Relevant bibliographies by topics / PKC inhibitors

Academic literature on the topic 'PKC inhibitors'

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Published: 10 December 2022
Last updated: 28 January 2023

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Journal articles on the topic "PKC inhibitors"

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Saberi, Behnam, Mie Shinohara, Maria D. Ybanez, Naoko Hanawa, William A. Gaarde, Neil Kaplowitz, and Derick Han. "Regulation of H2O2-induced necrosis by PKC and AMP-activated kinase signaling in primary cultured hepatocytes." American Journal of Physiology-Cell Physiology 295, no. 1 (July 2008): C50—C63. http://dx.doi.org/10.1152/ajpcell.90654.2007.

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Recent studies have suggested that, in certain cases, necrosis, like apoptosis, may be programmed, involving the activation and inhibition of many signaling pathways. In this study, we examined whether necrosis induced by H2O2 is regulated by signaling pathways in primary hepatocytes. A detailed time course revealed that H2O2 treated to hepatocytes is consumed within minutes, but hepatocytes undergo necrosis several hours later. Thus, H2O2 treatment induces a “lag phase” where signaling changes occur, including PKC activation, Akt (PKB) downregulation, activation of JNK, and downregulation of AMP-activated kinase (AMPK). Investigation of various inhibitors demonstrated that PKC inhibitors were effective in reducing necrosis caused by H2O2 (∼80%). PKC inhibitor treatment decreased PKC activity but, surprisingly, also upregulated Akt and AMPK, suggesting that various PKC isoforms negatively regulate Akt and AMPK. Akt did not appear to play a significant role in H2O2-induced necrosis, since PKC inhibitor treatment protected hepatocytes from H2O2 even when Akt was inhibited. On the other hand, compound C, a selective AMPK inhibitor, abrogated the protective effect of PKC inhibitors against necrosis induced by H2O2. Furthermore, AMPK activators protected against H2O2-induced necrosis, suggesting that much of the protective effect of PKC inhibition was mediated through the upregulation of AMPK. Work with PKC inhibitors suggested that atypical PKC downregulates AMPK in response to H2O2. Knockdown of PKC-α using antisense oligonucleotides also slightly protected (∼22%) against H2O2. Taken together, our data demonstrate that the modulation of signaling pathways involving PKC and AMPK can alter H2O2-induced necrosis, suggesting that a signaling “program” is important in mediating H2O2-induced necrosis in primary hepatocytes.
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Silva, J. M., M. Hamel, M. Sahmi, and C. A. Price. "Control of oestradiol secretion and of cytochrome P450 aromatase messenger ribonucleic acid accumulation by FSH involves different intracellular pathways in oestrogenic bovine granulosa cells in vitro." Reproduction 132, no. 6 (December 2006): 909–17. http://dx.doi.org/10.1530/rep-06-0058.

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The objective of this study was to determine the major intracellular signalling pathways used by FSH and insulin to stimulate cytochrome P450 aromatase (Cyp19) mRNA and oestradiol accumulation in oestrogenic bovine granulosa cellsin vitro. Bovine granulosa cells from small follicles (2–4 mm diameter) were cultured for 6 days under non-luteinizing conditions in the presence of insulin at 100 ng/ml, or insulin (10 ng/ml) and FSH (1 ng/ml). On day 4 of culture, specific inhibitors of phosphatidylinositol 3-kinase (PI3K; LY-294002), protein kinase C (PKC; GF-109203X), protein kinase A (PKA; H-89) or mitogen-activated protein (MAP) kinase activation (PD-98059) were added. The addition of PI3K and PKC inhibitors, but not of PKA inhibitor, significantly decreased insulin-stimulated Cyp19 mRNA levelsand oestradiol accumulation (P< 0.001). The PKA inhibitor significantly decreased FSH-stimulated Cyp19 mRNA abundance and oestradiol secretion, whereas PI3K and PKC inhibitors decreased oestradiol secretion without affecting Cyp19 mRNA accumulation. Inhibition of MAP kinase pathway significantly increased Cyp19 mRNA abundance ininsulin- and FSH-stimulated cells.P450scc mRNA levels and progesterone secretion were not affected by any inhibitor in either experiment. Although FSH stimulates Cyp19 expression predominantly through PKA, oestradiol secretion is altered by PI3K and PKC pathways independently of Cyp19 mRNA levels. In addition, we suggest that Cyp19 is under tonic inhibition mediated through a MAP kinase pathway.
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Liedtke, Carole M., and Thomas Cole. "Antisense oligodeoxynucleotide to PKC-δ blocks α1-adrenergic activation of Na-K-2Cl cotransport." American Journal of Physiology-Cell Physiology 273, no. 5 (November 1, 1997): C1632—C1640. http://dx.doi.org/10.1152/ajpcell.1997.273.5.c1632.

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A role for protein kinase C (PKC)-δ and -ζ isotypes in α1-adrenergic regulation of human tracheal epithelial Na-K-2Cl cotransport was studied with the use of isotype-specific PKC inhibitors and antisense oligodeoxynucleotides to PKC-δ or -ζ mRNA. Rottlerin, a PKC-δ inhibitor, blocked 72% of basolateral-to-apical, bumetanide-sensitive36Cl flux in nystatin-permeabilized cell monolayers stimulated with methoxamine, an α1-adrenergic agonist, with a 50% inhibitory concentration of 2.3 μM. Methoxamine increased PKC activity in cytosol and a particulate fraction; the response was insensitive to PKC-α and -βIIisotype-specific inhibitors, but was blocked by general PKC inhibitors and rottlerin. Rottlerin also inhibited methoxamine-induced PKC activity in immune complexes of PKC-δ, but not PKC-ζ. At the subcellular level, methoxamine selectively elevated cytosolic PKC-δ activity and particulate PKC-ζ activity. Pretreatment of cell monolayers with antisense oligodeoxynucleotide to PKC-δ for 48 h reduced the amount of whole cell and cytosolic PKC-δ, diminished whole cell and cytosolic PKC-δ activity, and blocked methoxamine-stimulated Na-K-2Cl cotransport. Sense oligodeoxynucleotide to PKC-δ and antisense oligodeoxynucleotide to PKC-ζ did not alter methoxamine-induced cotransport activity. These results demonstrate the selective activation of Na-K-2Cl cotransport by cytosolic PKC-δ.
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Hu, Hui-Juan, and Robert W. Gereau. "ERK Integrates PKA and PKC Signaling in Superficial Dorsal Horn Neurons. II. Modulation of Neuronal Excitability." Journal of Neurophysiology 90, no. 3 (September 2003): 1680–88. http://dx.doi.org/10.1152/jn.00341.2003.

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Protein kinases belonging to the protein kinase A (PKA), protein kinase C (PKC), and extracellular signal-related kinase (ERK) families have been identified as key players in modulating nociception at the level of the spinal cord dorsal horn, yet little is known about the effects of these kinases on membrane properties of the dorsal horn neurons. PKA, PKC, and ERK exert inhibitory effects on transient potassium currents (A-type currents or IA) in mouse superficial dorsal horn neurons ( Hu et al. 2003 ). Here we aimed to determine the effects of these kinases on action potential firing and membrane properties of these neurons to evaluate the impact of the modulation of IA (and other conductances) in these neurons. We found that activating PKC and PKA has dramatic effects on action potential firing, reflecting an increase in the excitability of superficial dorsal horn neurons. In addition, we found that inhibitors of both PKC and ERK signaling decrease the excitability of dorsal horn neurons, suggesting that these kinases exert a tonic excitation of these cells. Consistent with our findings that these kinases inhibit A-type currents, we found that PKA, PKC, and ERK act to shorten the first-spike latency after depolarization induced by current injection. In addition, activation of these kinases increases spike frequency and action potential amplitude of dorsal horn neurons. Interestingly, we found that the effects of PKA and PKC activators are blocked by inhibitors of ERK signaling, suggesting that PKA and PKC may exert their actions by activation of ERKs.
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Reilein, Amy R., Irina S. Tint, Natalia I. Peunova, Grigori N. Enikolopov, and Vladimir I. Gelfand. "Regulation of Organelle Movement in Melanophores by Protein Kinase A (PKA), Protein Kinase C (PKC), and Protein Phosphatase 2A (PP2A)." Journal of Cell Biology 142, no. 3 (August 10, 1998): 803–13. http://dx.doi.org/10.1083/jcb.142.3.803.

