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1.
Shreaya Chakroborty Clark Briggs Megan B. Miller Ivan Goussakov Corinne Schneider Joyce Kim Jaime Wicks Jill C. Richardson Vincent Conklin Benjamin G. Cameransi Grace E. Stutzmann 《PloS one》2012,7(12)
Alzheimer’s disease (AD) is a devastating neurodegenerative condition with no known cure. While current therapies target late-stage amyloid formation and cholinergic tone, to date, these strategies have proven ineffective at preventing disease progression. The reasons for this may be varied, and could reflect late intervention, or, that earlier pathogenic mechanisms have been overlooked and permitted to accelerate the disease process. One such example would include synaptic pathology, the disease component strongly associated with cognitive impairment. Dysregulated Ca2+ homeostasis may be one of the critical factors driving synaptic dysfunction. One of the earliest pathophysiological indicators in mutant presenilin (PS) AD mice is increased intracellular Ca2+ signaling, predominantly through the ER-localized inositol triphosphate (IP3) and ryanodine receptors (RyR). In particular, the RyR-mediated Ca2+ upregulation within synaptic compartments is associated with altered synaptic homeostasis and network depression at early (presymptomatic) AD stages. Here, we offer an alternative approach to AD therapeutics by stabilizing early pathogenic mechanisms associated with synaptic abnormalities. We targeted the RyR as a means to prevent disease progression, and sub-chronically treated AD mouse models (4-weeks) with a novel formulation of the RyR inhibitor, dantrolene. Using 2-photon Ca2+ imaging and patch clamp recordings, we demonstrate that dantrolene treatment fully normalizes ER Ca2+ signaling within somatic and dendritic compartments in early and later-stage AD mice in hippocampal slices. Additionally, the elevated RyR2 levels in AD mice are restored to control levels with dantrolene treatment, as are synaptic transmission and synaptic plasticity. Aβ deposition within the cortex and hippocampus is also reduced in dantrolene-treated AD mice. In this study, we highlight the pivotal role of Ca2+ aberrations in AD, and propose a novel strategy to preserve synaptic function, and thereby cognitive function, in early AD patients. 相似文献
2.
Philippe Lejeune Philippe Bertin Corinne Walon Karine Willemot Charles Colson Antoine Danchin 《Molecular & general genetics : MGG》1989,218(2):361-363
Summary Spontaneous mutants of Escherichia coli K12 displaying an increased level of the kanamycin resistance conferred by plasmid pGR71 were selected. Several mutants obtained in this way apparently carry large chromosomal deletions extending into galU and/or bglY (27 min). This positive selection of deletions allowed detection of a new locus located between galU and bglY. Deletions of this locus are responsible for increased resistance to kanamycin (Irk), decreased resistance to l-serine in minimal medium (Drs) and decreased resistance to chloramphenicol (Drc) when a cat gene is present in the bacteria. 相似文献
3.
Nitric oxide formation during microsomal hepatic denitration of glyceryl trinitrate: involvement of cytochrome P-450 总被引:4,自引:0,他引:4
D Servent M Delaforge C Ducrocq D Mansuy M Lenfant 《Biochemical and biophysical research communications》1989,163(3):1210-1216
Glyceryl trinitrate was denitrated by rat liver microsomes in the presence of NADPH with formation of a mixture of glyceryl dinitrates and glyceryl mononitrates. The highest activity was obtained under anaerobic conditions and the reaction was inhibited by O2 indicating that it is a reductive denitration. It was also inhibited by CO, metyrapone and miconazole showing that it was catalyzed by cytochrome P-450. Finally the formation of the cytochrome P-450-Fe(II)-NO complex during this reaction was shown by visible spectroscopy. These data demonstrate that microsomal reductive denitration of glyceryl trinitrate is catalyzed by cytochrome P-450 and can be involved in the formation of the endothelium-derived relaxing factor (EDRF = nitric oxide). 相似文献
4.
Ariella Oppenheim Avi Yaari Deborah Rund Eliezer A. Rachmilewitz David Nathan Corinne Wong Haig H. Kazazian Jr. Barbara Miller 《Human genetics》1990,86(2):175-180
Summary The mechanism for elevated production of fetal hemoglobin (Hb F) in a Druze patient with °-thalassemia intermedia was investigated. Heterozygous family members exhibited normal Hb F levels, suggesting that the increase in -gene expression in the propositus may be partly due to anemic stress. Erythroid progenitors of these family members cultured in vitro [burst forming units (erythroid); (BFUe)] showed elevated synthesis of Hb F, indicating the existence of a genetically determined intrinsic capacity for high Hb F production in this family. The propositus was found to be homozygous for a IVS2-position 1 mutation, on the background of Mediterranean haplotype I, which is not known to be linked to high Hb F production. Moreover, extensive molecular studies of the -globin gene cluster, including sequence analysis of the promoter regions of the -globin genes, did not reveal any cisacting mechanism that could account for the high Hb F production in the propositus. A young niece of the propositus with °-thalassemia major was recently discovered, who was homozygous for the same -globin allele and haplotype as the propositus. However, unlike her uncle, she does not have a high Hb F level and presents with a severe clinical course. Her inability to produce high Hb F suggests that the genetic determinant for increased -gene expression in the propositus is unlinked to the -globin gene cluster. 相似文献
5.
