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991.
Masako Okamoto Kiyoshi Takayama Tomoko Shimizu Ayumu Muroya Toshio Furuya 《Bioorganic & medicinal chemistry》2010,18(7):2728-2734
Death-associated protein kinase (DAPK) is a serine/threonine protein kinase implicated in diverse programmed cell death pathways. DAPK is a promising target protein for the treatment of ischemic diseases. We identified novel potent and selective DAPK inhibitors efficiently by structure-based virtual screening, then further developed the hit compounds. In this paper, we describe the development of the hit compounds and the structure–activity relationship studies of the DAPK inhibitors in detail, including calculation of the solvated interaction energy (SIE), and verification of selectivity using a kinase panel. 相似文献
992.
Liangkuan Bi Sara Gojestani Weihui Wu Yen-Michael S. Hsu Jiayuan Zhu Kiyoshi Ariizumi Xin Lin 《The Journal of biological chemistry》2010,285(34):25969-25977
The scaffold protein CARD9 plays an essential role in anti-fungus immunity and is implicated in mediating Dectin-1/Syk-induced NF-κB activation in response to Candida albicans infection. However, the molecular mechanism by which CARD9 mediates C. albicans-induced NF-κB activation is not fully characterized. Here we demonstrate that CARD9 is involved in mediating NF-κB activation induced by the hyphal form of C. albicans hyphae (Hyphae) but not by its heat-inactivated unicellular form. Our data show that inhibiting Dectin-2 expression selectively blocked Hyphae-induced NF-κB, whereas inhibiting Dectin-1 mainly suppressed zymosan-induced NF-κB, indicating that Hyphae-induced NF-κB activation is mainly through Dectin-2 and not Dectin-1. Consistently, we find that the hyphae stimulation induces CARD9 association with Bcl10, an adaptor protein that functions downstream of CARD9 and is also involved in C. albicans-induced NF-κB activation. This association is dependent on Dectin-2 but not Dectin-1 following the hyphae stimulation. Finally, we find that although both CARD9 and Syk are required for Hyphae-induced NF-κB activation, they regulate different signaling events in which CARD9 mediates IκBα kinase ubiquitination, whereas Syk regulates IκBα kinase phosphorylation. Together, our data demonstrated that CARD9 is selectively involved in Dectin-2-induced NF-κB activation in response to C. albicans hyphae challenging. 相似文献
993.
Lipid A deacylase PagL, which detoxifies endotoxin, is latent in Salmonella enterica. This study determined the biological significance of this latency. PagL latency was beneficial for bacteria in producing a robust permeation barrier through lipid A modifications under host-mimetic conditions that induced the modification enzymes, including PagL.The outer layer of the outer membrane in enteric Gram-negative bacteria is exclusively occupied by lipopolysaccharide (LPS), which contains lipid A as the membrane anchor, while the inner layer contains phospholipids. This asymmetric lipid bilayer serves as a permeation barrier to a large number of noxious compounds. The strength of this barrier is due to the strong lateral interactions between LPS molecules and the low fluidity of the saturated fatty acid portion of lipid A in the outer membrane (reviewed in reference 20). Large hydrophilic compounds are excluded by narrow porin channels, and lipophilic compounds cross the asymmetric bilayer very slowly.The prototype lipid A structure synthesized in Salmonella enterica serovar Typhimurium (S. Typhimurium) is shown in Fig. Fig.11 A. In S. Typhimurium, lipid A is further modified by enzymes that are induced upon activation of the two-component regulatory system PhoP-PhoQ (Fig. (Fig.1B)1B) (9). PhoP-PhoQ is essential for Salmonella virulence (3, 6, 18), and PhoP-PhoQ-regulated lipid A modifications are involved in many aspects of