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We used melanophores, cells specialized for regulated organelle transport, to study signaling pathways involved in the regulation of transport. We transfected immortalized Xenopus melanophores with plasmids encoding epitope-tagged inhibitors of protein phosphatases and protein kinases or control plasmids encoding inactive analogues of these inhibitors. Expression of a recombinant inhibitor of protein kinase A (PKA) results in spontaneous pigment aggregation. α-Melanocyte-stimulating hormone (MSH), a stimulus which increases intracellular cAMP, cannot disperse pigment in these cells. However, melanosomes in these cells can be partially dispersed by PMA, an activator of protein kinase C (PKC). When a recombinant inhibitor of PKC is expressed in melanophores, PMA-induced pigment dispersion is inhibited, but not dispersion induced by MSH. We conclude that PKA and PKC activate two different pathways for melanosome dispersion. When melanophores express the small t antigen of SV-40 virus, a specific inhibitor of protein phosphatase 2A (PP2A), aggregation is completely prevented. Conversely, overexpression of PP2A inhibits pigment dispersion by MSH. Inhibitors of protein phosphatase 1 and protein phosphatase 2B (PP2B) do not affect pigment movement. Therefore, melanosome aggregation is mediated by PP2A.
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Itoh, Hiroyuki, Shinji Yamamura, J. Anthony Ware, Shaobin Zhuang, Shinsuke Mii, Bo Liu, and K. Craig Kent. "Differential effects of protein kinase C on human vascular smooth muscle cell proliferation and migration." American Journal of Physiology-Heart and Circulatory Physiology 281, no. 1 (July 1, 2001): H359—H370. http://dx.doi.org/10.1152/ajpheart.2001.281.1.h359.

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Vascular smooth muscle cell (SMC) migration and proliferation contribute to intimal hyperplasia, and protein kinase C (PKC) may be required for both events. In this report, we investigated the role of PKC in proliferation and migration of SMC derived from the human saphenous vein. Activation of PKC by phorbol-12,13-dibutyrate (PDBu) or (−)-indolactam [(−)-ILV] increases SMC proliferation. Downregulation of PKC activity by prolonged incubation with phorbol ester or inhibition of PKC with chelerythrine in SMC diminished agonist-stimulated proliferation. In contrast, stimulation of PKC with PDBu or (−)-ILV inhibited basal and agonist-induced SMC chemotaxis. Moreover, downregulation of PKC or inhibition with chelerythrine accentuated migration. We postulated that the inhibitory effect of PKC on SMC chemotaxis was mediated through cAMP-dependent protein kinase (protein kinase A, PKA). In support of this hypothesis, we found that activation of PKC in SMC stimulated PKA activity. The cAMP agonist forskolin significantly inhibited SMC chemotaxis. Furthermore, the inhibitory effect of PKC on SMC chemotaxis was completely reversed by cAMP or PKA inhibitors. In search of the PKC isotype(s) underlying these differential effects of PKC in SMC, we identified eight isotypes expressed in human SMC. Only PKC-α, -βI, -δ, and -ε were eliminated by downregulation, suggesting that one or more of these four enzymes facilitate the observed phorbol ester-dependent effects of PKC in SMC. In summary, we found that PKC activation enhances proliferation but inhibits migration of human vascular SMC. These differential effect of PKC on vascular cells appears to be mediated through PKC-α, -βI, -δ, and/or -ε.
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Wilkinson, S. E., and J. S. Nixon. "PKC Inhibitors in the Therapy of Autoimmune Diseases." Current Pharmaceutical Design 2, no. 6 (December 1996): 596–609. http://dx.doi.org/10.2174/1381612802666221004184418.

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The protein kinase C ( PKC) family of isoenzymes was thought to mediate a wide range of signal transduction processes in cells. However, it is now widely accepted that its role may have been overstated. The advent of selective PKC inhibitors has led to a re-appraisal of the role this enzyme plays in these processes. This review shows how the structural lead provided by staurosporine, a non-selective protein kinase inhibitor, was used as a basis for the design of substituted bisindolylmaleimides with significantly improved selectivity for protein kinase C over cAMP-dependent protein kinase and phophorylase kinase. Evidence from studies with these inhibitors implicates PKC in inflammatory responses such as the neutrophil respiratory burst and antigen-driven T cell proliferation. Potent, orally bioavailable bisindolylmaleimide PKC inhibito_rs such as Ro 32-0432 inhibit phorbol ester -induced inflammation in rodents. These agents also selectively inhibit T cell mediated responses in animal models of arthritis and encephalomyelitis. Taken together, these results suggest that selective inhibitors of PKC may be useful in the therapy of autoimmune diseases such as rheumatoid arthritis, multiple sclerosis and psoriasis.
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Liu, Wen, Yuan Wei, Peng Sun, Wen-Hui Wang, Thomas R. Kleyman, and Lisa M. Satlin. "Mechanoregulation of BK channel activity in the mammalian cortical collecting duct: role of protein kinases A and C." American Journal of Physiology-Renal Physiology 297, no. 4 (October 2009): F904—F915. http://dx.doi.org/10.1152/ajprenal.90685.2008.

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Flow-stimulated net K secretion ( JK) in the cortical collecting duct (CCD) is mediated by an iberiotoxin (IBX)-sensitive BK channel, and requires an increase in intracellular Ca2+ concentration ([Ca2+]i). The α-subunit of the reconstituted BK channel is phosphorylated by PKA and PKC. To test whether the BK channel in the native CCD is regulated by these kinases, JK and net Na absorption ( JNa) were measured at slow (∼1) and fast (∼5 nl·min−1·mm−1) flow rates in rabbit CCDs microperfused in the presence of mPKI, an inhibitor of PKA; calphostin C, which inhibits diacylglycerol binding proteins, including PKC; or bisindolylmaleimide (BIM) and Gö6976, inhibitors of classic and novel PKC isoforms, added to luminal (L) and/or basolateral (B) solutions. L but not B mPKI increased JK in CCDs perfused at a slow flow rate; a subsequent increase in flow rate augmented JK modestly. B mPKI alone or with L inhibitor abolished flow stimulation of JK. Similarly, L calphostin C increased JK in CCDs perfused at slow flow rates, as did calphostin C in both L and B solutions. The observation that IBX inhibited the L mPKI- and calphostin C-mediated increases in JK at slow flow rates implicated the BK channel in this K flux, a notion suggested by patch-clamp analysis of principal cells. The kinase inhibited by calphostin C was not PKC as L and/or B BIM and Gö6976 failed to enhance JK at the slow flow rate. However, addition of these PKC inhibitors to the B solution alone or with L inhibitor blocked flow stimulation of JK. Interpretation of these results in light of the effects of these inhibitors on the flow-induced elevation of [Ca2+]i suggests that the principal cell apical BK channel is tonically inhibited by PKA and that flow stimulation of JK in the CCD is PKA and PKC dependent. The specific targets of the kinases remain to be identified.
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Wu, D., I. J. Clarke, and C. Chen. "The role of protein kinase C in GH secretion induced by GH-releasing factor and GH-releasing peptides in cultured ovine somatotrophs." Journal of Endocrinology 154, no. 2 (August 1997): 219–30. http://dx.doi.org/10.1677/joe.0.1540219.

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Abstract The involvement of protein kinase C (PKC) in the action of GH-releasing factor (GRF) and synthetic GH-releasing peptides (GHRP-2 and GHRP-6) was investigated in ovine somatotrophs in primary culture. In partially purified sheep somatotrophs, GRF and GHRP-2 caused translocation of PKC activity from the cytosol to the cell membranes and caused GH release in a dose- and time-dependent manner. GHRP-6 did not cause PKC translocation. The PKC inhibitors, calphostin C, staurosporine and chelerythrine, partially reduced GH release in response to GRF and GHRP-2 at doses which selectively inhibit PKC activity. These inhibitors totally abolished GH release caused by phorbol 12-myristate 13-acetate (PMA). Down-regulation of PKC by the treatment of cells with phorbol 12,13-dibutyrate for 16 h caused a significant (P<0·001) reduction in total PKC activity and totally abolished PKC translocation in response to a challenge with GRF, GHRP-2 or PMA. In addition, down-regulation abolished GH release in response to GRF, GHRP-2 or GHRP-6. Treatment of cells with H89, a selective PKA inhibitor, totally blocked GH release caused by either GRF or GHRP-2 and partially reduced PMA-induced GH release. H89 had no effect on PKC translocation caused by GRF, GHRP-2 or PMA and did not affect GH release caused by GHRP-6. These data suggest that GHRP-2 and GRF activate PKC in addition to stimulating adenylyl cyclase activity. Although the cAMP–protein kinase A (PKA) pathway is the major signalling pathway employed by GRF and GHRP-2, the activation of PKC may potentiate signalling via the cAMP–PKA pathway in ovine GH secretion. Importantly, the effect of PMA in increasing the secretion of GH from ovine somatotrophs is effected, in part, by up-regulation of the cAMP–PKA pathway. We conclude that there is cross-talk between the PKC pathway and the cAMP–PKA pathway in ovine somatotrophs during the action of GRF or GHRP. Journal of Endocrinology (1997) 154, 219–230
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Takahashi, Hideyuki, and Hideo Namiki. "Mechanism of membrane redistribution of protein kinase C by its ATP-competitive inhibitors." Biochemical Journal 405, no. 2 (June 27, 2007): 331–40. http://dx.doi.org/10.1042/bj20070299.

