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91.
92.
Guerrero CA Bouyssounade D Zárate S Isa P López T Espinosa R Romero P Méndez E López S Arias CF 《Journal of virology》2002,76(8):4096-4102
In this work, we have identified the heat shock cognate protein (hsc70) as a receptor candidate for rotaviruses. hsc70 was shown to be present on the surface of MA104 cells, and antibodies to this protein blocked rotavirus infectivity, while not affecting the infectivity of reovirus and poliovirus. Preincubation of the hsc70 protein with the viruses also inhibited their infectivity. Triple-layered particles (mature virions), but not double-layered particles, bound hsc70 in a solid-phase assay, and this interaction was blocked by monoclonal antibodies to the virus surface proteins VP4 and VP7. Rotaviruses were shown to interact with hsc70 at a postattachment step, since antibodies to hsc70 and the protein itself did not inhibit the virus attachment to cells. We propose that the functional rotavirus receptor is a complex of several cell surface molecules that include, among others, hsc70. 相似文献
93.
Dowd CS Leavitt S Babcock G Godillot AP Van Ryk D Canziani GA Sodroski J Freire E Chaiken IM 《Biochemistry》2002,41(22):7038-7046
HIV-1 enters a host cell after an initial interaction between viral envelope glycoprotein gp120 and cell surface receptor CD4, followed by a second interaction between gp120 and a cell surface chemokine receptor. CD4 residue Phe43 makes a significant contribution to the high-affinity interaction between CD4 and env. We and others have used scorpion toxin scaffolds to display and examine CD4 epitopes used for gp120 recognition. These peptides, which have a beta-turn Phe that acts as a Phe43 surrogate, compete with CD4 for gp120 binding and enhance the binding of gp120 to 17b, an antibody that binds near the co-receptor-binding site. In the current study, a scyllatoxin-scaffolded peptide, identified via phage epitope randomization and lacking a beta-turn Phe (indeed, containing no aromatic residues), was shown to behave in a distinctly CD4-like manner. This peptide, denoted [20EGLV23]ST, not only competed with CD4 for gp120 binding, but also enhanced the binding of gp120 to 17b. Quantitatively, an [20EGLV23]ST-gp120 complex exhibited the same 17b binding on-rate as a complex of gp120 with [20AGSF23]ST, a scyllatoxin-based CD4 mimetic peptide containing a beta-turn Phe. In view of this result, we examined the role of Phe43 in CD4 itself by comparing F43V D1D2 sCD4 versus D1D2 sCD4. Like the peptides, a close similarity was observed for both Phe43 and Phe43-less D1D2 sCD4s in enhancing gp120 binding to 17b. Further, when examined for their ability to enhance binding of gp120 to CCR5+ cells, [20EGLV23]ST and [20AGSF23]ST were found to have the same efficacy, after correcting for the difference in their gp120 affinities. These results show that, although Phe43 is important in maintaining high affinity in gp120 ligands, the aromatic residue is not necessary for triggering the conformational isomerization in gp120 that results in formation or exposure of the binding sites for the 17b antibody and the CCR5 receptor. 相似文献
94.
Srinivasan S Bernal-Mizrachi E Ohsugi M Permutt MA 《American journal of physiology. Endocrinology and metabolism》2002,283(4):E784-E793
The concentration of glucose in plasma is an important determinant of pancreatic beta-cell mass, whereas the relative contributions of hypertrophy, proliferation, and cell survival to this process are unclear. Glucose results in depolarization and subsequent calcium influx into islet beta-cells. Because depolarization and calcium (Ca(2+)) influx promote survival of neuronal cells, we hypothesized that glucose might alter survival of islet beta-cells through a similar mechanism. In the present studies, cultured mouse islet beta-cells showed a threefold decrease in apoptosis under conditions of 15 mM glucose compared with 2 mM glucose (P < 0.05). MIN6 insulinoma cells incubated in 25 mM glucose for 24 h showed a threefold decrease in apoptosis compared with cells in 5 mM glucose (1.7 +/- 0.2 vs. 6.3 +/- 1%, respectively, P < 0.001). High glucose (25 mM) enhanced survival-required depolarization and Ca(2+) influx and was blocked by phosphatidylinositol (PI) 3-kinase inhibitors. Glucose activation of the protein kinase Akt was demonstrated in both insulinoma cells and cultured mouse islets by means of an antibody specific for Ser(473) phospho-Akt and by an in vitro Akt kinase assay. Akt phosphorylation was dependent on PI 3-kinase but not on MAPK. Transfection of insulinoma cells with an Akt kinase-dead plasmid (Akt-K179M) resulted in loss of glucose-mediated protection, whereas transfection with a constitutively active Akt enhanced survival in glucose-deprived insulinoma cells. The results of these studies defined a novel pathway for glucose-mediated activation of a PI 3-kinase/Akt survival-signaling pathway in islet beta-cells. This pathway may provide important targets for therapeutic intervention. 相似文献
95.