virulence. PhoQ is a sensor histidine kinase that responds to environmental conditions, including those within mammalian tissues. The host environment is experimentally mimicked by magnesium limitation and/or mild acid pH in the culture medium (3, 4, 6, 18, 21). In response to specific environmental signals, PhoQ phosphorylates PhoP, leading to the activation of pagL and pagP, which encode outer membrane lipid A 3-O-deacylase and outer membrane lipid A palmitoyltransferase, respectively (2, 22). Lipid A 3-O-deacylation by PagL and palmitoylation by PagP reduce the ability of lipid A to activate host Toll-like receptor 4, indicating that PhoP-PhoQ-dependent lipid A modifications help pathogens evade innate immune recognition (12). The regulation of lpxO, which encodes lipid A hydroxylase, is also mediated, at least in part, by PhoP-PhoQ (5, 9). Activation of PhoP-PhoQ leads to the activation of a second two-component regulatory system, PmrA-PmrB (8, 10). PmrA-PmrB promotes the attachment of aminoarabinose and phosphoethanolamine to phosphate groups on lipid A, which are involved in bacterial resistance to cationic antimicrobial peptides (7, 15). Furthermore, PhoP-PhoQ activation produces a more robust permeation barrier in the outer membrane, and lipid A modifications are involved in the generation of this enhanced barrier (19). Mg2+ ions decreased membrane permeability strongly in a phoP-null strain but only modestly in a PhoP-constitutive strain (19), implying a biological relevance of lipid A modifications by magnesium limitation.Open in a separate windowFIG. 1.Structures of the prototype lipid A (A) and modified lipid A (B) of S. Typhimurium.Previous studies did not detect PagL-dependent lipid A deacylation when S. Typhimurium was grown under PhoP-PhoQ-activating conditions that induce PagL expression (11, 13, 22). In contrast, PagL-dependent lipid A deacylation was observed in pmrA-null and pmrE-null strains, both of which lacked aminoarabinose modification of lipid A (11, 13). These findings cannot be simply ascribed to the substrate specificity of PagL, since many lipid A species that are not modified with aminoarabinose exist in S. Typhimurium grown under PhoP-PhoQ-activating conditions (13). Therefore, it is thought that PagL is latent under these conditions and that aminoarabinose modification of lipid A is involved in the regulation of latency (13). PagL latency is consistent with an emerging paradigm of outer membrane enzyme regulation (1). It should be noted that PagL-dependent lipid A deacylation, which is beneficial for invading bacteria by allowing them to avoid Toll-like receptor 4 responses, would occur under some specific conditions such as those which activate PhoP-PhoQ without induction of lipid A aminoarabinose modification. Furthermore, we have identified several amino acid residues in the extracellular loops of PagL that are essential for latency but not for deacylase activity (17). The amino acid residues essential for latency were also necessary for PagL to associate with LPS (16). However, the biological significance of latency remains unknown.The influx rate of a lipophilic agent, ethidium bromide, is increased by a pmrA-null mutation in an S. Typhimurium strain with a PhoP-constitutive phenotype (19). The rate-limiting step of this influx is crossing of the asymmetric bilayer in the outer membrane. Therefore, these observations suggest that pmrA-dependent lipid A modifications, such as aminoarabinose and phosphoethanolamine attachment, help generate a more robust permeation barrier through PhoP-PhoQ activation. On the other hand, lipid A is deacylated by PagL in a pmrA strain under PhoP-PhoQ-activating conditions (13). These observations led us to examine whether PagL-dependent lipid A deacylation increases the membrane permeability of the pmrA mutant strain. 相似文献
994.
995.
