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841.
Simeone JP Bugianesi RL Ponpipom MM Yang YT Lo JL Yudkovitz JB Cui J Mount GR Ren RN Creighton M Mao AH Vincent SH Cheng K Goulet MT 《Bioorganic & medicinal chemistry letters》2002,12(22):3329-3332
The synthesis of a number of indole GnRH antagonists is described. Oxidation of the pyridine ring nitrogen, combined with alkylation at the two position, led to a compound with an excellent in vitro activity profile as well as oral bioavailability in both rats and dogs. 相似文献
842.
Reiner JE Siev DV Araldi GL Cui JJ Ho JZ Reddy KM Mamedova L Vu PH Lee KS Minami NK Gibson TS Anderson SM Bradbury AE Nolan TG Semple JE 《Bioorganic & medicinal chemistry letters》2002,12(8):1203-1208
Investigations on P(2)-P(3)-heterocyclic dipeptide surrogates directed towards identification of an orally bioavailable thrombin inhibitor led us to pursue novel classes of achiral, non-covalent P(1)-arginine derivatives. The design, synthesis, and biological activity of inhibitors NC1-NC30 that feature three classes of monocyclic P(1)-arginine surrogates will be disclosed: (1) (hetero)aromatic amidines, amines and hydroxyamidines, (2) 2-aminopyrazines, and (3) 2-aminopyrimidines and 2-aminotetrahydropyrimidines. 相似文献
843.
844.
The methylation of histone 3 lysine 4 (H3K4) is essential for gene activation. Flowering Locus C (FLC), an important flowering repressor, quantitatively regulates flowering time in Arabidopsis and its expression level is coincident with H3K4 trimethylation (H3K4me3) dynamics. The methylation state of FLC chromatin is determined by the balance between methylation and demethylation, which is mediated by histone methyltransferases and demethylases, respectively. However, little is known about the role of histone demethylase(s) in FLC regulation. Here, we characterized the biochemical activity and biological function of a novel JmjC domain-containing H3K4 demethylase, JMJ15, in Arabidopsis. JMJ15, which is a member of the H3K4 demethylase JARID1 family, displayed H3K4me3 demethylase activity both in vitro and in vivo. The mutation of JMJ15 did not produce an obvious phenotype; however, overexpression JMJ15 resulted in an obvious early flowering phenotype, which was associated with the repression of FLC level and reduction in H3K4me3 at the FLC locus, resulting in increased FT expression. Our results suggest that JMJ15 is a novel H3K4 demethylase, involved in the control of flowering time by demethylating H3K4me3 at FLC chromatin when it was overexpressed in Arabidopsis. KEY MESSAGE: Overexpression of a histone H3K4 demethylase, JMJ15, represses FLC expression by decreasing its chromatin H3K4me3 level, thereby controlling flowering time in Arabidopsis. 相似文献
845.
846.
847.
Yoon D Kim YJ Cui WY Van der Vaart A Cho YS Lee JY Ma JZ Payne TJ Li MD Park T 《Human genetics》2012,131(6):1009-1021
Diseases related to smoking are the second leading cause of death in the world. Cigarette smoking is a risk factor for several diseases such as cancer and cardiovascular and respiratory disorders. Despite increasing evidence of genetic determination, the susceptibility genes and loci underlying various aspects of smoking behavior are largely unknown. Moreover, almost all reported genome-wide association studies (GWASs) have been performed on samples of European origin, limiting the applicability of the results to other ethnic populations. In this first GWAS on smoking behavior in an Asian population, after analyzing 8,842 DNA samples from the Korea Association Resource project with 352,228 single nucleotide polymorphisms (SNPs) genotyped for each sample, we identified 8 SNPs significantly associated with smoking initiation (SI) and 4 with nicotine dependence (ND). Because of the current unavailability of an independent Asian smoking sample, we replicated the discoveries in independent samples of European-American and African-American origin. Of the 12 SNPs examined in the replicated samples, we identified two SNPs, in the regulator of G-protein signaling 17 gene (rs7747583, p value(meta)?=?6.40?×?10(-6); rs2349433, p value(meta)?=?5.57?×?10(-6)), associated with SI. Also, we found two SNPs significantly associated with ND; one in the FERM domain containing 4A (rs4424567, p value(meta)?=?2.30?×?10(-6)) and the other at 7q31.1 (rs848353, p value(meta)?=?9.16?×?10(-8)). These SNPs represent novel targets for examination of smoking behavior and warrant further investigation using independent samples. 相似文献
848.
