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91.
Andrew Grey Claire Chaussade Victoria Empson Jian-Ming Lin Susannah O’Sullivan Dorit Naot Peter Shepherd 《Biochemical and biophysical research communications》2010,391(1):564-569
Signaling through phosphatidylinositol-3 kinases (PI3K) regulates fundamental cellular processes such as survival and growth, and these lipid kinases are currently being investigated as therapeutic targets in several contexts. In skeletal tissue, experiments using pan-specific PI3K inhibitors have suggested that PI3K signaling influences both osteoclast and osteoblast function, but the contributions of specific PI3K isoforms to these effects have not been examined. In the current work, we assessed the effects of pharmacological inhibitors of the class Ia PI3Ks, α, β, and δ, on bone cell growth, differentiation and function in vitro. Each of the class Ia PI3K isoforms is expressed and functionally active in bone cells. No consistent effects of inhibitors of p110-β or p110-δ on bone cells were observed. Inhibitors of p110-α decreased osteoclastogenesis by 60-80% (p < 0.001 vs control) by direct actions on osteoclast precursors, and decreased the resorptive activity of mature osteoclasts by 60% (p < 0.01 vs control). The p110-α inhibitors also decreased the growth of osteoblastic and stromal cells (p < 0.001 vs control), and decreased differentiated osteoblast function by 30% (p < 0.05 vs control). These data suggest that signaling through the p110-α isoform of class Ia PI3Ks positively regulates the development and function of both osteoblasts and osteoclasts. Therapeutic agents that target this enzyme have the potential to significantly affect bone homeostasis, and evaluation of skeletal endpoints in clinical trials of such agents is warranted. 相似文献
92.
Deng Li Qingfeng He Tao Kang Huan Yin Xian Jin Weiqiong Gan Jingjing Hu Lifei Peng 《Biochemical and biophysical research communications》2010,392(2):155-159
Factor VIIa-tissue factor complex (fVIIa/TF) and factor XIa (fXIa) play important roles in the initiation and amplification of coagulation, respectively. They may be good targets for the development of novel anticoagulants to treat and prevent thromboembolic disease. In this study, we cloned, expressed and identified a novel anticoagulant peptide, AcaNAP10, from the blood-feeding nematode Ancylostoma caninum. AcaNAP10 showed potent anticoagulant activity and doubled the activated partial thromboplastin and prothrombin times at estimated concentrations of 92.9 nM and 28.8 nM, respectively. AcaNAP10 demonstrated distinct mechanisms of action compared with known anticoagulants. It inhibited fXIa and fVIIa/TF with IC50 values of 25.76 ± 1.06 nM and 123.9 ± 1.71 nM, respectively. This is the first report on an anticoagulant that can inhibit both fXIa and fVIIa/TF. This anticoagulant peptide may be an alternative molecule for the development of novel anticoagulants. 相似文献
93.
Cdk5 dysregulation is a major event in the neurodegenerative process of Alzheimer's disease (AD). In vitro studies using differentiated neurons exposed to Aβ exhibit Cdk5-mediated tau hyperphosphorylation, cell cycle re-entry and neuronal loss. In this study we aimed to determine the role of Cdk5 in neuronal injury occurring in an AD mouse model obtained through the intracerebroventricular (icv) injection of the Aβ1–40 synthetic peptide. In mice icv-injected with Aβ, Cdk5 activator p35 is cleaved by calpains, leading to p25 formation and Cdk5 overactivation. Subsequently, there was an increase in tau hyperphosphorylation, as well as decreased levels of synaptic markers. Cell cycle reactivation and a significant neuronal loss were also observed. These neurotoxic events in Aβ-injected mice were prevented by blocking calpain activation with MDL28170 , which was administered intraperitoneally (ip). As MDL prevents p35 cleavage and subsequent Cdk5 overactivation, it is likely that this kinase is involved in tau hyperphosphorylation, cell cycle re-entry, synaptic loss and neuronal death triggered by Aβ. Altogether, these data demonstrate that Cdk5 plays a pivotal role in tau phosphorylation, cell cycle induction, synaptotoxicity, and apoptotic death in postmitotic neurons exposed to Aβ peptides in vivo , acting as a link between diverse neurotoxic pathways of AD. 相似文献
94.
95.
Jahnke U Higginbottom K Newland AC Cotter FE Allen PD 《Biochemical and biophysical research communications》2007,361(4):928-933
Etoposide is a potent inducer of mitotic catastrophe; a type of cell death resulting from aberrant mitosis. It is important in p53 negative cells where p53 dependent apoptosis and events at the G1 and G2 cell cycle checkpoints are compromised. Passenger proteins regulate many aspects of mitosis and siRNA interference or direct inhibition of Aurora B kinase results in mitotic catastrophe. However, there is little available data of clinical relevance in leukaemia models. Here, in p53 negative K562 myeloid leukemia cells, etoposide-induced mitotic catastrophe is shown to be time and/or concentration dependent. Survivin and Aurora remained bound to chromosomes. Survivin and Aurora were also associated with Cdk1 and were shown to form complexes, which in pull down experiments, included INCENP. There was no evidence of Aurora B kinase suppression. These data suggests etoposide will complement Aurora B kinase inhibitors currently in clinical trials for cancer. 相似文献
96.