Corinne Vander Wauven Alfred Jann Dieter Haas Thomas Leisinger Victor Stalon 《Archives of microbiology》1988,150(4):400-404
Most Pseudomonas aeruginosa PAO mutants which were unable to utilize l-arginine as the sole carbon and nitrogen source (aru mutants) under aerobic conditions were also affected in l-ornithine utilization. These aru mutants were impaired in one or several enzymes involved in the conversion of N2-succinylornithine to glutamate and succinate, indicating that the latter steps of the arginine succinyltransferase pathway can be used for ornithine catabolism. Addition of aminooxyacetate, an inhibitor of the N2-succinylornithine 5-aminotransferase, to resting cells of P. aeruginosa in ornithine medium led to the accumulation of N2-succinylornithine. In crude extracts of P. aeruginosa an ornithine succinyltransferase (l-ornithine:succinyl-CoA N2-succinyltransferase) activity could be detected. An aru mutant having reduced arginine succinyltransferase activity also had correspondingly low levels of ornithine succinyltransferase. Thus, in P. aeruginosa, these two activities might be due to the same enzyme, which initiates aerobic arginine and ornithine catabolism.Abbreviations OAT
ornithine 5-aminotransferase
- SOAT
N2-succinylornithine 5-aminotransferase
- Oru
ornithine utilization
- Aru
arginine utilization 相似文献
6.
C. Lapouniéroulie O. Dunda R. Ducrocq G. Trabuchet M. Mony-Lobé J. M. Bodo P. Carnevale D. Labie J. Elion R. Krishnamoorthy 《Human genetics》1992,89(3):333-337
Summary The sickle cell mutation (s) arose as at least three independent events in Africa and once in Asia, being termed the Senegal, Benin, Bantu and Indian types respectively. An investigation in Cameroon was carried out to determine whether the atypical sickle genes observed in the neighboring countries are the result of recombination or the presence of a sickle cell mutation of a different genetic origin. It was conducted on 40 homozygous SS patients followed at the Blood Transfusion Center in the capital city of Yaoundé. On 80 s chromosomes, 13 exhibited a novel polymorphic pattern that was observed three times in the homozygous state. This chromosome contains an AT gene. The restriction fragment length polymorphism haplotype is different from all the other s chromosomes in both the 5 and 3 regions, but has previously been reported in sporadic cases. The (AT)8(T)5 sequence in the — 500 region of the gene is specific and different from that of the Senegal, Benin, Bantu or Indian s genes. All the carriers of this specific chromosome belong to the Eton ethnic group and originate from the Sanaga river valley. This observation strongly argues for yet another independent origin of the sickle cell mutation in Africa, here referred to as the Cameroon type. The Benin haplotype and a Benin/ Bantu recombinant haplotype have been observed in the other studied populations: Ewondo, Bamiléké, Bassa, Yambassa and Boulou. 相似文献
7.
D Servent C Ducrocq Y Henry C Servy M Lenfant 《Biotechnology and applied biochemistry》1992,15(3):257-266
A study of glyceryl trinitrate metabolism by a filamentous fungus, Phanerochaete chrysosporium, carried out with the 14C-labeled substrate, provides evidence for a multienzymatic system leading to di- and mononitrate derivatives. At least two independent enzymatic activities were detected in the cytosolic fraction: an aerobic glutathione S-transferase activity and an anaerobic NADPH-dependent soluble cytochrome P450-like activity. Other hemoproteins with enzymatic activities dependent upon the presence of NADPH or ferrous ions were also detected in the microsomal fraction. Electron paramagnetic resonance spectra characteristic of an interaction between a hemoprotein and nitric oxide appeared in these two subcellular fractions during the anaerobic metabolism of glyceryl trinitrate. 相似文献
8.
Inhibition of chlorophyll synthesis inHordeum vulgare by 3-amino 2,3-dihydrobenzoic acid (gabaculin) 总被引:10,自引:0,他引:10
Corinne M. Hill Sharon A. Pearson Arnold J. Smith Lyndon J. Rogers 《Bioscience reports》1985,5(9):775-781
Gabaculin (3-amino 2,3-dihydrobenzoic acid) is shown to be a very potent inhibitor of chlorophyll formation inHordeum vulgate. Exposure of leaf segments to 30/M gabaculin results in an 80% inhibition of chlorophyll synthesis, and this is paralleled by a decrease in carotenoid. Dual-inhibitor studies with dioxoheptanoic acid, which is an inhibitor of inolaevulinic acid dehydratase, show that gabaculin inhibits an earlier step than dioxoheptanoic acid and affects -aminolaevulinic acid synthesis rather than its subsequent metabolism. 相似文献
9.
10.