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排序方式: 共有171条查询结果,搜索用时 187 毫秒
11.
Thomas Ross Karol Szczepanek Elizabeth Bowler Ying Hu Andrew Larner Edward J. Lesnefsky Qun Chen 《Biochimica et Biophysica Acta (BBA)/General Subjects》2013
Background
The reverse electron flow-induced ROS generation (RFIR) is decreased in ischemia-damaged mitochondria. Cardiac ischemia leads to decreased complex I activity and depolarized inner mitochondrial membrane potential (ΔΨ) that are two key factors to affect the RFIR in isolated mitochondria. We asked if a partial inhibition of complex I activity without alteration of the ΔΨ is able to decrease the RFIR.Methods
Cardiac mitochondria were isolated from mouse heart (C57BL/6) with and without ischemia. The rate of H2O2 production from mitochondria was determined using amplex red coupled with horseradish peroxidase. Mitochondria were isolated from the mitochondrial-targeted STAT3 overexpressing mouse (MLS-STAT3E) to clarify the role of partial complex I inhibition in RFIR production.Results
The RFIR was decreased in ischemia-damaged mouse heart mitochondria with decreased complex I activity and depolarized ΔΨ. However, the RFIR was not altered in the MLS-STAT3E heart mitochondria with complex I defect but without depolarization of the ΔΨ. A slight depolarization of the ΔΨ in wild type mitochondria completely eliminated the RFIR.Conclusions
The mild uncoupling but not the partially decreased complex I activity contributes to the observed decrease in RFIR in ischemia-damaged mitochondria.General significance
The RFIR is less likely to be a key source of cardiac injury during reperfusion. 相似文献12.
13.
The tumor suppressor p53 is believed to play an essential role in maintaining genome stability. Although it is currently unknown how p53 is involved in this important biological safeguard, several previous publications indicate that p53 can help to maintain genome integrity through the recombination-mediated DNA repair process. The integration of linearized plasmid DNA into the host chromosome utilizes the same repair process, and the frequency can be measured by clonogenic assays in which cells that were stably transfected by plasmid integration can be scored by their colony-forming abilities. To gain insight into whether p53 has a direct role in plasmid integration into the host chromosome, we determined the frequency of stable transfection with CHO cells expressing either wild-type or mutant p53 in the presence and absence of irradiation. We found that low-dose irradiation (50 to 100 cGy) increased stable transfection frequencies in CHO cells regardless of their p53 status. However, the increase of transfection frequency was significantly lower in CHO cells expressing wild-type p53. Our data thus suggest that wild-type p53 can suppress plasmid DNA integration into the host genome. This p53 function may play a direct and significant role in maintaining genome stability. 相似文献
14.
Control of germination and lipid mobilization by COMATOSE,the Arabidopsis homologue of human ALDP 总被引:5,自引:0,他引:5
Footitt S Slocombe SP Larner V Kurup S Wu Y Larson T Graham I Baker A Holdsworth M 《The EMBO journal》2002,21(12):2912-2922
Embryo dormancy in flowering plants is an important dispersal mechanism that promotes survival of the seed through time. The subsequent transition to germination is a critical control point regulating initiation of vegetative growth. Here we show that the Arabidopsis COMATOSE (CTS) locus is required for this transition, and acts, at least in part, by profoundly affecting the metabolism of stored lipids. CTS encodes a peroxisomal protein of the ATP binding cassette (ABC) transporter class with significant identity to the human X-linked adrenoleukodystrophy protein (ALDP). Like X-ALD patients, cts mutant embryos and seedlings exhibit pleiotropic phenotypes associated with perturbation in fatty acid metabolism. CTS expression transiently increases shortly after imbibition during germination, but not in imbibed dormant seeds, and genetic analyses show that CTS is negatively regulated by loci that promote embryo dormancy through multiple independent pathways. Our results demonstrate that CTS regulates transport of acyl CoAs into the peroxisome, and indicate that regulation of CTS function is a major control point for the switch between the opposing developmental programmes of dormancy and germination. 相似文献
15.