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ATP-competitive inhibitors of PKC (protein kinase C) such as the bisindolylmaleimide GF 109203X, which interact with the ATP-binding site in the PKC molecule, have also been shown to affect several redistribution events of PKC. However, the reason why these inhibitors affect the redistribution is still controversial. In the present study, using immunoblot analysis and GFP (green fluorescent protein)-tagged PKC, we showed that, at commonly used concentrations, these ATP-competitive inhibitors alone induced redistribution of DAG (diacylglycerol)-sensitive PKCα, PKCβII, PKCδ and PKCϵ, but not atypical PKCζ, to the endomembrane or the plasma membrane. Studies with deletion and point mutants showed that the DAG-sensitive C1 domain of PKC was required for membrane redistribution by these inhibitors. Furthermore, membrane redistribution was prevented by the aminosteroid PLC (phospholipase C) inhibitor U-73122, although an ATP-competitive inhibitor had no significant effect on acute DAG generation. Immunoblot analysis showed that an ATP-competitive inhibitor enhanced cell-permeable DAG analogue- or phorbol-ester-induced translocation of endogenous PKC. Furthermore, these inhibitors also enhanced [3H]phorbol 12,13-dibutyrate binding to the cytosolic fractions from PKCα–GFP-overexpressing cells. These results clearly demonstrate that ATP-competitive inhibitors cause redistribution of DAG-sensitive PKCs to membranes containing endogenous DAG by altering the DAG sensitivity of PKC and support the idea that the inhibitors destabilize the closed conformation of PKC and make the C1 domain accessible to DAG. Most importantly, our findings provide novel insights for the interpretation of studies using ATP-competitive inhibitors, and, especially, suggest caution about the interpretation of the relationship between the redistribution and kinase activity of PKC.
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Dissertations / Theses on the topic "PKC inhibitors"

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Aaltonen, V. (Vesa). "PKC and neurofibromin in the molecular pathology of urinary bladder carcinoma:the effect of PKC inhibitors on carcinoma cell junctions, movement and death." Doctoral thesis, University of Oulu, 2007. http://urn.fi/urn:isbn:9789514285899.

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Abstract This study examined the role of tumor suppressor neurofibromin and Protein kinase C (PKC) in urinary bladder cancer, and the effect of PKC inhibitors on cancer cell behaviour. Tumor suppressor protein neurofibromin is a product of the NF1 gene, a mutation of which causes the most common hereditary tumor syndrome, type 1 neurofibromatosis. NF1 gene mutations and changes in expression have been demonstrated in malignancies, unrelated to type 1 neurofibromatosis. The best known function of neurofibromin is its Ras GTPase accelerating function. Thus, it functions as a Ras inactivator. This study demonstrated for the first time that the NF1 gene is expressed in normal and malignant urinary bladder epithelium and in cultured bladder carcinoma cells in mRNA and at the protein level. Furthermore, neurofibromin expression is decreased during bladder carcinogenesis. It can be speculated that this may lead to increased Ras activity in urinary bladder cancer. The PKC family is composed of several different isoenzymes which are responsible for a number of important intracellular events and cellular functions. Many of these are also important in cancer development and progression. The results demonstrate changes in expression of PKC α and βI isoenzymes in urinary bladder carcinoma. Furthermore, the results relate the increased expression of isoenzymes to increased PKC enzyme activity and the high proliferation rate of the cancer cells. In addition, this study utilizes small molecular inhibitors of PKC isoenzymes in order to study the effect of the inhibition of these isoenzymes on cancer cell behaviour in vitro and in vivo. The study mainly focuses on the function of PKC α and βI isoenzymes and on the effects of inhibition of these by using Go6976. The results show that Go6976 inhibits cancer cell growth, migration and invasion in vitro, and tumor growth in a mouse model. The use of Go6976 induces changes in desmosomes and adherens junctions, and in focal adhesions and hemidesmosomes. The results also show that Go6976 functions as a cell cycle checkpoint abrogator and increases the cytotoxicity of two classical chemotherapeutic agents, doxorubicin and paclitaxel. In the future, it may be possible that Go6976 or related drugs could be used in clinical cancer treatments.
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Ratnayake, Wishrawana Sarathi Bandara. "Role of Oncogenic Protein Kinase C-iota in Melanoma Progression; A Study Based on Atypical Protein Kinase-C Inhibitors." Scholar Commons, 2019. https://scholarcommons.usf.edu/etd/7895.

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Irrespective of plentiful efforts to enhance primary prevention and early detection, the number of melanoma cases in the United States has increased steadily over the past 30 years, thus greatly affecting public health and the economy. We have investigated the effects of five novel aPKC inhibitors; 2-acetyl-1,3-cyclopentanedione (ACPD), 3,4-Diaminonaphthalene-2,7-disulfonic acid (DNDA), [4-(5-amino-4-carbamoylimidazol-1-yl)-2,3-dihydroxycyclopentyl] methyl dihydrogen phosphate (ICA-1T) along with its nucleoside analog 5-amino-1-((1R,2S,3S,4R)-2,3-dihydroxy-4-methylcyclopentyl)-1H-imidazole-4-carboxamide (ICA-1S) and 8-hydroxy-1,3,6-naphthalenetrisulfonic acid (ζ-Stat) on cell proliferation, apoptosis, migration and invasion of two malignant melanoma cell lines compared to normal melanocyte cell lines. Molecular docking data suggested that both ACPD and DNDA specifically bind to protein kinase C-zeta (PKC-ζ) and PKC-iota (PKC-ι) while both ICA-1 compounds specifically bind to PKC-ι, and ζ-Stat showed a high affinity towards PKC-ζ. Kinase activity assays were carried out to confirm these observations. Results suggest that PKC-ι is involved in melanoma malignancy than PKC-ζ. Both isoforms promote the activation of nuclear factor (NF)-κB and protein kinase B (AKT) thereby supporting survival and progression. In addition, we demonstrated that PKC-ι induced the metastasis of melanoma cells by activating Vimentin, and PKC-ι inhibition downregulated epithilial-mesencymal transition (EMT), while inducing apoptosis. Of note, PKC-ἱ specific inhibitors downregulated the expression of both PKC-ι and phosphorylated PKC-ι, suggesting that PKC-ι plays a role in regulating its own expression in melanoma. We also report the underlaying mechanisms of the transcriptional regulation of PKC-ι (PRKCI gene) expression in melanoma. c-Jun, interferon-stimulated gene factor 3 (ISGF3), paired box gene 3 (PAX3), early growth response protein 1 (EGR1) and forkhead box protein O1 (FOXO1), which bind on or near the promoter sequence of the PRKCI gene, were analyzed for their role in PKC-ι regulation in SK-MEL-2 and MeWo cell lines. We silenced selected transcription factors using siRNA, and the results revealed that the silencing of c-Jun and FOXO1 significantly altered the expression of PRKCI. The levels of both phosphorylated and total PKC-ι increased upon FOXO1 silencing and decreased upon c-Jun silencing, suggesting that c-Jun acts as an upregulator, while FOXO1 acts as a downregulator of PRKCI expression. We also used a multiplex ELISA to analyze multiple pathways other than NF-κB that were affected by treatment with PKC-ι inhibitor. The silencing of NF-κB p65 and PKC-ι by siRNA suggested that the regulation of PKC-ι expression was strongly associated with FOXO1. In addition, we observed a significant decrease in the mRNA levels of both interleukin (IL)-6 and IL-8, with a significant increase in the levels of IL-17E and intercellular adhesion molecule 1 (ICAM-1) upon the knockdown of expression of PKC-ι in both cell lines. This suggested that PKC-ι expression was affected by these cytokines in an autocrine manner. Overall, the findings of this study suggest that PKC-ι inhibition suppresses its own expression, diminishing oncogenic signaling, while upregulating anti-tumor signaling, thus rendering it an effective novel biomarker for use in the design of novel targeted therapeutics for melanoma.
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Panek, Anna [Verfasser]. "Rolle des Connective Tissue Growth Factors (CTGF) und des PKC-enhanced Protein-Phosphatase 1 Inhibitors (KEPI) für die Funktion des adulten Herzen : Studien an transgenen Tiermodellen / Anna Naila Panek." Berlin : Freie Universität Berlin, 2008. http://d-nb.info/1023375095/34.

