排序方式: 共有61条查询结果,搜索用时 62 毫秒
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Rosalind A. Rosenthal Karl D. Huffman Leslie W. Fisette Christy A. Damphousse Wyeth B. Callaway Bernard Malfroy Susan R. Doctrow 《Journal of biological inorganic chemistry》2009,14(6):979-991
Superoxide dismutase/catalase mimetics, such as salen Mn complexes and certain metalloporphyrins, catalytically neutralize
reactive oxygen and nitrogen species, which have been implicated in the pathogenesis of many serious diseases. Both classes
of mimetic are protective in animal models of oxidative stress. However, only AEOL11207 and EUK-418, two uncharged Mn porphyrins,
have been shown to be orally bioavailable. In this study, EUK-418 and several new analogs (the EUK-400 series) were synthesized
and shown to exhibit superoxide dismutase, catalase, and peroxidase activities in vitro. Some also protected PC12 cells against
staurosporine-induced cell death. All EUK-400 compounds were stable in simulated gastric fluid, and most were substantially
more lipophilic than the salen Mn complexes EUK-189 and EUK-207, which lack oral activity. Pharmacokinetics studies demonstrate
the presence of all EUK-400 series compounds in the plasma of rats after oral administration. These EUK-400 series compounds
are potential oral therapeutic agents for cellular damage caused by oxidative stress.
Electronic supplementary material The online version of this article (doi:) contains supplementary material, which is available to authorized users. 相似文献
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Alzheimer disease is characterized by cerebral Abeta deposition, which we have recently discovered occurs also in the lens as cataracts in Alzheimer disease patients. Here we report the presence of significantly increased cataracts in the lenses of an Abeta-transgenic mouse model for Alzheimer disease and their amelioration upon treatment with EUK-189, a synthetic SOD/catalase mimetic. These data support an oxidative etiology for AD-associated lens cataracts and their potential to be treated preventatively with antioxidants. 相似文献
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Free iron has been assumed to potentiate oxygen toxicity by generating reactive oxygen species (ROS) via the iron-catalyzed Haber-Weiss reaction, leading to oxidative stress. ROS-mediated iron cytotoxicity may trigger apoptotic cell death. In the present study, we used iron treatment of organotypic cultures of hippocampal slices to study potential mechanisms involved in iron-induced neuronal damage. Exposure of mature hippocampal slices to ferrous sulfate resulted in concentration- and time-dependent cell death. After iron treatment, markers of ROS formation and lipid peroxidation, i.e. intensity of dichlorofluorescein (DCF) fluorescence and levels of thiobarbiturate reactive substances (TBARS), were significantly increased. Levels of cytochrome c were increased while levels of pro-caspase-9 and pro-caspase-3 were decreased in cytosolic fractions of iron-treated hippocampal slice cultures. Treatment of cultured slices with a synthetic catalytic ROS scavenger, EUK-134, provided between 50 and 70% protection against various parameters of cell damage and markers of oxidative stress. In addition, inhibition of caspase-3 activity by Ac-DEVDcho partially protected cells from iron toxicity. The combination of EUK-134 and Ac-DEVDcho resulted in an almost complete blockade of iron-induced damage. These results indicate that iron elicits cellular damage predominantly by oxidative stress, and that ROS-mediated iron toxicity may involve cytochrome c- and caspase-3-dependent apoptotic pathways. 相似文献
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The use of the antiplatelet agents abciximab and clopidogrel is now accepted therapy in percutaneous coronary intervention. We present a case in which these agents were used in a patient with idiopathic thrombocytopaenic purpura and a platelet count of 40x10(9)/l undergoing primary multivessel coronary stenting. This case shows that unstable coronary syndromes can occur in patients with thrombocytopaenia and that antiplatelet agents may be used safely in this context. 相似文献
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Protein kinase C activators suppress stimulation of capillary endothelial cell growth by angiogenic endothelial mitogens 总被引:4,自引:4,他引:4
