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91.
Dudley RW Khairallah M Mohammed S Lands L Des Rosiers C Petrof BJ 《American journal of physiology. Regulatory, integrative and comparative physiology》2006,291(3):R704-R710
The precise mechanisms underlying skeletal muscle damage in Duchenne muscular dystrophy (DMD) remain ill-defined. Functional ischemia during muscle activation, with subsequent reperfusion during rest, has been documented. Therefore, one possibility is the presence of increased oxidative stress. We applied a model of acute hindlimb ischemia/reperfusion (I/R) in mdx mice (genetic homolog of DMD) to evaluate dynamic in vivo responses of dystrophic muscles to this form of oxidative stress. Before the application of I/R, mdx muscles showed: 1) decreased levels of total glutathione (GSH) with an increased oxidized (GSSG)-to-reduced (GSH) glutathione ratio; 2) greater activity of the GSH-metabolizing enzymes glutathione peroxidase (GPx) and glutathione reductase; and 3) lower activity levels of NADP-linked isocitrate dehydrogenase (ICDH) and aconitase, two metabolic enzymes that are sensitive to inactivation by oxidative stress and also implicated in GSH regeneration. Interestingly, nondystrophic muscles subjected to I/R exhibited similar changes in total glutathione, GSSG/GSH, GPx, ICDH, and aconitase. In contrast, all of the above remained stable in mdx muscles subjected to I/R. Taken together, these results suggest that mdx muscles are chronically subjected to increased oxidative stress, leading to adaptive changes that attempt to protect (although only in part) the dystrophic muscles from acute I/R-induced oxidative stress. In addition, mdx muscles show significant impairment of the redox-sensitive metabolic enzymes ICDH and aconitase, which may further contribute to contractile dysfunction in dystrophic muscles. 相似文献
92.
Li Q Woods KW Thomas S Zhu GD Packard G Fisher J Li T Gong J Dinges J Song X Abrams J Luo Y Johnson EF Shi Y Liu X Klinghofer V Des Jong R Oltersdorf T Stoll VS Jakob CG Rosenberg SH Giranda VL 《Bioorganic & medicinal chemistry letters》2006,16(7):2000-2007
Structure-based design and synthesis of the 3,4'-bispyridinylethylene series led to the discovery of 3-isoquinolinylpyridine 13a as a potent PKB/Akt inhibitor with an IC(50) of 1.3nM against Akt1. Compound 13a shows excellent selectivity against distinct families of kinases such as tyrosine kinases and CAMK, and displays poor to marginal selectivity against closely related kinases in the AGC and CMGC families. Moreover, 13a demonstrates potent cellular activity comparable to staurosporine, with IC(50) values of 0.42 and 0.59microM against MiaPaCa-2 and the Akt1 overexpressing FL5.12-Akt1, respectively. Inhibition of phosphorylation of the Akt downstream target GSK3 was also observed in FL5.12-Akt1 cells with an EC(50) of 1.5microM. The X-ray structures of 12 and 13a in complex with PKA in the ATP-binding site were determined. 相似文献
93.
Growth arrest and DNA damage-45 alpha (GADD45alpha) 总被引:1,自引:0,他引:1
Rosemary Siafakas A Richardson DR 《The international journal of biochemistry & cell biology》2009,41(5):986-989
Regulation of cell cycle and growth is integral for cell survival. The intricate mechanisms that control proliferation and cell cycle are numerous. The growth arrest and DNA damage (GADD)-inducible gene family is often up-regulated in response to various environmental stresses and drug therapies. GADD45alpha was the first stress-inducible gene determined to be up-regulated by p53 and is also a target for the p53 homologues, p63 and p73. When GADD45alpha is deleted or repressed, cells show uncontrolled proliferation. Furthermore, decreased GADD45alpha expression is also considered a survival mechanism, as cancer cells without this control can evade the apoptotic pathway leading to increased tumourigenesis. Drug therapies can act to directly or indirectly up-regulate GADD45alpha and promote apoptosis. As GADD45alpha is an essential component of many metabolic pathways that control proliferating cancer cells, it presents itself as an emerging drug target worthy of further investigation. 相似文献
94.
