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991.
Hyojin Ko Arijit Das Rhonda L. Carter Ingrid P. Fricks Yixing Zhou Andrei A. Ivanov Artem Melman Bhalchandra V. Joshi Pavol Kováč Jan Hajduch Kenneth L. Kirk T. Kendall Harden Kenneth A. Jacobson 《Bioorganic & medicinal chemistry》2009,17(14):5298-5311
The P2Y14 receptor, a nucleotide signaling protein, is activated by uridine-5′-diphosphoglucose 1 and other uracil nucleotides. We have determined that the glucose moiety of 1 is the most structurally permissive region for designing analogues of this P2Y14 agonist. For example, the carboxylate group of uridine-5′-diphosphoglucuronic acid proved to be suitable for flexible substitution by chain extension through an amide linkage. Functionalized congeners containing terminal 2-acylaminoethylamides prepared by this strategy retained P2Y14 activity, and molecular modeling predicted close proximity of this chain to the second extracellular loop of the receptor. In addition, replacement of glucose with other sugars did not diminish P2Y14 potency. For example, the [5′′]ribose derivative had an EC50 of 0.24 μM. Selective monofluorination of the glucose moiety indicated a role for the 2′′- and 6′′-hydroxyl groups of 1 in receptor recognition. The β-glucoside was twofold less potent than the native α-isomer, but methylene replacement of the 1′′-oxygen abolished activity. Replacement of the ribose ring system with cyclopentyl or rigid bicyclo[3.1.0]hexane groups abolished activity. Uridine-5′-diphosphoglucose also activates the P2Y2 receptor, but the 2-thio analogue and several of the potent modified-glucose analogues were P2Y14-selective. 相似文献
992.
Maika Deffieu Ingrid Bhatia-Ki??ová Bénédicte Salin Anne Galinier Stéphen Manon Nadine Camougrand 《The Journal of biological chemistry》2009,284(22):14828-14837
The antioxidant N-acetyl-l-cysteine prevented the
autophagy-dependent delivery of mitochondria to the vacuoles, as examined by
fluorescence microscopy of mitochondria-targeted green fluorescent protein,
transmission electron microscopy, and Western blot analysis of mitochondrial
proteins. The effect of N-acetyl-l-cysteine was specific
to mitochondrial autophagy (mitophagy). Indeed, autophagy-dependent activation
of alkaline phosphatase and the presence of hallmarks of non-selective
microautophagy were not altered by N-acetyl-l-cysteine.
The effect of N-acetyl-l-cysteine was not related to its
scavenging properties, but rather to its fueling effect of the glutathione
pool. As a matter of fact, the decrease of the glutathione pool induced by
chemical or genetical manipulation did stimulate mitophagy but not general
autophagy. Conversely, the addition of a cell-permeable form of glutathione
inhibited mitophagy. Inhibition of glutathione synthesis had no effect in the
strain Δuth1, which is deficient in selective mitochondrial
degradation. These data show that mitophagy can be regulated independently of
general autophagy, and that its implementation may depend on the cellular
redox status.Autophagy is a major pathway for the lysosomal/vacuolar delivery of
long-lived proteins and organelles, where they are degraded and recycled.
Autophagy plays a crucial role in differentiation and cellular response to
stress and is conserved in eukaryotic cells from yeast to mammals
(1,
2). The main form of autophagy,
macroautophagy, involves the non-selective sequestration of large portions of
the cytoplasm into double-membrane structures termed autophagosomes, and their
delivery to the vacuole/lysosome for degradation. Another process,
microautophagy, involves the direct sequestration of parts of the cytoplasm by
vacuole/lysosomes. The two processes coexist in yeast cells but their extent
may depend on different factors including metabolic state: for example, we
have observed that nitrogen-starved lactate-grown yeast cells develop
microautophagy, whereas nitrogen-starved glucose-grown cells preferentially
develop macroautophagy (3).Both macroautophagy and microautophagy are essentially non-selective, in
the way that autophagosomes and vacuole invaginations do not appear to
discriminate the sequestered material. However, selective forms of autophagy
have been observed (4) that
target namely peroxisomes (5,
6), chromatin
(7,
8), endoplasmic reticulum
(9), ribosomes
(10), and mitochondria
(3,
11–13).
Although non-selective autophagy plays an essential role in survival by
nitrogen starvation, by providing amino acids to the cell, selective autophagy
is more likely to have a function in the maintenance of cellular structures,
both under normal conditions as a “housecleaning” process, and
under stress conditions by eliminating altered organelles and macromolecular
structures
(14–16).
Selective autophagy targeting mitochondria, termed mitophagy, may be
particularly relevant to stress conditions. The mitochondrial respiratory
chain is both the main site and target of
ROS4 production
(17). Consequently, the
maintenance of a pool of healthy mitochondria is a crucial challenge for the
cells. The progressive accumulation of altered mitochondria
(18) caused by the loss of
efficiency of the maintenance process (degradation/biogenesis de
novo) is often considered as a major cause of cellular aging
(19–23).