96.
Plasmepsin II is a key enzyme in the life cycle of the Plasmodium parasites responsible for malaria, a disease that afflicts more than 300 million individuals annually. Since plasmepsin II inhibition leads to starvation of the parasite, it has been acknowledged as an important target for the development of new antimalarials. In this paper, we identify and characterize high-affinity inhibitors of plasmepsin II based upon the allophenylnorstatine scaffold. The best compound, KNI-727, inhibits plasmepsin II with a K(i) of 70 nM and a 22-fold selectivity with respect to the highly homologous human enzyme cathepsin D. KNI-727 binds to plasmepsin II in a process favored both enthalpically and entropically. At 25 degrees C, the binding enthalpy (DeltaH) is -4.4 kcal/mol and the entropic contribution (-TDeltaS) to the Gibbs energy is -5.56 kcal/mol. Structural stability measurements of plasmepsin II were also utilized to characterize inhibitor binding. High-sensitivity differential scanning calorimetry experiments performed in the absence of inhibitors indicate that, at pH 4.0, plasmepsin II undergoes thermal denaturation at 63.3 degrees C. The structural stability of the enzyme increases with inhibitor concentration in a manner for which the binding energetics of the inhibitor can quantitatively account. The effectiveness of the best compounds in killing the malaria parasite was validated by performing cytotoxicity assays in red blood cells infected with Plasmodium falciparum. EC50s ranging between 6 and 10 microM (3-6 microg/mL) were obtained. These experiments demonstrate the viability of the allophenylnorstatine scaffold in the design of powerful and selective plasmepsin inhibitors. 相似文献
97.
98.
Two novel 9,11-secosterols, aplidiasterols A (3β,6β,11-trihydroxy-9,11-seco-5α-cholest-7-en-9-one, 1) and B (3β,5α,6β,11-tetrahydroxy-9,11-secocholest-7-en-9-one, 2), along with the known secosterols 3 and 4, were isolated from the Mediterranean ascidian Aplidium conicum and their structures were determined by spectroscopic data. Aplidiasterols A and B were found to be cytotoxic against rat glioma (C6) and murine monocyte/macrophage (J774) tumor cells in vitro. Compounds 1-4 represent the first example of secosterols isolated from tunicates. 相似文献
99.
Apoptosis is prevalent during development of the central nervous system (CNS), yet very little is known about the signals that specify an apoptotic cell fate. In this paper, we examine the role of Numb/Notch signaling in the development of the serotonin lineage of Drosophila and show that it is necessary for regulating apoptosis. Our results indicate that when Numb inhibits Notch signaling, cells undergo neuronal differentiation, whereas cells that maintain Notch signaling initiate apoptosis. The apoptosis inhibitor p35 can counteract Notch-mediated apoptosis and rescue cells within the serotonin lineage that normally undergo apoptosis. Furthermore, we observe tumor-like overproliferation of cells in the CNS when Notch signaling is reduced. These data suggest that the distribution of Numb during terminal mitotic divisions of the CNS can distinguish between a neuronal cell fate and programmed cell death. 相似文献
100.
Villalobos Virginia Suárez Jacqueline Estévez Jesús Novo Ernesto Bonilla Ernesto 《Neurochemical research》2001,26(10):1157-1161
In the present study the effects of chronic manganese (Mn) treatment on adenosine A2a receptor binding in mouse brain have been assessed. Male albino mice were divided in two groups: In the Mn-treated group, the animals were injected intraperitoneally (i.p.) with MnCl2 (5 mg/kg/day) five days per week during 9 weeks; in the control group, they were injected likewise with a saline solution. A significant decrease of the Kd without alteration of Bmax in the cerebellum and, an increase of the Kd and Bmax in hippocampus of mice treated with Mn were found. Also, an increase of Kd in frontal cortex was observed. The binding parameters in caudate nucleus, olfactory bulb and hypothalamus were not altered by Mn. A significant decrease in the adenosine concentration in caudate nucleus, olfactory bulb and hypothalamus, without significant changes in hippocampus, frontal cortex and cerebellum was also detected. These findings suggest that chronic administration of Mn could affect adenosine receptor function and turnover, depending on the brain region analyzed. 相似文献