Zou T Rao JN Liu L Xiao L Cui YH Jiang Z Ouyang M Donahue JM Wang JY 《American journal of physiology. Cell physiology》2012,303(1):C102-C111
Polyamines regulate multiple signaling pathways and are implicated in many aspects of cellular functions, but the exact molecular processes governed by polyamines remain largely unknown. In response to environmental stress, repression of translation is associated with the assembly of stress granules (SGs) that contain a fraction of arrested mRNAs and are thought to function as mRNA storage. Here we show that polyamines modulate the assembly of SGs in normal intestinal epithelial cells (IECs) and that induced SGs following polyamine depletion are implicated in the protection of IECs against apoptosis. Increasing the levels of cellular polyamines by ectopic overexpression of the ornithine decarboxylase gene decreased cytoplasmic levels of SG-signature constituent proteins eukaryotic initiation factor 3b and T-cell intracellular antigen-1 (TIA-1)-related protein and repressed the assembly of SGs induced by exposure to arsenite-induced oxidative stress. In contrast, depletion of cellular polyamines by inhibiting ornithine decarboxylase with α-difluoromethylornithine increased cytoplasmic eukaryotic initiation factor 3b and TIA-1 related protein abundance and enhanced arsenite-induced SG assembly. Polyamine-deficient cells also exhibited an increase in resistance to tumor necrosis factor-α/cycloheximide-induced apoptosis, which was prevented by inhibiting SG formation with silencing SG resident proteins Sort1 and TIA-1. These results indicate that the elevation of cellular polyamines represses the assembly of SGs in normal IECs and that increased SGs in polyamine-deficient cells are crucial for increased resistance to apoptosis. 相似文献
849.
Chen X Shang H Qiu X Fujiwara N Cui L Li XM Gao TM Kong J 《Neurochemical research》2012,37(4):835-845
Converging evidence indicates that SOD1 aggregation is a common feature of mutant SOD1-linked fALS, and seems to be directly
related to the gain-of-function toxic property. However, the mechanism inducing the aggregation is not understood. To study
the contribution of oxidative modification of cysteine residues in SOD1 aggregation, we systematically examined the redox
state of SOD1 cysteine residues in the G37R transgenic mouse model at different stages of the disease and under oxidative
stress induced by H2O2. Our data suggest that under normal circumstance, cysteine 111 residue in SOD1 is free; however, under oxidative stress,
it is prone to oxidative modification by providing the thiolate anion (S−). With the progression of the disease, increased
levels of oxidative insults facilitated the oxidation of thiol groups of cysteine residues; human mutant SOD1 could generate
an upper shift band in reducing SDS-PAGE, which turned out to be a Cys111-peroxidized SOD1 species. We also detected the formation
of SOD1 multimers at different stages of the disease, and found that accumulated oxidative stress facilitated the formation
of aggregates, which were not mediated by disulfide bond. This oxidative modification of cysteine 111 therefore promotes the
formation of disulfide bond-independent aggregation of SOD1. 相似文献
850.
Wen‐Jing Chen Sheng Zhang Wei‐Guang Zhang Jun Fan Xia Yin Sheng‐Run Zheng Wen‐Cui Su Zhi Zhang Tao Hong 《Chirality》2012,24(10):804-809
Quartz crystal microbalance (QCM) biosensor was used for the chiral recognition of five pairs of enantiomers by using goat serum albumin (GSA) and rabbit serum albumin (RbSA) as chiral selectors. Serum albumin (SA) was immobilized on the QCM through the self‐assembled monolayer technique, and the surface concentration of GSA and RbSA were 8.8 × 10?12 mol cm?2 and 1.2 × 10?11 mol cm?2, respectively. The QCM biosensors showed excellent sensitivity and selectivity. Meanwhile, the chiral recognition of SA sensors was quite species dependent. There were differences between GSA and RbSA sensors in the ability and the preference of chiral recognition. To R,S‐1,2,3,4‐tetrahydro‐1‐naphthylamine (R,S‐1‐TNA), R,S‐1‐(4‐methoxyphenyl)ethylamine (R,S‐4‐MPEA), and R,S‐1‐(3‐methoxyphenyl)ethylamine (R,S‐3‐MPEA), the preference of the stereoselective SA‐drug binding of the two kinds of SA sensors were consistent. However, to R,S‐2‐octanol (R, S‐2‐OT) and R,S‐methyl lactate (R,S‐MEL), the two kinds of SA sensors had opposite chiral recognition preference. Moreover, the interactions of SA and the five pairs of enantiomers have been further investigated through ultraviolet (UV) and fluorescent (FL) spectra. The UV/FL results were in accordance with the consequence of QCM. Chirality 24:804–809, 2012. © 2012 Wiley Periodicals, Inc. 相似文献