In mammalian cells, autophagic removal of mitochondria has been shown to be
triggered following induction/blockade of apoptosis
(23), suggesting that
autophagy of mitochondria was required for cell survival following
mitochondria injury (14).
Consistent with this idea, a direct alteration of mitochondrial permeability
properties has been shown to induce mitochondrial autophagy
(13,
24,
25). Furthermore, inactivation
of catalase induced the autophagic elimination of altered mitochondria
(26). In the yeast
Saccharomyces cerevisiae, the alteration of
F0F1-ATPase biogenesis in a conditional mutant has been
shown to trigger autophagy
(27). Alterations of
mitochondrial ion homeostasis caused by the inactivation of the
K+/H+ exchanger was shown to cause both autophagy and
mitophagy (28). We have
reported that treatment of cells with rapamycin induced early ROS production
and mitochondrial lipid oxidation that could be inhibited by the hydrophobic
antioxidant resveratrol (29).
Furthermore, resveratrol treatment impaired autophagic degradation of both
cytosolic and mitochondrial proteins and delayed rapamycin-induced cell death,
suggesting that mitochondrial oxidation events may play a crucial role in the
regulation of autophagy. This existence of regulation of autophagy by ROS has
received molecular support in HeLa cells
(30): these authors showed
that starvation stimulated ROS production, namely H2O2,
which was essential for autophagy. Furthermore, they identified the cysteine
protease hsAtg4 as a direct target for oxidation by
H2O2. This provided a possible connection between the
mitochondrial status and regulation of autophagy.Investigations of mitochondrial autophagy in nitrogen-starved lactate-grown
yeast cells have established the existence of two distinct processes: the
first one occurring very early, is selective for mitochondria and is dependent
on the presence of the mitochondrial protein Uth1p; the second one occurring
later, is not selective for mitochondria, is not dependent on Uth1p, and is a
form of bulk microautophagy
(3). The absence of the
selective process in the Δuth1 mutant strongly delays and
decreases mitochondrial protein degradation
(3,
12). The putative protein
phosphatase Aup1p has been also shown to be essential in inducing mitophagy
(31). Additionally several Atg
proteins were shown to be involved in vacuolar sequestration of mitochondrial
GFP (3,
12,
32,
33). Recently, the protein
Atg11p, which had been already identified as an essential protein for
selective autophagy has also been reported as being essential for mitophagy
(33).The question remains as to identify of the signals that trigger selective
mitophagy. It is particularly intriguing that selective mitophagy is activated
very early after the shift to a nitrogen-deprived medium
(3). Furthermore, selective
mitophagy is very active on lactate-grown cells (with fully differentiated
mitochondria) but is nearly absent in glucose-grown cells
(3). In the present paper, we
investigated the relationships between the redox status of the cells and
selective mitophagy, namely by manipulating glutathione. Our results support
the view that redox imbalance is a trigger for the selective elimination of
mitochondria. 相似文献
993.
994.
Andrey V. Kozlov J. Catharina Duvigneau Ingrid Miller Sylvia Nürnberger Bernd Gesslbauer Andreas Kungl Wolfgang Öhlinger Romana T. Hartl Lars Gille Katrin Staniek Wolfgang Gregor Susanne Haindl Heinz Redl 《生物化学与生物物理学报:疾病的分子基础》2009,1792(6):521-530
Inflammatory response has recently been shown to induce endoplasmic reticulum (ER) stress and the unfolded protein response (UPR), which either recovers proper ER function or activates apoptosis. Here we show that endotoxin (lipopolysaccharide = LPS) can lead to functional ER failure tentatively via a mitochondrion-dependent pathway in livers of rats. Histological examination did not reveal significant damage to liver in form of necroses. Electron microscopy displayed transparent rings appearing around morphologically unchanged mitochondria, which were identified as dilated ER. The spliced mRNA variant of X-box protein-1 (XBP1) and also the mRNA of 78 kDa glucose-regulated protein (GRP78) were up-regulated, both typical markers of ER stress. However, GRP78 was down-regulated at the protein level. A pro-apoptotic shift in the bax/bcl-XL mRNA ratio was not accompanied by translocation of apoptosis inducing factor (AIF) to the nucleus, suggesting that the cells entered a pre-apoptotic state, but apoptosis was not executed. Monooxygenase activity of p450, representing the detoxification system in ER, was decreased after administration of endotoxin. Biochemical analysis of proteins important for ER function revealed the impairment of protein folding, transport, and detoxification suggesting functional ER failure. We suggest that functional ER failure may be a reason for organ dysfunction upon excessive inflammatory response mediated by endotoxin. 相似文献
995.