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Lakshmanan, Aparna. "Modulation of Sodium Iodide Symporter-mediated Thyroidal Radioiodide Uptake by Small Molecule Inhibitors, Natural Plant-based Products and microRNAs." The Ohio State University, 2015. http://rave.ohiolink.edu/etdc/view?acc_num=osu1429407914.

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Esvan, Yannick. "Conception et synthèse de nouveaux composés hétéroaromatiques inhibiteurs potentiels de kinases." Thesis, Clermont-Ferrand 2, 2016. http://www.theses.fr/2016CLF22743.

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Depuis la mise en évidence de l’existence des protéines kinases vers la fin des années 1950 cette famille d’enzymes s’est vu attribuer d’importants rôles dans divers mécanismes pathologiques notamment dans des processus de cancérisations. Plus récemment ces enzymes ont été identifiées comme potentiellement impliquées dans d’autres types de maladies telles que les maladies neurodégénératives.Deux projets de recherche seront présentés. Le premier projet expose la conception et la synthèse de nouveaux composés tricycliques de la famille des pyrido[3,4-g]quinazolines. Les propriétés inhibitrices de kinases des premiers dérivés ont été évaluées sur un panel de cinq kinases (CDK5, CK1, GSK3, CLK1 and DYRK1A) connues pour leurs implications dans la maladie d’Alzheimer. L’intérêt de ces nouveaux squelettes tricycliques comme inhibiteurs de kinases a été validé par des activités inhibitrices nanomolaire à l’encontre des kinases DYRK1A et CLK1. D’autre part l’obtention de structures co-crystallographiques d’interaction de deux dérivés avec le site ATP de la kinase CLK1 a permis de rationnaliser la substitution du motif pyrido[3,4-g]quinazoline. Le second projet présente le développement d’un nouveau dérivé de la staurosporine aglycone (K252c) dans lequel la partie lactame a été remplacée par un noyau pyrazole. Une étude préliminaire des propriétés biologiques de l’indolopyrazolocarbazole obtenu met en avant une cytotoxicité, du même ordre de grandeur que K252c, contre les lignées cellulaires K562 (leucémie humaine) et HCT116 (carcinome du colon). En revanche, le composé chef de file s’est révélé être un faible inhibiteur de cibles connues de K252c, les isoformes α and γ de la protéine kinase C et présente un bon potentiel inhibiteur des kinases Pim 1-3. Ce nouveau chemotype pourrait être un inhibiteur de kinases prometteur
In 1950’s protein kinases were found to play a critical role in cell signaling, rising strong research potential for this enzyme family. Initially investigated for their implications in cancerogenesis they were more recently found to be involved in a wide variety of diseases including neurodegenerative pathologies. Herein will be presented two research projects that offer bright new perspectives for the inhibition of kinases involved whether in neurodegenerative diseases or cancers.First, the design and synthesis of new pyrido[3,4-g]quinazoline derivatives will be described as well as their protein kinase inhibitory potencies toward five CMGC family members (CDK5, CK1, GSK3, CLK1 and DYRK1A) that are known to play a potential role in Alzheimer’s disease. The interest for this original tricyclic heteroaromatic scaffold as modulators of CLK1/ DYRK1A activity was validated by nanomolar potencies. CLK1 co-crystal structures with two inhibitors revealed the binding mode of these compounds within the ATP-binding pocket and led to the synthesis of new diversely substituted pyrido[3,4-g]quinazolines.Then the synthesis of a new derivative of the staurosporine aglycon (K252c), in which the lactam ring was replaced by a pyrazole moiety, will be depicted. The resulting indolopyrazolocarbazole inhibited Pim isoforms 1–3 whereas it did not impair the activity of two known targets of K252c, protein kinase C isoforms α and γ . The lead compound exhibited same cytotoxic activity as K252c toward both human leukemia and colon carcinoma cell lines (K562 and HCT116), strongly suggesting that this new scaffold deserves further investigations for treatment of malignancies associated with kinases activities
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Trachsel, Sébastien Auguste Charles. "Selective responses (Actin polymerization, shape changes, locomotion, pinocytosis) to the PKC-inhibitor Ro 31-8220 suggest thath PKC discriminately regulates functions of human blood lymphocytes /." [S.l : s.n.], 1996. http://www.ub.unibe.ch/content/bibliotheken_sammlungen/sondersammlungen/dissen_bestellformular/index_ger.html.

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Makhoul, Stephanie [Verfasser]. "GPIb-V-IX- and GPVI-specific intracellular signaling and their regulation by PKA/PKG-dependent inhibitory pathways in washed human platelets / Stephanie Makhoul." Mainz : Universitätsbibliothek Mainz, 2019. http://d-nb.info/1194096891/34.

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Hofstetter, Barbara. "Klinisch relevante PKC-Inhibitoren als radiosensibilisierende Substanzen für Tumorzellen genaue Untersuchung der Wirkung auf die PI3K/Akt-Signalübermittlungskaskade /." Zürich : ETH, Eidgenössische Technische Hochschule Zürich, Departement Angewandte Biowissenschaften, Institut für Pharmazeutische Wissenschaften, 2001. http://e-collection.ethbib.ethz.ch/show?type=dipl&nr=5.

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Heinzmann, Kathrin. "Investigating the effects or AKT/PKB inhibitors on [18F]-FDG uptake in cancer cells." Thesis, Institute of Cancer Research (University Of London), 2012. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.553702.

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Increased AKT activity due to hyperactivated PI3K or inactivation of PTEN is frequently found in cancer. Thus the development of AKT inhibitors and pharmacodynamic (PO) biomarkers for AKT inhibition is of major interest for cancer therapy. [18F]-FDG PET is a non-invasive imaging technique which allows the isualization of glucose metabolism. As AKT activity has been associated with glucose uptake and phosphorylation, it has been hypothesized that CSF]-FOG PET is a potential PO biomarker for the assessment of AKT inhibitor action in the clinic. The primary aim of the work presented in this thesis was to investigate whether (18F]-FOG uptake can be used as a PO biomarker for AKT inhibition. An in vitro system was established including assembly of a gamma counter which was used to demonstrate that both ATP competitive and allosteric inhibitors of AKT block [18F]-FDG uptake in the PTEN null U87MG human glioblastoma cell line. These results led to a detailed investigation of the mechanism(s) by which the AKT inhibitors affect [18F]-FDG uptake. However, no change in expression or translocation of the glucose transporters GLUT-1 and GLUT-4, or in hexokinase phosphorylation or activity was seen after inhibitor treatment. Reduction of [18F]-FDG uptake was then confirmed with a later generation of AKT inhibitors and in a second cellular model, namely the human breast cancer cell line BT474. These results were also complimented by MRS studies of lactate production. AKT knock down studies using siRNA were also carried out. However, complete functional removal of AKT was not achieved, although AKT protein level was substantially reduced. In addition, in vivo studies demonstrated that [18F]-FDG uptake and AKT signalling were decreased in U87MG xenografts by the AKT inhibitor CCT129254. Hence, it was concluded that [18F]-FDG uptake can be used as a PD biomarker of AKT inhibition for the types of compound studied.
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Gottlieb, Rachel. "Use of S. pombe to Characterize Mammalian Adenylyl Cyclases and Their Inhibitors." Thesis, Boston College, 2015. http://hdl.handle.net/2345/bc-ir:104220.