Allosteric activation of protein phosphatase 2C by D-chiro-inositol-galactosamine, a putative mediator mimetic of insulin action 总被引:4,自引:0,他引:4
Brautigan DL Brown M Grindrod S Chinigo G Kruszewski A Lukasik SM Bushweller JH Horal M Keller S Tamura S Heimark DB Price J Larner AN Larner J 《Biochemistry》2005,44(33):11067-11073
Insulin-stimulated glucose disposal in skeletal muscle proceeds predominantly through a nonoxidative pathway with glycogen synthase as a rate-limiting enzyme, yet the mechanisms for insulin activation of glycogen synthase are not understood despite years of investigation. Isolation of putative insulin second messengers from beef liver yielded a pseudo-disaccharide consisting of pinitol (3-O-methyl-d-chiro-inositol) beta-1,4 linked to galactosamine chelated with Mn(2+) (called INS2). Here we show that chemically synthesized INS2 has biological activity that significantly enhances insulin reduction of hyperglycemia in streptozotocin diabetic rats. We used computer modeling to dock INS2 onto the known three-dimensional crystal structure of protein phosphatase 2C (PP2C). Modeling and FlexX/CScore energy minimization predicted a unique favorable site on PP2C for INS2 in a surface cleft adjacent to the catalytic center. Binding of INS2 is predicted to involve formation of multiple H-bonds, including one with residue Asp163. Wild-type PP2C activity assayed with a phosphopeptide substrate was potently stimulated in a dose-dependent manner by INS2. In contrast, the D163A mutant of PP2C was not activated by INS2. The D163A mutant and wild-type PP2C in the absence of INS2 had the same Mn(2+)-dependent phosphatase activity with p-nitrophenyl phosphate as a substrate, showing that this mutation did not disrupt the catalytic site. We propose that INS2 allosterically activates PP2C, fulfilling the role of a putative mediator mimetic of insulin signaling to promote protein dephosphorylation and metabolic responses. 相似文献
16.
Amino acid starvation induced autophagic cell death in PC-12 cells: Evidence for activation of caspase-3 but not calpain-1 总被引:2,自引:0,他引:2
Sadasivan S Waghray A Larner SF Dunn WA Hayes RL Wang KK 《Apoptosis : an international journal on programmed cell death》2006,11(9):1573-1582
While the apoptotic and necrotic cell death pathways have been well studied, there lacks a comprehensive understanding of
the molecular events involving autophagic cell death. We examined the potential roles of the apoptosis-linked caspase-3 and
the necrosis/apoptosis-linked calpain-1 after autophagy induction under prolonged amino acid (AA) starvation conditions in
PC-12 cells. Autophagy induction was observed as early as three hours following amino acid withdrawal. Cell death, measured
by lactate dehydrogenase (LDH) and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assays occurred within
24 h following starvation and was accompanied by an upregulation in caspase-3 activity but not calpain-1. The cell death that
occurred following AA starvation was significantly alleviated by treatment with the autophagy inhibitor 3-methyl adenine but
not with the broad spectrum caspase inhibitors. Thus, this study demonstrates that 3-methyladenine-sensitive autophagic cell
death due to AA starvation in PC-12 cells is mechanistically and biochemically similar to, yet distinct from, classic caspase
dependent apoptosis.
Shankar Sadasivan and Anu Waghray have contributed equally to this work. 相似文献
17.
18.
