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111.
112.
Pickhardt M Larbig G Khlistunova I Coksezen A Meyer B Mandelkow EM Schmidt B Mandelkow E 《Biochemistry》2007,46(35):10016-10023
One of the key pathological features of Alzheimer's disease is the aggregation of tau protein. We are therefore searching for compounds capable of inhibiting this reaction. On the basis of an initial screen of 200000 compounds [Pickhardt, M., Gazova, Z., von Bergen, M., Khlistunova, I., Wang, Y., Hascher, A., Mandelkow, E. M., Biernat, J., and Mandelkow, E. (2005) Anthraquinones inhibit tau aggregation and dissolve Alzheimer's paired helical filaments in vitro and in cells, J. Biol. Chem. 280, 3628-3635], we performed an in silico screen and predicted a new phenylthiazolyl-hydrazide (PTH) compound as a possible hit [Larbig, G., Pickhardt, M., Lloyd, D. G., Schmidt, B., and Mandelkow, E. (2007) Screening for inhibitors of tau protein aggregation into Alzheimer paired helical filaments: A ligand based approach results in successful scaffold hopping. Curr. Alzheimer Res. 4 (3), 315-323.]. Synthesis of this compound showed that it was indeed active in terms of inhibiting de novo tau aggregation and disassembling preformed aggregates (IC50 = 7.7 microM and DC50 = 10.8 microM). We have now synthesized 49 similar structures and identified the core of the PTHs to be crucial for activity, thus representing a lead structure. Analysis of the binding epitope by saturation transfer difference NMR shows strong interactions between the tau protein and the ligand in the aromatic regions of the inhibitor. By chemical variation of the core, we improved the inhibitory potency five-fold. The compounds showed a low toxicity as judged by an N2A cell model of tau aggregation and lend themselves for further development. 相似文献
113.
Corona-Rivera A Urbina-Cano P Bobadilla-Morales L Vargas-Lares Jde J Ramirez-Herrera MA Mendoza-Magaua ML Troyo-Sanroman R Diaz-Esquivel P Corona-Rivera JR 《Journal of applied genetics》2007,48(4):389-396
Curcumin is a phytochemical with antiinflammatory, antioxidant and anticarcinogenic activities. Apparently, curcumin is not genotoxic in vivo, but in vitro copper and curcumin interactions induce genetic damage. The aim of this study was to test if in vivo copper excess induces DNA damage measured by comet and micronucleus assays in the presence of curcumin. We tested 0.2% curcumin in Balb-C mice at normal (13 ppm) and high (65, 130 and 390 ppm) copper ion concentrations. The comet and micronucleus assays were performed 48 hr after chemical application. Comet tail length in animals treated with 0.2% curcumin was not significantly different from the control. Animals exposed to copper cations (up to 390 ppm) exhibited higher oxidative DNA damage. Curcumin reduced the DNA damage induced by 390 ppm copper. We observed statistically significant increase in damage in individuals exposed to 390 ppm copper versus the control or curcumin groups, which was lowered by the presence of curcumin. Qualitative data on comets evidenced that cells from individuals exposed to 390 ppm copper had longer tails (categories 3 and 4) than in 390 ppm copper + curcumin. A statistically significant increase in frequency of micronucleated erythrocytes (MNE/10000TE) was observed only in 390 ppm copper versus the control and curcumin alone. Also cytotoxicity measured as the frequency of polychromatic erythrocytes (PE/1000TE) was attributable to 390 ppm copper. The lowest cytotoxic effect observed was attributed to curcumin. In vivo exposure to 0.2% curcumin for 48 hr did not cause genomic damage, while 390 ppm copper was genotoxic, but DNA damage induced by 390 ppm copper was diminished by curcumin. Curcumin seems to exert a genoprotective effect against DNA damage induced by high concentrations of copper cations. The comet and micronucleus assays prove to be suitable tools to detect DNA damage by copper in the presence of curcumin. 相似文献
114.
New fluorescein and rhodamine B-labeled antifilarial drug DEC analogues for use in drug localization studies with confocal microscopy have been prepared by a high-yield three-step synthesis. The resulting beta-amine-substituted DEC analogue has a single ethyl substituent which is beta-aminated to accommodate the fluorophore of either fluorescein isothiocyananate or rhodamine B. Confocal microscopy is used to show that the drug accumulates in the adult filarial worms in the pharynx, esophagus, and near the nerve ring of all adults, as well as in the uteri and vulva and the testes of the females and males. 相似文献
115.