Frédéric Heymans Adrien Fischer Nicholas W. Stow Myriam Girard Zacharias Vourexakis Antoine Des Courtis Gesuele Renzi Elzbieta Huggler Stefan Vlaminck Pierre Bonfils Ranko Mladina Valerie Lund Jacques Schrenzel Patrice Fran?ois Jean Silvain Lacroix 《PloS one》2010,5(3)
Background
Staphylococcus aureus secretes numerous exotoxins which may exhibit superantigenic properties. Whereas the virulence of several of them is well documented, their exact biological effects are not fully understood. Exotoxins may influence the immune and inflammatory state of various organs, including the sinonasal mucosa: their possible involvement in chronic rhinosinusitis has been suggested and is one of the main trends in current research. The aim of this study was to investigate whether the presence of any of the 22 currently known staphylococcal exotoxin genes could be correlated with chronic rhinosinusitis.Methodology/Principal Findings
We conducted a prospective, multi-centred European study, analysing 93 Staphylococcus aureus positive swabs taken from the middle meatus of patients suffering from chronic rhinosinusitis, with or without nasal polyposis, and controls. Strains were systematically tested for the presence of the 22 currently known exotoxin genes and genotyped according to their agr groups. No direct correlation was observed between chronic rhinosinusitis, with or without nasal polyposis, and either agr groups or the presence of the most studied exotoxins genes (egc, sea, seb, pvl, exfoliatins or tsst-1). However, genes for enterotoxins P and Q were frequently observed in nasal polyposis for the first time, but absent in the control group. The number of exotoxin genes detected was not statistically different among the 3 patient groups.Conclusions/Significance
Unlike many previous studies have been suggesting, we did not find any evident correlation between staphylococcal exotoxin genes and the presence or severity of chronic rhinosinusitis with or without nasal polyposis. 相似文献95.
Storage protein profiles in Spanish and runner market type peanuts and potential markers 总被引:1,自引:0,他引:1
Background
Proteomic analysis has proven to be the most powerful method for describing plant species and lines, and for identification of proteins in complex mixtures. The strength of this method resides in high resolving power of two-dimensional electrophoresis (2-DE), coupled with highly sensitive mass spectrometry (MS), and sequence homology search. By using this method, we might find polymorphic markers to differentiate peanut subspecies. 相似文献96.
97.
98.
Vincent G Bouchard B Khairallah M Des Rosiers C 《American journal of physiology. Heart and circulatory physiology》2004,286(1):H257-H266
The objective of this study was to test the effect of increasing fatty acid concentrations on substrate fluxes through pathways leading to citrate synthesis and release in the heart. This was accomplished using semirecirculating work-performing rat hearts perfused with substrate mixtures mimicking the in situ milieu (5.5 mM glucose, 8 nM insulin, 1 mM lactate, 0.2 mM pyruvate, and 0.4 mM oleate-albumin) and 13C methods. Raising the fatty acid concentration from 0.4 to 1 mM with long-chain oleate or medium-chain octanoate resulted in a lowering ( approximately 20%) of cardiac output and efficiency with unaltered O2 consumption. At the metabolic level, beyond the expected effects of high fatty acid levels on the contribution of pyruvate decarboxylation (reduced >3-fold) and beta-oxidation (enhanced approximately 3-fold) to citrate synthesis, there was also a 2.4-fold lowering of anaplerotic pyruvate carboxylation. Despite the dual inhibitory effect of high fatty acids on pyruvate decarboxylation and carboxylation, tissue citrate levels were twofold higher, but citrate release rates remained unchanged at 11-14 nmol/min, representing <0.5% of citric acid cycle flux. A similar trend was observed for most metabolic parameters after oleate or octanoate addition. Together, these results emphasize a differential modulation of anaplerotic pyruvate carboxylation and citrate release in the heart by fatty acids. We interpret the lack of effects of high fatty acid concentrations on citrate release rates as suggesting that, under physiological conditions, this process is maximal, probably limited by the activity of its mitochondrial or plasma membrane transporter. Limited citrate release at high fatty acid concentrations may have important consequences for the heart's fuel metabolism and function. 相似文献
99.