Chang Y Guo David L Brautigan James M Larner 《The Journal of biological chemistry》2002,277(7):4839-4844
Ionizing radiation (IR) is known to activate multiple cell cycle checkpoints that are thought to enhance the ability of cells to respond to DNA damage. Protein phosphatase 2A (PP2A) has been implicated in IR-induced activation of checkpoints; therefore, Jurkat cells were exposed to an activating dose of IR or sham treatment as control, and nuclear extracts were analyzed for PP2A by Mono Q anion exchange chromatography and microcystin affinity chromatography. PP2A exists in eukaryotic cells both as a heterodimer consisting of a 65-kDa scaffolding subunit (A) plus a 36-kDa catalytic subunit (C) and as ABC heterotrimers, containing one of a variety of regulatory (B) subunits. Here we show that IR produces a transient and reversible reduction in the amount of nuclear AB55C heterotrimer without affecting the AB'C heterotrimer or AC heterodimer. In ataxia telangiectasia-mutated (ATM)-deficient cells the amount of nuclear PP2A heterotrimer relative to heterodimer was not reduced by radiation, but the radiation response was restored by transfection of these cells with plasmids encoding ATM. Wortmannin, an inhibitor of kinases such as phosphatidylinositol 3-kinase, also prevented the IR-induced reduction in nuclear PP2A heterotrimer. The changes in nuclear PP2A occurred without a noticeable difference in the carboxyl-terminal methylation of the C subunit, which is known to influence association with B subunits. We conclude a novel ATM-dependent mechanism is regulating association of B55 subunits with nuclear PP2A in response to IR. 相似文献
19.
Pavel N. Shashkin Laura C. Huang Joseph Larner George E. Vandenhoff Abram Katz 《Experimental diabetes research》2002,3(3):163-169
Two classes of inositol phosphoglycans have been implicated as
second messengers of insulin, one that activates pyruvate dehydrogenase
and contains D-chiroinositol, and one that inhibits cyclic
AMP–dependent protein kinase and contains myoinositol. We examined
the effects of a 3-day fast on muscle contents of inositols
in healthy humans. An oral glucose tolerance test was performed
and a biopsy was obtained from the quadriceps femoris muscle
after an overnight fast and after a 72-hour fast. The 72-hour fast
significantly increased plasma glucose (1.5- to 2-fold) and insulin
(2- to 4-fold) after glucose ingestion versus the values after the
overnight fast, indicating the manifestation of peripheral insulin
resistance. The 72-hour fast resulted in an ∼20% decrease in the
muscle content of D-chiroinositol (P < 0.02), but no change in the
myoinositol content. These data demonstrate that fasting specifically
decreases the muscle content of D-chiroinositol in human muscle
and this may contribute to the finding that insulin-mediated activation
of pyruvate dehydrogenase is attenuated after short-term
starvation. 相似文献
20.
The acute effects after administration of 3-O-Methyl-D-Chiro-inositol, D-Chiro-inositol and manganese, components of the pH 2.0 putative mediator of insulin action, on plasma glucose were examined in low dose streptozotocin-treated rats. 3-O-Methyl-D-Chiro-inositol at a bolus dose of 5 mg/kg decreased plasma glucose 6% at 120 min (p < 0.05). A higher bolus dose of 3-O-Methyl-D-Chiro-inositol (15 mg/kg) promoted a more persistent hypoglycemic effect of 22% at 120 min (p < 0.05). Infusion of 8.3 microg/min of manganese chloride lowered plasma glucose by 23% (p < 0.05). 3-O-Methyl-D-Chiro-inositol (15 mg/kg) together with manganese chloride (8.3 microg/min) promoted a reduction of 49% in 120 min (p < 0.05). D-Chiro-inositol at a bolus dose of 5 mg/kg had no effect. A single dose of 15 mg/kg produced a reduction of 21% (p < 0.05) in 120 min. D-Chiro-inositol (15 mg/kg) associated with manganese chloride (8.3 microg/min) decreased elevated plasma glucose 47% (p < 0.05) in 120 min. D-Chiro-inositol coadministered with manganese reduced glucose concentrations during the final 60 min (p < 0.05). 3-O-Methyl-D-Chiro-inositol and D-chiro-inositol are components of the mediator structure. Manganese is also a presumed component of the mediator, having an important role in glucose uptake, insulin release and mediator generation. These compounds have also been identified in the literature as hypoglycemic agents. 相似文献