Kiyoshi Tajima Hideyuki Ohmori Rustam I. Aminov Yuri Kobashi Tomoyuki Kawashima 《Anaerobe》2010,16(1):6-11
Because of limitations imposed on the antibiotic use in animal industry, there is a need for alternatives to maintain the efficiency of production. One of them may be the use of fermented liquid feed (FLF) but how it affects gut ecology is poorly understood. We investigated the effect of three diets, standard dry feed (control), dry feed supplemented with antibiotics, and fermented liquid feed (FLF, fermented with Lactobacillus plantarum), on gut bacterial diversity in piglets. The structure of the ileal and caecal communities was estimated by sequencing the SSU rRNA gene libraries. Antibiotic-supplemented feed slightly increased bacterial diversity in the ileum but reduced it in the caecum while in FLF-fed animals bacterial diversity was elevated. The majority of bacterial sequences in the ileum of all three groups belonged to lactobacilli (92–98%). In the caecum the lactobacilli were still dominant in control and antibiotic-fed animals (59% and 64% of total bacterial sequences, respectively) but in FLF-fed animals they fell to 31% with the concomitant increase in the Firmicutes diversity represented by the Dorea, Coprococcus, Roseburia and Faecalibacterium genera. Thus FLF affects the gut ecology in a different way than antibiotics and contributes to the enhanced bacterial diversity in the gastrointestinal tract. 相似文献
996.
997.
998.
Inoue H Ogawa W Asakawa A Okamoto Y Nishizawa A Matsumoto M Teshigawara K Matsuki Y Watanabe E Hiramatsu R Notohara K Katayose K Okamura H Kahn CR Noda T Takeda K Akira S Inui A Kasuga M 《Cell metabolism》2006,3(4):267-275
STAT3 regulates glucose homeostasis by suppressing the expression of gluconeogenic genes in the liver. The mechanism by which hepatic STAT3 is regulated by nutritional or hormonal status has remained unknown, however. Here, we show that an increase in the plasma insulin concentration, achieved either by glucose administration or by intravenous insulin infusion, stimulates tyrosine phosphorylation of STAT3 in the liver. This effect of insulin was mediated by the hormone's effects in the brain, and the increase in hepatic IL-6 induced by the brain-insulin action is essential for the activation of STAT3. The inhibition of hepatic glucose production and of expression of gluconeogenic genes induced by intracerebral ventricular insulin infusion was impaired in mice with liver-specific STAT3 deficiency or in mice with IL-6 deficiency. These results thus indicate that IL-6-STAT3 signaling in the liver contributes to insulin action in the brain, leading to the suppression of hepatic glucose production. 相似文献
999.
Sariego I Annoura T Nara T Hashimoto M Tsubouchi A Iizumi K Makiuchi T Murata E Kita K Aoki T 《Parasitology international》2006,55(1):11-16
Dihydroorotate dehydrogenase (DHOD) is the fourth enzyme in the de novo pyrimidine biosynthetic pathway and is essential in Trypanosoma cruzi, the parasitic protist causing Chagas' disease. T. cruzi and human DHOD have different biochemical properties, including the electron acceptor capacities and cellular localization, suggesting that T. cruzi DHOD may be a potential chemotherapeutic target against Chagas' disease. Here, we report nucleotide sequence polymorphisms of T. cruzi DHOD genes and the kinetic properties of the recombinant enzymes. T. cruzi Tulahuen strain possesses three DHODgenes: DHOD1 and DHOD2, involved in the pyrimidine biosynthetic (pyr) gene cluster on an 800 and a 1000 kb chromosomal DNA, respectively, and DHOD3, located on an 800 kb DNA. The open reading frames of all three DHOD genes are comprised of 942 bp, and encode proteins of 314 amino acids. The three DHOD genes differ by 26 nucleotides, resulting in replacement of 8 amino acid residues. In contrast, all residues critical for constituting the active site are conserved among the three proteins. Recombinant T. cruzi DHOD1 and DHOD2 expressed in E. coli possess similar enzymatic properties, including optimal pH, optimal temperature, Vmax, and Km for dihydroorotate and fumarate. In contrast, DHOD3 had a higher Vmax and Km for both substrates. Orotate competitively inhibited all three DHOD enzymes to a comparable level. These results suggest that, despite their genetic variations, kinetic properties of the three T. cruziDHODs are conserved. Our findings facilitate further exploitation of T. cruzi DHOD inhibitors, as chemotherapeutic agents against Chagas' disease. 相似文献
1000.