Kinase, human leukocytes

In addition to the aforementioned allenic steroids, prostaglandins, amino acids and nucleoside analogs, a number of other functionalized allenes have been employed (albeit with limited success) in enzyme inhibition (Scheme 18.56) [154-159]. Thus, the 7-vinylidenecephalosporin 164 and related allenes did not show the expected activity as inhibitors of human leukocyte elastase, but a weak inhibition of porcine pancreas elastase [156], Similarly disappointing were the immunosuppressive activity of the allenic mycophenolic acid derivative 165 [157] and the inhibition of 12-lipoxygenase by the carboxylic acid 166 [158]. In contrast, the carboxyallenyl phosphate 167 turned out to be a potent inhibitor of phosphoenolpyruvate carboxylase and pyruvate kinase [159]. Hydrolysis of this allenic phosphate probably leads to 2-oxobut-3-enoate, which then undergoes an irreversible Michael addition with suitable nucleophilic side chains of the enzyme. 

Several 9-(phosphonoalkyl)- and 9-(difluoroalkyl)-guanine derivatives (12, X = H or F) have been studied as potential inhibitors of guanylate kinase. The most pronounced effect was observed with n - 5 Phenoxymethylene bisphosphonates (13, where R R and R represent a variety of substituents) were prepared and found to act as inositol phosphatase inhibitors and antimanic agents some inhibited the enzyme with IC50 < 50 pmol 4-(Phosphonomethylphenoxy)-l-carbamoylazetidine-2-ones (14) inhibited human leukocyte elastase for 14 (R R = OEt = 1.2 x 10 moL s (ref. 38). 

Additional information <98,119> (<98>, two alternative exons, Illb and IIIc, encode the C-terminal half of Ig domain 3. The alternative splicing choice between Illb and IIIc exons of the FGFR-3 is not strictly tissue-specific epithelial cells show exclusively Illb transcripts while fibroblastic cells show a mixture of Illb and IIIc transcripts [297] <119>, differently spliced cDNAs of human leukocyte tyrosine kinase receptor tyrosine kinase predict receptor proteins with and without a tyrosine kinase domain and a soluble receptor protein [340]) [297, 340]... 

Mechanisms Interferons are glycoproteins produced in human leukocytes (IFN-a), fibroblasts (IFN-(3), and immune cells (IFN-y)- They exert multiple actions that affect viral RNA and DNA synthesis. Interferons induce the formation of enzymes, including a protein kinase that phosphorylates a factor which blocks peptide chain initiation, a phosphodiesterase that degrades terminal nucleotides of tRNA. and enzymes that activate RNase. 

Knaus, U.G., Morris, S., Dong, H.-J., Chemoff, J. and Bokoch, G.M. (1995). Regulation of human leukocyte p21-activated kinases through G-protein coupled receptors. Science 269, 221-223. 

Chuang, T.T. Sallese, M. Ambrosini, G. Parruti, G. De Blasi, A. High expression of )8-adrenergic receptor kinase in human peripheral blood leukocytes. Isoproterenol and platelet activating factor can induce kinase translocation. J. Biol. Chem., 267, 6886-6892 (1992)... 

Apoptotic cell death is regulated by NO and ONOO" in several cell types including myeloid-derived leukocytes such as neutrophils. The biological effects of NO and ONOO" have been recently reviewed [68]. GEA3162 is able to promote apoptotic cell death in human neutrophils in a caspase-dependent manner [69]. The tumor suppressor p53 is suggested to play a crucial role in apoptosis induced by oxidants. However, functional p53 is not a requirement for ONOO -mediated cell death, as GEA3162 induces mitochondrial permeability in a p53-deficient murine bone marrow cell line, Jaws II. GEA3162 activates caspases 3 and 2 which are important for apoptosis to proceed, with roles for caspases 8 and 9, and p38 MAP kinase [70]. 

W. Yu, J. Cassara, and P.F. Weller, Phosphatidylinositide 3-kinase localizes to cytoplasmic lipid bodies in human polymorphonuclear leukocytes and other myeloid-derived cells. Blood, 2000, 95, 1078-1085. 

Expression of vascular cell adhesion molecule-1 (VCAM-1) and intercellular adhesion molecule-1 (ICAM-1) is known to be elevated at sites of inflammation. Studies have been conducted into the effects of EGCG and TF-3 on the expression of these adhesion molecules induced by interleukin-ip (IL-lp) in cultured human umbilical vein endothelial cells (HUVECs). Both compounds significantly inhibited IL-ip-induced protein expression of VCAM and ICAM in dose-dependent manners and were associated with reduced adhesion of leukocytes to HUVECs. The m-RNA level of VCAM-1 was also inhibited by these tea polyphenolics, as was the NF-KB-dependent transcriptional activity induced by IL-lp. It is concluded that these molecules exhibit anti-inflammatory and anti-invasion properties, probably via a route involving blockage of IkB kinase. 

Ho YS, Lin JK, Hung LF, Lin SY, Pan S, Liang YC. Suppression of leukocyte adhesion molecules through inhibition of IkB kinase by tea polyphenols in human vascular endothelial cells. New Taipei J Med 2002 4 249-254. 

Another human cDNA array study was performed on LPS-stimulated PMN (4h) and revealed 134 genes that were upregulated [121, 122]. These included chemokines, cytokines, signaling molecules and transcriptional regulators. Proteomic analysis revealed upregulation of the proinflammatory molecules annexin 111, leukocyte elastase inhibitor, and the signaling molecules phosphostathmin, protein phosphatase 1 and p-catalytic subunit, as well as structural proteins such as protein tyrosine kinase 9-like, nonmuscle myosin heavy chain and moesin [121]. 

Thelen, M., Uguccioni, M. and Bosiger, J. (1995). PI 3-kinase-dependent and independent chemotaxis of human neutrophil leukocytes. Biochem. Biophys. Res. Commun. 217, 1255-1262. 

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