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Thesis advisor: Charles Hoffman
The study of mammalian cAMP signaling has often been confounded by the fact that ten different genes encode adenylyl cyclases (ACs) that produce cAMP from ATP and 16 different genes encode phosphodiesterases (PDEs) that hydrolyze cAMP to AMP. In this study, mammalian AC cDNAs were cloned and integrated into strains of the fission yeast Schizosaccharomyces pombe that lack their endogenous AC to determine the basal activity of all ten AC isoforms. In addition, response to the stimulatory mammalian Gsα was determined by co-expression of a mutationally-activated form of the human GNAS1 gene. AC activity was assessed using an fbp1-GFP reporter that is repressed by cAMP production and PKA activity. Results confirm that all ten isoforms have detectable basal activity, and AC1-9 definitively respond to Gsα stimulation. When matched with a sufficiently potent mammalian phosphodiesterase (PDE), strains expressing mammalian ACs make good candidates for small molecule high throughput screening (HTS) to detect AC inhibitors. A 100,000 compound screen was recently performed to detect AC and Gsα inhibitors as well as PDE activators. A promising “hit” was progesterone, which has been previously suggested to inhibit ACs in Xenopus. Initial results suggest that progesterone inhibits AC1 and the closely-related AC3. These data demonstrate the utility of using S. pombe as an effective platform for identifying inhibitors of both basal and GNAS1-stimulated AC activity
Thesis (BS) — Boston College, 2015
Submitted to: Boston College. College of Arts and Sciences
Discipline: Departmental Honors
Discipline: Biology
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Book chapters on the topic "PKC inhibitors"

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Soro-Paavonen, Aino, and Mark Cooper. "Glycosylation Inhibitors, PKC Inhibitors and Related Interventions Against Complications." In Pharmacotherapy of Diabetes: New Developments, 219–28. Boston, MA: Springer US, 2007. http://dx.doi.org/10.1007/978-0-387-69737-6_20.

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Young, Lindon H., Aisha Phillipson, Didi Omiyi, Norrell Atkinson, Manoj Jivani, Jovan Adams, Ellen E. Peterman, Philip Taormina, Richard J. Brue, and Margaret Harvey. "Protein Kinase C Isoform (PKC) Peptide Activator/Inhibitors Exert Cardioprotective Effects in Polymorphonuclear Leukocyte (PMN)-induced Ischemia/Reperfusion (I/R) Injury." In Understanding Biology Using Peptides, 457–58. New York, NY: Springer New York, 2006. http://dx.doi.org/10.1007/978-0-387-26575-9_194.

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Zoukhri, Driss, Philippe Mauduit, and Bernard Rossignol. "Characterization of Rat Lacrimal Gland Protein Kinase C: Effects of Phorbol Esters and PKC Inhibitors on Histone Kinase Activity and Labelled Protein Discharge." In Advances in Experimental Medicine and Biology, 121–25. Boston, MA: Springer US, 1994. http://dx.doi.org/10.1007/978-1-4615-2417-5_21.

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de Medeiros, Ana Santos, Grace Kwak, Jordan Vanderhooft, Sam Rivera, Rachel Gottlieb, and Charles S. Hoffman. "Fission Yeast-Based High-Throughput Screens for PKA Pathway Inhibitors and Activators." In Methods in Molecular Biology, 77–91. New York, NY: Springer New York, 2014. http://dx.doi.org/10.1007/978-1-4939-2269-7_6.

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Williams, R. E., B. R. Chakravarthy, and J. P. Durkin. "Minimum structural requirements of myristoylated protein kinase C (PKC) inhibitory peptides: Minimizing the structure of a MARCKS protein derived peptide." In Peptides 1994, 662–63. Dordrecht: Springer Netherlands, 1995. http://dx.doi.org/10.1007/978-94-011-1468-4_303.

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Bentley, Fiona K., and Julian J. Eaton-Rye. "The Effect of Protein Synthesis Inhibitors on Recovery of Photodamaged Photosystem II in Synechocystis sp. PCC 6803 Lacking PsbM or PsbT." In Photosynthesis. Energy from the Sun, 711–14. Dordrecht: Springer Netherlands, 2008. http://dx.doi.org/10.1007/978-1-4020-6709-9_158.

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Egbring, R., R. Seitz, L. Lerch, G. Fuchs, H. Blanke, M. Wolf, and T. Menges. "Disseminierte intravaskuläre Gerinnung (DIG): Diagnostik mit Hilfe von Proteinase-Inhibitor-Komplexen (PIC), Therapie mit Antithrombin III-Konzentraten und anderen Plasmaderivaten." In 17. Hämophilie-Symposion, 393–402. Berlin, Heidelberg: Springer Berlin Heidelberg, 1988. http://dx.doi.org/10.1007/978-3-642-72830-3_93.

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Liu, Zhaoping, Andrea Gomez-Donart, Caroline Weldon, Nina Senutovitch, and John O’Rourke. "Developing a Novel Multiplexed Immune Assay Platform to Screen Kinase Modulators of T Cell Activation." In High-Throughput Screening for Drug Discovery [Working Title]. IntechOpen, 2021. http://dx.doi.org/10.5772/intechopen.97304.

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T cell activation plays a central role in inflammation, autoimmune diseases and cancer. Cancer immunotherapies, such as immune checkpoint inhibitor, bi-specific antibody, chimeric antigen receptor T (CAR T) cell, and adoptive tumor-infiltrating lymphocyte (TIL) therapies require the characterization and monitoring of T cell activation. Here we describe a novel, multiplex immune assay platform based on high-throughput flow cytometry technology and advanced computational algorithms for data analysis. The assay simultaneously measures T cell dynamics including phenotype, time-dependent expression of activation markers, secreted effector cytokines, and proliferation. The assay screened a kinase chemogenomic library and identified 25 kinase inhibitors with distinct inhibition profiles on early (CD69) and late (CD25) activation markers and the cytokines IFNγ and TNFα. We identified 5 kinase inhibitors with dissimilar effects on CD69 and CD25 expression, and a cluster of total 4 MEK1//2 inhibitors with similar activation profiles. The screening revealed 3 kinase inhibitors for PKC, IKK2, and MEK1/2 respectively, all with a phenotypic signature similar to ruxolitinib, a Jak1/2 inhibitor used to treat myelofibrosis disease. These results suggest this multiplexed assay platform, combined with a chemogenomic library screening, may be used as primary screen for phenotypic or target-based drug discovery, target identification, and potential drug repositioning.
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Youdim, Moussa, Tamar Amit, Yael Avramovich, Orit Bar-Am, Marta Weinstock, and Merav Yogev-Falach. "PKC and MAP kinase-dependent processing of amyloid precursor protein (APP) by neuroprotective propargylamine cholinesterase inhibitors derived from rasagiline and nonsteroidal anti-inflammatory drugs." In Cholinergic Mechanisms, 353–61. CRC Press, 2004. http://dx.doi.org/10.3109/9780203493878-51.

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Bello, Martiniano, and Miguel Ángel Vargas Mejía. "Structural Insight of the Anticancer Properties of Doxazosin on Overexpressing EGFR/HER2 Cell Lines." In Breast Cancer [Working Title]. IntechOpen, 2021. http://dx.doi.org/10.5772/intechopen.96628.

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The selective α1-adrenergic receptor antagonist doxazosin is used for the treatment of hypertension. More recently, an experimental report demonstrated that this compound exhibits antiproliferative activity in breast cancer cell lines with similar inhibitory activity to gefitinib, a selective inhibitor of EGFR in the active state (EGFRAC). This experimental study provided evidence that doxazosin can be employed as an anticancer compound, however, the structural basis for its inhibitory properties is poorly understood at the atomic level. To gain insight about this molecule, molecular dynamics (MD) simulation with the molecular mechanics generalized Born surface area (MMGBSA) approach was employed to explore the structural and energetic features that guide the inhibitory properties of doxazosin and gefitinib in overexpressing EGFR/HER2 cell lines. Our result suggest that doxazosin exerts its inhibitory properties in breast cancer cell lines by targeting EGFR/HER2 but mainly HER2 in the inactive state (HER2IN), whereas gefitinib by targeting mainly EGFRAC, in line with previous literature. Decomposition of the binding affinity into individual contributions of HER2IN-doxazosin and EGFRAC-gefitinib systems detected hot spot residues but also showed polar interactions of Met801/Met793 with the quinazoline ring of both compounds. Principal component (PC) analysis revealed that the molecular recognition of the HER2IN-doxazosin system was linked to conformational changes but EGFRAC-gefitinib was not.
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Conference papers on the topic "PKC inhibitors"

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Hopple, Sara, Mark Bushfield, Fiona Murdoch, and D. Euan MacIntyre. "REGULATION OF PLATELET cAMP FORMATION BY PROTEIN KINASE C." In XIth International Congress on Thrombosis and Haemostasis. Schattauer GmbH, 1987. http://dx.doi.org/10.1055/s-0038-1644512.