Piperazinyl-glutamate-pyrimidines as potent P2Y12 antagonists for inhibition of platelet aggregation
John J. Parlow Mary W. Burney Brenda L. Case Thomas J. Girard Kerri A. Hall Ronald R. Hiebsch Rita M. Huff Rhonda M. Lachance Deborah A. Mischke Stephen R. Rapp Rhonda S. Woerndle Michael D. Ennis 《Bioorganic & medicinal chemistry letters》2009,19(21):6148-6156
Piperazinyl-glutamate-pyrimidines were prepared with oxygen, nitrogen, and sulfur substitution at the 4-position of the pyrimidine leading to highly potent P2Y12 antagonists. In particular, 4-substituted piperidine-4-pyrimidines provided compounds with exceptional potency. Pharmacokinetic and physicochemical properties were fine-tuned through modifications at the 4-position of the piperidine ring leading to compounds with good human PRP potency, selectivity, clearance and oral bioavailability. 相似文献
996.
John J. Parlow Mary W. Burney Brenda L. Case Thomas J. Girard Kerri A. Hall Ronald R. Hiebsch Rita M. Huff Rhonda M. Lachance Deborah A. Mischke Stephen R. Rapp Rhonda S. Woerndle Michael D. Ennis 《Bioorganic & medicinal chemistry letters》2009,19(16):4657-4663
Polymer-assisted solution-phase (PASP) parallel library synthesis was used to discover a piperazinyl-glutamate-pyridine as a P2Y12 antagonist. Exploitation of this lead provided compounds with excellent inhibition of platelet aggregation as measured in a human platelet rich plasma (PRP) assay. Pharmacokinetic and physiochemical properties were optimized leading to compound (4S)-4-[({4-[4-(methoxymethyl)piperidin-1-yl]-6-phenylpyridin-2-yl}carbonyl)amino]-5-oxo-5-{4-[(pentyloxy)carbonyl]piperazin-1-yl}pentanoic acid 22J with good human PRP potency, selectivity, in vivo efficacy and oral bioavailability. 相似文献
997.
Heike Pflanz Karen Vana Gerda Mitteregger Ingrid Renner-Müller Helmut Küchenhoff Eckhard Wolf 《Journal of molecular biology》2009,388(4):721-729
The 37-kDa/67-kDa laminin receptor (LRP/LR) was identified as a cell surface receptor for prion proteins. The laminin receptor mutant LRP102-295∷FLAG interfered with PrPSc propagation in murine neuronal cells presumably acting as a decoy in a transdominant negative fashion by trapping PrP molecules in the extracellular matrix. Here, we generated hemizygous transgenic mice expressing LRP102-295∷FLAG in the brain. Scrapie-infected transgenic mice exhibit a significantly prolonged incubation time in comparison to scrapie-infected wild-type (FVB) mice. At the terminal stage, transgenic mice revealed significantly reduced proteinase-K-resistant PrP levels by 71% compared to wild-type mice. Our results recommend the laminin receptor decoy mutant as an alternative therapeutic tool for treatment of transmissible spongiform encephalopathies. 相似文献
998.
Laila Berg Rahmi Lale Ingrid Bakke Nigel Burroughs Svein Valla 《Microbial biotechnology》2009,2(3):379-389
999.
We describe 12 microsatellite loci isolated from lake trout (Salvelinus namaycush). The number of alleles at these loci ranged from two to 11 with an average of 5.3 alleles per locus. The expected heterozygosity ranged from 0.29 to 0.76, with an average of 0.68. Accidental (or illegal) introductions of lake trout into watersheds are decimating native trout populations in the northern Rocky Mountains, and these loci will be useful for identifying the source of these introductions and for estimating the number of founding individuals. 相似文献
1000.
Jun Wu James S. Pankow Russell P. Tracy Kari E. North Richard H. Myers Mary E. Feitosa Michael A. Province Ingrid B. Borecki 《Obesity (Silver Spring, Md.)》2009,17(3):525-531
It has been recognized that obese individuals are intrinsically in a state of chronic inflammation, as indicated by positive correlations between serum levels of C‐reactive protein (CRP) and various anthropometric measures of obesity. To explore the hypothesis that a gene(s) may underlie this relationship, we conducted bivariate linkage analyses of BMI and CRP in white and African‐American (AA) families of the National Heart, Lung, and Blood Institute (NHLBI) Family Heart Study (FHS). Variance components linkage analysis as implemented in SOLAR was performed in 1,825 whites (840 men and 985 women) and 548 AAs (199 men and 351 women). CRP exhibited significant genetic correlations with BMI in women (0.54 ± 0.10 for white and 0.53 ± 0.14 for AA) and the combined samples (0.37 ± 0.09 for white and 0.56 ± 0.13 for AA), but not in men. We detected a maximum bivariate lod score of 3.86 on chromosome 12q24.2–24.3 at 139 cM and a suggestive linkage signal (lod = 2.19) on chromosome 19p13.1 (44 cM) in white women. Both bivariate peaks were substantially higher than their respective univariate lods at the same locus for each trait. No significant lod scores were detected in AAs. Our results indicate that chromosome 12q may harbor quantitative trait loci (QTLs) jointly regulating BMI and CRP in white women. 相似文献