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The intracellular events regulating endothelial cell proliferation and organization into formalized capillaries are not known. We report that the protein kinase C activator beta-phorbol 12,13-dibutyrate (PDBu) suppresses bovine capillary endothelial (BCE) cell proliferation (K50 = 6 +/- 4 nM) and DNA synthesis in response to human hepatoma-derived growth factor, an angiogenic endothelial mitogen. In contrast, PDBu has no effect on the proliferation of bovine aortic endothelial cells and is mitogenic for bovine aortic smooth muscle and BALB/c 3T3 cells. Several observations indicate that the inhibition of human hepatoma-derived growth factor-stimulated BCE cell growth by PDBu is mediated through protein kinase C. Different phorbol compounds inhibit BCE cell growth according to their potencies as protein kinase C activators (12-O-tetradecanoylphorbol 13-acetate greater than PDBu much greater than beta-phorbol 12,13-diacetate much much greater than beta-phorbol; alpha-phorbol 12,13-dibutyrate; alpha-phorbol 12,13-didecanoate). PDBu binds to a single class of specific, saturable sites on the BCE cell with an apparent Kd of 8 nM, in agreement with reported affinities of PDBu for protein kinase C in other systems. Specific binding of PDBu to BCE cells is displaced by sn-1,2-dioctanoylglycerol, a protein kinase C activator and an analog of the putative second messenger activating this kinase in vivo. The weak protein kinase C activator, sn-1,2-dibutyrylglycerol, does not affect PDBu binding. A cytosolic extract from BCE cells contains a calcium/phosphatidylserine-dependent protein kinase that is activated by sn-1,2-dioctanoylglycerol and PDBu, but not by beta-phorbol. These findings indicate that protein kinase C activation can cause capillary endothelial cells to become desensitized to angiogenic endothelial mitogens. This intracellular regulatory mechanism might be invoked during certain phases of angiogenesis, for example when proliferating endothelial cells become differentiated to organize into nongrowing tubes. 相似文献
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Contrasting population structure from nuclear intron sequences and mtDNA of humpback whales 总被引:21,自引:4,他引:21
Powerful analyses of population structure require information from multiple
genetic loci. To help develop a molecular toolbox for obtaining this
information, we have designed universal oligonucleotide primers that span
conserved intron-exon junctions in a wide variety of animal phyla. We test
the utility of exon-primed, intron-crossing amplifications by analyzing the
variability of actin intron sequences from humpback, blue, and bowhead
whales and comparing the results with mitochondrial DNA (mtDNA) haplotype
data. Humpback actin introns fall into two major clades that exist in
different frequencies in different oceanic populations. It is surprising
that Hawaii and California populations, which are very distinct in mtDNAs,
are similar in actin intron alleles. This discrepancy between mtDNA and
nuclear DNA results may be due either to differences in genetic drift in
mitochondrial and nuclear genes or to preferential movement of males, which
do not transmit mtDNA to offspring, between separate breeding grounds.
Opposing mtDNA and nuclear DNA results can help clarify otherwise hidden
patterns of structure in natural populations.
相似文献
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Aida Rodríguez‐Nuevo Angels Díaz‐Ramos Eduard Noguera Francisco Díaz‐Sáez Xavier Duran Juan Pablo Muñoz Montserrat Romero Natàlia Plana David Sebastián Caterina Tezze Vanina Romanello Francesc Ribas Jordi Seco Evarist Planet Susan R Doctrow Javier González Miquel Borràs Marc Liesa Manuel Palacín Joan Vendrell Francesc Villarroya Marco Sandri Orian Shirihai Antonio Zorzano 《The EMBO journal》2018,37(10)
Opa1 participates in inner mitochondrial membrane fusion and cristae morphogenesis. Here, we show that muscle‐specific Opa1 ablation causes reduced muscle fiber size, dysfunctional mitochondria, enhanced Fgf21, and muscle inflammation characterized by NF‐κB activation, and enhanced expression of pro‐inflammatory genes. Chronic sodium salicylate treatment ameliorated muscle alterations and reduced the muscle expression of Fgf21. Muscle inflammation was an early event during the progression of the disease and occurred before macrophage infiltration, indicating that it is a primary response to Opa1 deficiency. Moreover, Opa1 repression in muscle cells also resulted in NF‐κB activation and inflammation in the absence of necrosis and/or apoptosis, thereby revealing that the activation is a cell‐autonomous process and independent of cell death. The effects of Opa1 deficiency on the expression NF‐κB target genes and inflammation were absent upon mitochondrial DNA depletion. Under Opa1 deficiency, blockage or repression of TLR9 prevented NF‐κB activation and inflammation. Taken together, our results reveal that Opa1 deficiency in muscle causes initial mitochondrial alterations that lead to TLR9 activation, and inflammation, which contributes to enhanced Fgf21 expression and to growth impairment. 相似文献