest that initial cell adhesion triggers arachidonic acid release, and that a lipoxygenase metabolite of arachidonate activates PKC, which then triggers cell spreading. It was also observed that PKC activation augmented the release of arachidonic acid, suggesting a positive feedback circuit in which production of diacylglycerol and arachidonate each stimulates the other to amplify an initial signal.
Organic dust-induced lung injury and repair: Bi-directional regulation by TNFα and IL-10
Published in Journal of Immunotoxicology, 2020
T. A. Wyatt, M. Nemecek, D. Chandra, J. M. DeVasure, A. J. Nelson, D. J. Romberger, J. A. Poole
To confirm that PKCζ could be activated in alveolar macrophages – and to connect this activation to HDE-stimulated production of IL-10, the role of PKCζ in cultured MH-S alveolar macrophages was investigated. The data show that HDE (1%) significantly and maximally stimulated PKCζ activity in MH-S cells after 1 h (Figure 7(A)). While 1 h pre-treatment with 1 µM of the pan-PKC isoform-inhibitor Calphostin C inhibited HDE-stimulated TNFα release, specific inhibition of PKCζ by myrZ had no effect on HDE-stimulated TNFα release (Figure 7(B)). Conversely, HDE stimulation of IL-10 release was significantly blocked by either the non-specific (Calphostin C) or specific (myrZ) inhibitors of PKCζ (Figure 7(C)).
New avenues for therapeutic discovery against West Nile virus
Published in Expert Opinion on Drug Discovery, 2020
Alessandro Sinigaglia, Elektra Peta, Silvia Riccetti, Luisa Barzon
The idea of repurposing against viral infections drugs already licensed for other applications was at the basis of the work of Blazquez et al. [169], who assessed the effects on WNV of antiparkinsonian drugs L-dopa, isatin, and amantadine, with the latter in particular resulting in a strong inhibition of WNV replication in vitro. Testing in vivo and understanding the possible molecular mechanisms of action are expected as next steps. The same research group [170] also found that calphostin C and chelerythrine can reduce WNV replication in vitro by inhibiting members of the protein kinase C family. The exact mechanism of antiviral action needs to be better understood.
Undernutrition – thirty years of the Regional Basic Diet: the legacy of Naíde Teodósio in different fields of knowledge
Published in Nutritional Neuroscience, 2022
Larissa B. Jannuzzi, Amaury Pereira-Acacio, Bruna S. N. Ferreira, Debora Silva-Pereira, João P. M. Veloso-Santos, Danilo S. Alves-Bezerra, Jarlene A. Lopes, Glória Costa-Sarmento, Lucienne S. Lara, Leucio D. Vieira, Ricardo Abadie-Guedes, Rubem C.A. Guedes, Adalberto Vieyra, Humberto Muzi-Filho
Finally, RBD was also used in studies involving Ca2+ handling and signaling in heart. de Belchior et al. [79] demonstrated that myocardial contractility is compromised in the offspring of rats that were given RBD during gestation and lactation, which could be ascribed to alterations in intracellular Ca2+ handling. There was a reduction in the myocardial content of SERCA2a and phosphorylated phospholamban, in addition to an increase in the Na+/Ca2+-exchanger protein content. These data indicate that hypertension associated with altered sympathetic and parasympathetic responses in the heart is potentiated by alterations in the abundance of Ca2+-handling proteins. Similar data emerged from Mendes et al. [80] using the post-weaning undernutrition model. Their study demonstrated that RBD induced profound changes in physiological, morphometrical and functional parameters of the heart. Cardiac output, ejection fraction, stroke volume, left ventricle diameter and muscular area were reduced in rats given RBD. Furthermore, recently infarcted areas were evident, indicating that chronically undernourished rats develop heart failure (Figure 7). They also found changes in cardiac contractility, isoproterenol (β1-adrenoceptor agonist)-induced inotropism, and intracellular Ca2+ handling and signaling. Since PMCA activity increased, SERCA activity decreased, non-phosphorylated phospholamban content was augmented, Na+/Ca2+ exchanger content was decreased, and calphostin C-sensitive protein kinase (PKC)-mediated phosphorylations were increased. The authors demonstrated that RBD after weaning completely deregulated the complex machinery by which Ca2+ regulates cardiac function [80].