Michael Li-Hsuan Huang Christopher J. D. Austin Marie-Agnès Sari Yohan Suryo Rahmanto Prem Ponka Daniel Vyoral Des R. Richardson 《The Journal of biological chemistry》2013,288(35):25450-25465
Hepcidin regulates iron metabolism by down-regulating ferroportin-1 (Fpn1). We demonstrated that hepcidin is complexed to the blood transport protein, α2-macroglobulin (α2M) (Peslova, G., Petrak, J., Kuzelova, K., Hrdy, I., Halada, P., Kuchel, P. W., Soe-Lin, S., Ponka, P., Sutak, R., Becker, E., Huang, M. L., Suryo Rahmanto, Y., Richardson, D. R., and Vyoral, D. (2009) Blood 113, 6225–6236). However, nothing is known about the mechanism of hepcidin binding to α2M or the effects of the α2M·hepcidin complex in vivo. We show that decreased Fpn1 expression can be mediated by hepcidin bound to native α2M and also, for the first time, hepcidin bound to methylamine-activated α2M (α2M-MA). Passage of high molecular weight α2M·hepcidin or α2M-MA·hepcidin complexes (≈725 kDa) through a Sephadex G-25 size exclusion column retained their ability to decrease Fpn1 expression. Further studies using ultrafiltration indicated that hepcidin binding to α2M and α2M-MA was labile, resulting in some release from the protein, and this may explain its urinary excretion. To determine whether α2M-MA·hepcidin is delivered to cells via the α2M receptor (Lrp1), we assessed α2M uptake and Fpn1 expression in Lrp1−/− and Lrp1+/+ cells. Interestingly, α2M·hepcidin or α2M-MA·hepcidin demonstrated similar activities at decreasing Fpn1 expression in Lrp1−/− and Lrp1+/+ cells, indicating that Lrp1 is not essential for Fpn1 regulation. In vivo, hepcidin bound to α2M or α2M-MA did not affect plasma clearance of α2M/α2M-MA. However, serum iron levels were reduced to a significantly greater extent in mice treated with α2M·hepcidin or α2M-MA·hepcidin relative to unbound hepcidin. This effect could be mediated by the ability of α2M or α2M-MA to retard kidney filtration of bound hepcidin, increasing its half-life. A model is proposed that suggests that unlike proteases, which are irreversibly bound to activated α2M, hepcidin remains labile and available to down-regulate Fpn1. 相似文献
100.
Heparin and its derivatives bind to HIV-1 recombinant envelope glycoproteins, rather than to recombinant HIV-1 receptor, CD4 总被引:1,自引:0,他引:1
We have employed a direct radiolabel binding assay to investigate the
interaction between3H-heparin and recombinant envelope glycoproteins,
rgp120s, derived from several different isolates of HIV-1. Comparable
dose-dependent binding is exhibited by rgp120s from isolates IIIB, GB8, MN
and SF-2. Under identical experimental conditions the binding of3H- heparin
to a recombinant soluble form of the cellular receptor for gp120, CD4, is
negligible. The binding of3H-heparin to rgp120 is competed for by excess
unlabeled heparin and certain other, but not all, glycosaminoglycan and
chemically modified heparins. Of a range of such polysaccharides tested,
ability to compete with3H-heparin for binding was strictly correlated with
inhibition of HIV-1 replication in vitro. Those possessing potent
anti-HIV-1 activity were effective competitors, whereas those having no or
little anti-HIV-1 activity were poor competitors. Scatchard analysis
indicates that the K d of the interaction between heparin and rgp120 is 10
nM. Binding studies conducted in increasing salt concentrations confirm
that the interaction is ionic in nature. Synthetic 33-35 amino acid
peptides based on the sequence of the V3 loop of gp120 also bind to heparin
with high affinity. V3 loop peptides that are cyclized due to terminal
cysteine residues show more selective binding than their uncyclized
counterparts. Overall, these data demonstrate further that heparin exerts
its anti-HIV-1 activity by binding to the envelope glycoprotein of HIV-1,
rather than its cellular receptor, CD4. This study confirms that the V3
loop of gp120 is the site at which heparin exerts its anti- HIV-1 activity.
Moreover, it reveals that high affinity binding to heparin is shared by all
four rgp120s examined, despite amino acid substitutions within the V3 loop.
相似文献