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Exogenous synthetic 1,2-diacylglycerols (e.g. 1,2-dioctanoylglycerol, DiC8) and 4β Phorbol esters (e.g. phorbol myristate acetate, PMA) routinely are used to probe the effects of protein Kinase C (PKC) on cellular responsiveness. Such agents act either independently or synergistically with elevated [Ca2+]i to induce platelet activation, but also inhibit agonist-induced inositol lipid metabolism and Ca2+ flux. These findings led to the concept that activated PKC can function as a bi-directional regulator of platelet reactivity. Therefore, DiCg and PMA were utilized to examine the effects of activated PKC on receptor-mediated stimulation and inhibition of adenylate cyclase, as monitored by cAMP accumulation. All studies were performed using intact human platelets in a modified Tyrodes solution, and cAMP was quantified by radioimmunoassay. Pretreatment (2 min.; 37°C) of platelets with PMA (≤ 300 nM) but not DiCg (200 μM) attenuated the elevation of platelet cAMP content evoked by PGD2 300 nM) but not by PGE1 (≤300 nM), PGI2 (≤100 nM) or adenosine (≤ 100 μM).These effects of PMA were unaffected by ADP scavengers, by Flurbiprofen (10 μM) or by cAMP phosphodiesterase inhibitors (IBMX, 1 mM) but were abolished by the PKC inhibitor Staurosporine (STP, 100 nM). In contrast, DiC8 (200 μM), but not PMA ( ≤ 300 nM), reduced the inhibitory effect of adrenaline (5 μM) on PGE1 (300 nM)-induced cAMP formation. This effect of DiCg was unaltered by STP (100 nM). Selective inhibition of PGD2-induced cAMP formation by PMA most probably can be attributed to PKC catalysed phosphorylation of the DP receptor. Reduction of the inhibitory effect of adrenaline by DiC8 could occur via an action at the α2 adrenoreceptor or Ni. These differential effects of PMA and DiC8 may result from differences in their distribution or efficacy, or to heterogeneity of platelet PKC.
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Takashima, Asami, Zhihong Chen, Brandon English, Robert M. Williams, and Douglas V. Faller. "Abstract B36: Targeting oncogenic RAS with small molecule PKC-delta inhibitors." In Abstracts: AACR Special Conference on RAS Oncogenes: From Biology to Therapy; February 24-27, 2014; Lake Buena Vista, FL. American Association for Cancer Research, 2014. http://dx.doi.org/10.1158/1557-3125.rasonc14-b36.

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Shah, Minjel, Christopher Apostolatos, Hercules Apostolatos, and Mildred Acevedo-Duncan. "Abstract 1037: Inverse regulation of p53 by atypical PKC inhibitors in ovarian cancer cells." In Proceedings: AACR 106th Annual Meeting 2015; April 18-22, 2015; Philadelphia, PA. American Association for Cancer Research, 2015. http://dx.doi.org/10.1158/1538-7445.am2015-1037.

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Breedy, Sloan, Wishrawana S. Ratnayake, Christopher Apostolatos, Avijit Dey, and Mildred Acevedo-Duncan. "Abstract 5216: Atypical PKC inhibitors ICA-1S and ζ-Stat show inhibition of neuroblastoma cell proliferation." In Proceedings: AACR Annual Meeting 2020; April 27-28, 2020 and June 22-24, 2020; Philadelphia, PA. American Association for Cancer Research, 2020. http://dx.doi.org/10.1158/1538-7445.am2020-5216.

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Shah, Minjel, Christopher Apostolatos, Hercules Apostolatos, and Mildred Acevedo-Duncan. "Abstract POSTER-THER-1428: Effects of atypical PKC inhibitors on ovarian cancer proliferation and RNA levels." In Abstracts: 10th Biennial Ovarian Cancer Research Symposium; September 8-9, 2014; Seattle, WA. American Association for Cancer Research, 2015. http://dx.doi.org/10.1158/1557-3265.ovcasymp14-poster-ther-1428.

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Walshe, K., I. Mackie, M. Gallimore, and S. J. Machin. "PERTURBATION OF THE KALLIKREIN-KININ SYSTEM IN ADULT RESPIRATORY DISTRESS SYNDROME (ARDS)." In XIth International Congress on Thrombosis and Haemostasis. Schattauer GmbH, 1987. http://dx.doi.org/10.1055/s-0038-1644336.

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Platelet and fibrin deposition in the small blood vessels of the lung as well as activation of the contact system with consequent kinin generation have been described in ARDS. It is thought that these haemostatic changes may play a role in the pathogenesis of the disease which include dyspnoea, hypoxaemia, pulmonary oedema, and pulmonary hypertension. We have studied a complete battery of tests for the proteases and inhibitors of the kallikrein-kinin system in an ongoing study of ARDS and haemostasis. 12 patients have so far been studied, with the following factors complicating ARDS: 5 had sepsis, 3 post surgical, 1 head injury, chronic renal and airways disease, renal transplant rejection, or after smoke inhalation during a fire. Assays for: FXI, FXII, prekallikrein (PKK), kallikrein inhibitor (KKi), betaFXIIa inhibitor, (BXIIAi), alpha-2-macroglobulin (α-2-M), alpha-l-antitrypsin (α-1-AT), and antithrombin III (ATIII) were performed by microtitre amidolytic assays to allow the economic processing of large numbers of samples. FXII, PKK, ATIII and α-2-M were invariably low, returning towards normal as the patient became clinically well. The PKK level in particular reflected the clinical course of the patient and appeared to have prognostic significance. Surprisingly, the BXIIai and KKi tended to be increased when the FXII and PKK were decreased. FXI and -1-AT levels showed no change. These results suggest that clinical concentrates of haemostatic inhibitors may be of benefit in ARDS, to stop the continuous activation of the kallikrein-kinin system and generation of biologically active peptides.
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Barrett, Rosemary, Ribo Guo, Jing Yuan, Vesselina Cooke, Anthony Vattay, Joshua Korn, Guiqing Liang, et al. "Abstract C149: The PKC inhibitor Sotrastaurin selectively inhibits the growth of GNAQ mutant uveal melanoma." In Abstracts: AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics--Oct 19-23, 2013; Boston, MA. American Association for Cancer Research, 2013. http://dx.doi.org/10.1158/1535-7163.targ-13-c149.

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Steiner, J., and D. Strickland. "INTERACTION OF PLASMIN WITH ALPHA-2 MACROGLOBULIN (α2 M): EFFECT OF ANTIFIBRINOLYTIC AGENTS." In XIth International Congress on Thrombosis and Haemostasis. Schattauer GmbH, 1987. http://dx.doi.org/10.1055/s-0038-1644382.

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Harpel (Harpel, P.C. (1981) J. Clin. Invest 68, 46-55) reported that levels of α2M-plasmin complexes are elevated in patients receiving urokinase. He found that the distribution of plasmin between the two inhibitors, α2M and α2-plasmin inhibitor (α2PI) is dependent upon whether plasmin is added directly to plasma, or whether plasminogen in plasma is activated to plasmin by urokinase. In order to investigate possible mechanisms regulating the distribution of plasmin between these two inhibitors, a study was initiated to examine the effects of antifibrinolytic agents on the reaction of plasmin with α2M. The kinetics of the reaction were measured by monitoring conformational changes in the inhibitor resulting from exomplex formation. In order to minimize nonspecific proteolysis of the inhibitor by plasmin, the reaction was performed under conditions where the concentration of α2M was greater than that of the enzyme. The reaction between Lys77-plasmin and α2M followed second order kinetics with a rate constant of 1.8 X 105M-1 s-1. This rate was not affected 1 mM EACA or by 10 uM histidine rich glycoprotein (HRG). Further, it was found that the rate of Val442-plasmin was essentially the same as that found for Lys77-plasmin. Therefore, the binding of these ligands to the lysine binding sites of plasmin do not affect the association rate between plasmin and α2M. This is in contrast to the reaction of plasmin with α2-PI, where the binding of ligands to the lysine binding sites of plasmin reduce the rate of the reaction (Petersen & Clerrmensen (1981) Biochem. J. 199, 121-127). The kinetic constants measured predict that under conditions when the lysine binding sites of plasmin are occupied, α2M will effectively compete with α2PI in inhibiting plasmin. Further, these studies inplicate HRG as a molecule capable of regulating the distribution of plasmin between these two inhibitors.
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Bhayankara, Aravind P., Rekha Patel, Hla Win-Piazza, Prajit Pillai, and Mildred E. Acevedo-Duncan. "Abstract LB-437: ICA-1: A novel PKC-i inhibitor inhibits the proliferation of prostate cancer cells." In Proceedings: AACR 102nd Annual Meeting 2011‐‐ Apr 2‐6, 2011; Orlando, FL. American Association for Cancer Research, 2011. http://dx.doi.org/10.1158/1538-7445.am2011-lb-437.