97.
Lin MC Hwang MT Chang HG Lin CS Lin G 《Journal of biochemical and molecular toxicology》2007,21(6):348-353
Benzene-1,2-, 1,3-, and 1,4-di-N-substituted carbamates (1-15) are synthesized as the conformationally constrained inhibitors of acetylcholinesterase and mimic gauche, eclipsed, and anti-conformations of acetylcholine, respectively. All carbamates 1-15 are characterized as the pseudo substrate inhibitors of acetylcholinesterase. For a series of geometric isomers, the inhibitory potencies are as follows: benzene-1,4-di-N-substituted carbamate (para compound) > benzene-1,3-di-N-substituted carbamate (meta compound) > benzene-1,2-di-N-substituted carbamate (ortho compound). Therefore, benzene-1,4-di-N-substituted carbamates (para compounds), with the angle of 180 degrees between two C(benzene)-O bonds, mimic the preferable anti C-O/C-N conformers of acetylcholine for the choline ethylene backbone in the acetylcholinesterase catalysis. 相似文献
98.
Higginbottom K Jahnke U Newland AC Cotter FE Allen PD 《Apoptosis : an international journal on programmed cell death》2007,12(10):1847-1855
Cell cycle arrest is a major cellular response to DNA damage preceding the decision to repair or die. Many malignant cells
have non-functional p53 rendering them more “aggressive” in nature. Arrest in p53-negative cells occurs at the G2M cell cycle
checkpoint. Failure of DNA damaged cells to arrest at G2 results in entry into mitosis and potential death through aberrant
mitosis and/or apoptosis. The pivotal kinase regulating the G2M checkpoint is Cdk1/cyclin B whose activity is controlled by
phosphorylation. The p53-negative myeloid leukemia cell lines K562 and HL-60 were used to determine Cdk1 phosphorylation status
during etoposide treatment. Cdk1 tyrosine 15 phosphorylation was associated with G2M arrest, but not with cell death. Cdk1
tyrosine 15 phosphorylation also led to suppression of nuclear cyclin B-associated Cdk1 kinase activity. However cell death,
associated with broader tyrosine phosphorylation of Cdk1 was not attributed to tyrosine 15 alone. This broader phosphoryl
isoform of Cdk1 was associated with cyclin A and not cyclin B. Alternative phosphorylations sites were predicted as tyrosines
4, 99 and 237 by computer analysis. No similar pattern was found on Cdk2. These findings suggest novel Cdk1 phosphorylation
sites, which appear to be associated with p53-independent cell death following etoposide treatment. 相似文献
99.
Deregulation of Wnt/β-catenin pathway is closely related to the pathogenesis of neurodegenerative diseases such as Alzheimer’s disease (AD), and glycogen synthase kinase 3β (GSK-3β), the central negative regulator of Wnt pathway, is regarded as an important target for these diseases. Here, we report a series of benzo[e]isoindole-1,3-dione derivatives as selective GSK-3β inhibitors by rational-design and synthesis, which show high selectivity against GSK-3β over Cyclin-dependent kinase 2 (CDK2), and significantly activate the cellular Wnt/β-catenin pathway. The structure–activity relationship of these GSK-3β inhibitors was also explored by in silico molecular docking. 相似文献
100.
Hanjiang Yang Felix Christof Wahlmüller Bettina Sarg Margareta Furtmüller Margarethe Geiger 《The Journal of biological chemistry》2015,290(5):3081-3091
Protein C inhibitor (PCI) is a serpin with broad protease reactivity. It binds glycosaminoglycans and certain phospholipids that can modulate its inhibitory activity. PCI can penetrate through cellular membranes via binding to phosphatidylethanolamine. The exact mechanism of PCI internalization and the intracellular role of the serpin are not well understood. Here we showed that testisin, a glycosylphosphatidylinositol-anchored serine protease, cleaved human PCI and mouse PCI (mPCI) at their reactive sites as well as at sites close to their N terminus. This cleavage was observed not only with testisin in solution but also with cell membrane-anchored testisin on U937 cells. The cleavage close to the N terminus released peptides rich in basic amino acids. Synthetic peptides corresponding to the released peptides of human PCI (His1–Arg11) and mPCI (Arg1–Ala18) functioned as cell-penetrating peptides. Because intact mPCI but not testisin-cleaved mPCI was internalized by Jurkat T cells, a truncated mPCI mimicking testisin-cleaved mPCI was created. The truncated mPCI lacking 18 amino acids at the N terminus was not taken up by Jurkat T cells. Therefore our model suggests that testisin or other proteases could regulate the internalization of PCI by removing its N terminus. This may represent one of the mechanisms regulating the intracellular functions of PCI. 相似文献