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Joseph, S. K., S. Krishnamurthi, and V. V. Kakkar. "R59022, A DIACYLGLYCEROL (DG) KINASE INHIBITOR POTENTIATES THROMBIN-INDUCED PLATELET AGGREGATION AND GRANULE RELEASE." In XIth International Congress on Thrombosis and Haemostasis. Schattauer GmbH, 1987. http://dx.doi.org/10.1055/s-0038-1644504.

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R59022 is a recently described inhibitor of the enzyme DG kinase [1], which converts DG to phosphatidic acid. While R59002 inhibits DG conversion in platelets resulting in enhanced protein kinase C (PrkC) activation [1], little is known on its effect on other platelet responses. In this study, we have examined the effect of R59022 on agonist-induced platelet aggregation and [14C]-5-hydroxytryptamine (5HT) release using washed human platelets. With a sub-maximal concentration of thrombin (T, 0.05U/ml) R59022 (10-30μM) significantly potentiated T-induced platelet aggregation and [14C]-5HT release eg % [14C]-5HT release:- 0.05U/ml T-52±5,30μM R59022+T-76±8. Removal of external Ca2+ (ImM) using EGTA (5mM) reduced T-induced 5HT release but not the potentiation of it by R59022 eg EGTA+ 0.05U/ml T-36±6%, EGTA+R59022+T- 72±5%. These results show that in the presence of EGTA and R59022 the increased DG levels can compensate for the diminished rise in T-induced Ca/2+ mobilisation thus re-emphasizing the importance of DG in promoting granule secretion. In addition to inhibiting DG phosphorylation, R59022 also inhibits the phosphorylation of the DG analogue 1-oleoyl 2-acetylglycerol (OAG) [1]. OAG (63μM) with pre-incubation times of 10-60 sec, significantly potentiated threshold T (0.03U/ml)-induced [l4C]-5HT release, though with longer incubation times, this potentiatory effect was gradually lost eg 0.03U/ml T-l±0.3%, OAG+T (10 sec)- 33±4%, OAG+T (1 min)-11±3%, 0AG+veh.-0%. However, in the presence of R59022 (30μM), OAG retained its potentiatory effect for longer periods eg R59022+0AG+T (1 min)-45+10%, R59022+T-2±l%. With incubation times > 5 min the potentiatory effects of OAG were lost even in the presence of R59022. This is possibly due to the metabolism of OAG by DG lipase. Our results demonstrate that R59022, which has been reported to inhibit DG kinase leading to enhanced PrkC activation, also enhances agonist-induced platelet aggregation and 5HT release. It may therefore be a useful compound in elucidating further the role of DG in terms of both stimulatory and inhibitory effects on platelet activation.[1]. de Chaffoy de Coucelles, D. et al (1985) J Biol Chem 260, 15762.
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Reports on the topic "PKC inhibitors"

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Dickman, Martin B., and Oded Yarden. Role of Phosphorylation in Fungal Spore Germination. United States Department of Agriculture, August 1993. http://dx.doi.org/10.32747/1993.7568761.bard.

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Spore germination is a common and fundamental event in fungal development and in many instances an essential phase of fungal infection and dissemination. Spore germination is also critical for hyperparasites to function as biocontrol agents as well as in fermentation proceses. Our common objective is to understand the mechanisms which regulated spore germination and identify factors involved in pathogenicity related prepenetration development. Our approach is to exploit the overall similarity among filamentous fungi using both a plant pathogen (Colletotricum trifolii) and a model system that is genetically sophisticated (Neurospora crassa). The simulataneous use of two organisms has the advantage of the available tools in Neurospora to rapidly advance the functional analysis of genes involved in spore germination and development of an economically important fungal phytopathogen. Towards this we have isolated a protein kinase gene from C. trifolii (TB3) that is maximally expressed during the first hour of conidial germination and prior to any visible gene tube formation. Based on sequence similarities with other organisms, this gene is likely to be involved in the proliferative response in the fungus. In addition, TB3 was able to functionally complement a N. crassa mutant (COT-1). Pharmacological studies indicated the importance of calmodulin in both germination and appressorium differentiation. Using an antisense vector from N. crassa, direct inhibition of calmodulin results in prevention of differentiation as well as pathogenicity. Both cAMP dependent protein kinase (PKA) and protein kinase C (PKC) like genes have been cloned from C. trifolii. Biochemical inhibition of PKA prevents germination; biochemical inhibitors of PKC prevents appressorium differentiation. In order to analyze reversible phosphorylation as a regulatory mechanism, some ser.thr dephosphorylative events have also been analyzed. Type 2A and Type 2B (calcineurin) phosphatases have been identified and structurally and functionally analyzed in N. crassa during this project. Both phosphatases are essential for hyphal growth and maintenance of proper hyphal architecture. In addition, a first novel-type (PPT/PP5-like) ser/thr phosphatase has been identified in a filamentous fungus. The highly collaborative project has improved our understanding of a fundamental process in fungi, and has identified targets which can be used to develop new approaches for control of fungal plant pathogens as well as improve the performance of beneficial fungi in the field and in industry. In addition, the feasibility of molecular technology transfer in comparative mycology has been demonstrated.
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Saha, Debabrata. Enhancement of Radiation Therapy in Prostate Cancer by DNA-PKcs Inhibitor. Fort Belvoir, VA: Defense Technical Information Center, September 2014. http://dx.doi.org/10.21236/ada612831.

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Saha, Debabrata. Enhancement of Radiation Therapy in Prostate Cancer by DNA-PKcs Inhibitor. Fort Belvoir, VA: Defense Technical Information Center, July 2013. http://dx.doi.org/10.21236/ada584219.

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Saha, Debabrata. Enhancement of Radiation Therapy in Prostate Cancer by DNA-PKcs Inhibitor. Fort Belvoir, VA: Defense Technical Information Center, July 2012. http://dx.doi.org/10.21236/ada626324.

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Barron, Elizabeth A. Training HBCU Faculty and Students in Prostate Cancer (PC) Research: Signal Transduction and Receptor-Inhibitor in the Progress of PC. Fort Belvoir, VA: Defense Technical Information Center, March 2005. http://dx.doi.org/10.21236/ada446889.

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Wiese, Thomas E., and R. B. Klassen. Training HBCU Faculty and Students in Prostate Cancer (PC) Research: Signal Transduction and Receptor-Inhibitor Interactions in the Progress of PC. Fort Belvoir, VA: Defense Technical Information Center, March 2007. http://dx.doi.org/10.21236/ada486576.

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Wiese, Thomas E., and R. B. Klassen. Training HBCU Faculty and Students in Prostate Cancer (PC) Research: Signal Transduction and Receptor-Inhibitor Interactions in the Progress of PC. Fort Belvoir, VA: Defense Technical Information Center, March 2008. http://dx.doi.org/10.21236/ada486710.

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Wiese, Thomas E., and R. B. Klassen. Training HBCU Faculty and Students in Prostate Cancer (PC) Research: Signal Transduction and Receptor-Inhibitor Interactions in the Progress of PC. Addendum. Fort Belvoir, VA: Defense Technical Information Center, March 2009. http://dx.doi.org/10.21236/ada512650.

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Altstein, Miriam, and Ronald J. Nachman. Rational Design of Insect Control Agent Prototypes Based on Pyrokinin/PBAN Neuropeptide Antagonists. United States Department of Agriculture, August 2013. http://dx.doi.org/10.32747/2013.7593398.bard.

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The general objective of this study was to develop rationally designed mimetic antagonists (and agonists) of the PK/PBAN Np class with enhanced bio-stability and bioavailability as prototypes for effective and environmentally friendly pest insect management agents. The PK/PBAN family is a multifunctional group of Nps that mediates key functions in insects (sex pheromone biosynthesis, cuticular melanization, myotropic activity, diapause and pupal development) and is, therefore, of high scientific and applied interest. The objectives of the current study were: (i) to identify an antagonist biophores (ii) to develop an arsenal of amphiphilic topically active PK/PBAN antagonists with an array of different time-release profiles based on the previously developed prototype analog; (iii) to develop rationally designed non-peptide SMLs based on the antagonist biophore determined in (i) and evaluate them in cloned receptor microplate binding assays and by pheromonotropic, melanotropic and pupariation in vivo assays. (iv) to clone PK/PBAN receptors (PK/PBAN-Rs) for further understanding of receptor-ligand interactions; (v) to develop microplate binding assays for screening the above SMLs. In the course of the granting period A series of amphiphilic PK/PBAN analogs based on a linear lead antagonist from the previous BARD grant was synthesized that incorporated a diverse array of hydrophobic groups (HR-Suc-A[dF]PRLa). Others were synthesized via the attachment of polyethylene glycol (PEG) polymers. A hydrophobic, biostablePK/PBAN/DH analog DH-2Abf-K prevented the onset of the protective state of diapause in H. zea pupae [EC50=7 pmol/larva] following injection into the preceding larval stage. It effectively induces the crop pest to commit a form of ‘ecological suicide’. Evaluation of a set of amphiphilic PK analogs with a diverse array of hydrophobic groups of the formula HR-Suc-FTPRLa led to the identification of analog T-63 (HR=Decyl) that increased the extent of diapause termination by a factor of 70% when applied topically to newly emerged pupae. Another biostablePK analog PK-Oic-1 featured anti-feedant and aphicidal properties that matched the potency of some commercial aphicides. Native PK showed no significant activity. The aphicidal effects were blocked by a new PEGylated PK antagonist analog PK-dF-PEG4, suggesting that the activity is mediated by a PK/PBAN receptor and therefore indicative of a novel and selective mode-of-action. Using a novel transPro mimetic motif (dihydroimidazole; ‘Jones’) developed in previous BARD-sponsored work, the first antagonist for the diapause hormone (DH), DH-Jo, was developed and shown to block over 50% of H. zea pupal diapause termination activity of native DH. This novel antagonist development strategy may be applicable to other invertebrate and vertebrate hormones that feature a transPro in the active core. The research identifies a critical component of the antagonist biophore for this PK/PBAN receptor subtype, i.e. a trans-oriented Pro. Additional work led to the molecular cloning and functional characterization of the DH receptor from H. zea, allowing for the discovery of three other DH antagonist analogs: Drosophila ETH, a β-AA analog, and a dF analog. The receptor experiments identified an agonist (DH-2Abf-dA) with a maximal response greater than native DH. ‘Deconvolution’ of a rationally-designed nonpeptide heterocyclic combinatorial library with a cyclic bis-guanidino (BG) scaffold led to discovery of several members that elicited activity in a pupariation acceleration assay, and one that also showed activity in an H. zea diapause termination assay, eliciting a maximal response of 90%. Molecular cloning and functional characterization of a CAP2b antidiuretic receptor from the kissing bug (R. prolixus) as well as the first CAP2b and PK receptors from a tick was also achieved. Notably, the PK/PBAN-like receptor from the cattle fever tick is unique among known PK/PBAN and CAP2b receptors in that it can interact with both ligand types, providing further evidence for an evolutionary relationship between these two NP families. In the course of the granting period we also managed to clone the PK/PBAN-R of H. peltigera, to express it and the S. littoralis-R Sf-9 cells and to evaluate their interaction with a variety of PK/PBAN ligands. In addition, three functional microplate assays in a HTS format have been developed: a cell-membrane competitive ligand binding assay; a Ca flux assay and a whole cell cAMP ELISA. The Ca flux assay has been used for receptor characterization due to its extremely high sensitivity. Computer homology studies were carried out to predict both receptor’s SAR and based on this analysis 8 mutants have been generated. The bioavailability of small linear antagonistic peptides has been evaluated and was found to be highly effective as sex pheromone biosynthesis inhibitors. The activity of 11 new amphiphilic analogs has also been evaluated. Unfortunately, due to a problem with the Heliothis moth colony we were unable to select those with pheromonotropic antagonistic activity and further check their bioavailability. Six peptides exhibited some melanotropic antagonistic activity but due to the low inhibitory effect the peptides were not further tested for bioavailability in S. littoralis larvae. Despite the fact that no new antagonistic peptides were discovered in the course of this granting period the results contribute to a better understanding of the interaction of the PK/PBAN family of Nps with their receptors, provided several HT assays for screening of libraries of various origin for presence of PK/PBAN-Ragonists and antagonists and provided important practical information for the further design of new, peptide-based insecticide prototypes aimed at the disruption of key neuroendocrine physiological functions in pest insects.
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10

Altstein, Miriam, and Ronald Nachman. Rationally designed insect neuropeptide agonists and antagonists: application for the characterization of the pyrokinin/Pban mechanisms of action in insects. United States Department of Agriculture, October 2006. http://dx.doi.org/10.32747/2006.7587235.bard.

Full text
Abstract:
The general objective of this BARD project focused on rationally designed insect neuropeptide (NP) agonists and antagonists, their application for the characterization of the mechanisms of action of the pyrokinin/PBAN (PK-PBAN) family and the development of biostable, bioavailable versions that can provide the basis for development of novel, environmentally-friendly pest insect control agents. The specific objectives of the study, as originally proposed, were to: (i) Test stimulatory potencies of rationally designed backbone cyclic (BBC) peptides on pheromonotropic, melanotropic, myotropic and pupariation activities; (ii) Test the inhibitory potencies of the BBC compounds on the above activities evoked either by synthetic peptides (PBAN, LPK, myotropin and pheromonotropin) or by the natural endogenous mechanism; (iii) Determine the bioavailability of the most potent BBC compounds that will be found in (ii); (iv) Design, synthesize and examine novel PK/PBAN analogs with enhanced bioavailability and receptor binding; (v) Design and synthesize ‘magic bullet’ analogs and examine their ability to selectively kill cells expressing the PK/PBAN receptor. To achieve these goals the agonistic and antagonistic activities/properties of rationally designed linear and BBC neuropeptide (NP) were thoroughly studied and the information obtained was further used for the design and synthesis of improved compounds toward the design of an insecticide prototype. The study revealed important information on the structure activity relationship (SAR) of agonistic/antagonistic peptides, including definitive identification of the orientation of the Pro residue as trans for agonist activity in 4 PK/PBANbioassays (pheromonotropic, pupariation, melanotropic, & hindgut contractile) and a PK-related CAP₂b bioassay (diuretic); indications that led to the identification of a novel scaffold to develop biostbiostable, bioavailable peptidomimetic PK/PBANagonists/antagonists. The work led to the development of an arsenal of PK/PBAN antagonists with a variety of selectivity profiles; whether between different PKbioassays, or within the same bioassay between different natural elicitors. Examples include selective and non-selective BBC and novel amphiphilic PK pheromonotropic and melanotropic antagonists some of which are capable of penetrating the moth cuticle in efficacious quantities. One of the latter analog group demonstrated unprecedented versatility in its ability to antagonize a broad spectrum of pheromonotropic elicitors. A novel, transPro mimetic motif was proposed & used to develop a strong, selective PK agonist of the melanotropic bioassay in moths. The first antagonist (pure) of PK-related CAP₂b diuresis in flies was developed using a cisPro mimetic motif; an indication that while a transPro orientation is associated with receptor agonism, a cisPro orientation is linked with an antagonist interaction. A novel, biostablePK analog, incorporating β-amino acids at key peptidase-susceptible sites, exhibited in vivo pheromonotropic activity that by far exceeded that of PBAN when applied topically. Direct analysis of neural tissue by state-of-the-art MALDI-TOF/TOF mass spectrometry was used to identify specific PK/PK-related peptides native to eight arthropod pest species [house (M. domestica), stable (S. calcitrans), horn (H. irritans) & flesh (N. bullata) flies; Southern cattle fever tick (B. microplus), European tick (I. ricinus), yellow fever mosquito (A. aegypti), & Southern Green Stink Bug (N. viridula)]; including the unprecedented identification of mass-identical Leu/Ile residues and the first identification of NPs from a tick or the CNS of Hemiptera. Evidence was obtained for the selection of Neb-PK-2 as the primary pupariation factor of the flesh fly (N. bullata) among native PK/PK-related candidates. The peptidomic techniques were also used to map the location of PK/PK-related NP in the nervous system of the model fly D. melanogaster. Knowledge of specific PK sequences can aid in the future design of species specific (or non-specific) NP agonists/antagonists. In addition, the study led to the first cloning of a PK/PBAN receptor from insect larvae (S. littoralis), providing the basis for SAR analysis for the future design of 2ⁿᵈgeneration selective and/or nonselective agonists/antagonists. Development of a microplate ligand binding assay using the PK/PBAN pheromone gland receptor was also carried out. The assay will enable screening, including high throughput, of various libraries (chemical, molecular & natural product) for the discovery of receptor specific agonists/antagonists. In summary, the body of work achieves several key milestones and brings us significantly closer to the development of novel, environmentally friendly pest insect management agents based on insect PK/PBANNPs capable of disrupting critical NP-regulated functions.
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