116.
Analysis of the three-dimensional structures of three closely related mesophilic, thermophilic, and hyperthermophilic alcohol dehydrogenases (ADHs) from the respective microorganisms Clostridium beijerinckii (CbADH), Entamoeba histolytica (EhADH1), and Thermoanaerobacter brockii (TbADH) suggested that a unique, strategically located proline residue (Pro100) might be crucial for maintaining the thermal stability of EhADH1. To determine whether proline substitution at this position in TbADH and CbADH would affect thermal stability, we used site-directed mutagenesis to replace the complementary residues in both enzymes with proline. The results showed that replacing Gln100 with proline significantly enhanced the thermal stability of the mesophilic ADH: DeltaT(1/2) (60 min) = + 8 degrees C (temperature of 50% inactivation after incubation for 60 min), DeltaT(1/2) (CD) = +11.5 degrees C (temperature at which 50% of the original CD signal at 218 nm is lost upon heating between 30 degrees and 98 degrees C). A His100 --> Pro substitution in the thermophilic TbADH had no effect on its thermostability. An analysis of the three-dimensional structure of the crystallized thermostable mutant Q100P-CbADH suggested that the proline residue at position 100 stabilized the enzyme by reinforcing hydrophobic interactions and by reducing the flexibility of a loop at this strategic region. 相似文献
117.
Correlating EPR and X-ray structural analysis of arsenite-inhibited forms of aldehyde oxidoreductase
Anders Thapper D. R. Boer Carlos D. Brondino José J. G. Moura Maria J. Romão 《Journal of biological inorganic chemistry》2007,12(3):353-366
Two arsenite-inhibited forms of each of the aldehyde oxidoreductases from Desulfovibrio gigas and Desulfovibrio desulfuricans have been studied by X-ray crystallography and electron paramagnetic resonance (EPR) spectroscopy. The molybdenum site of
these enzymes shows a distorted square-pyramidal geometry in which two ligands, a hydroxyl/water molecule (the catalytic labile
site) and a sulfido ligand, have been shown to be essential for catalysis. Arsenite addition to active as-prepared enzyme
or to a reduced desulfo form yields two different species called A and B, respectively, which show different Mo(V) EPR signals.
Both EPR signals show strong hyperfine and quadrupolar couplings with an arsenic nucleus, which suggests that arsenic interacts
with molybdenum through an equatorial ligand. X-ray data of single crystals prepared from EPR-active samples show in both
inhibited forms that the arsenic atom interacts with the molybdenum ion through an oxygen atom at the catalytic labile site
and that the sulfido ligand is no longer present. EPR and X-ray data indicate that the main difference between both species
is an equatorial ligand to molybdenum which was determined to be an oxo ligand in species A and a hydroxyl/water ligand in
species B. The conclusion that the sulfido ligand is not essential to determine the EPR properties in both Mo–As complexes
is achieved through EPR measurements on a substantial number of randomly oriented chemically reduced crystals immediately
followed by X-ray studies on one of those crystals. EPR saturation studies show that the electron transfer pathway, which
is essential for catalysis, is not modified upon inhibition.
Electronic supplementary material Supplementary material is available in the online version of this article at and is accessible for authorized users. 相似文献
118.
During the course of an immune response, antigen-reactive T cells clonally expand and then are removed by apoptosis to maintain immune homeostasis. Life and death of T cells is determined by multiple factors, such as T-cell receptor triggering, co-stimulation or cytokine signalling, and by molecules, such as caspase-8 (FLICE)-like inhibitory protein (FLIP) and haematopoietic progenitor kinase 1 (HPK1), which regulate the nuclear factor-kappaB (NF-kappaB) pathway. Here, we discuss the concepts of activation-induced cell death (AICD) and activated cell-autonomous death (ACAD) in the regulation of life and death in T cells. 相似文献
119.
Tree growth,mortality, and above-ground biomass accumulation in a holm oak forest under a five-year experimental field drought 总被引:2,自引:0,他引:2
A holm oak forest was exposed to an experimental drought during 5 years to elucidate the growth responses of the dominant
species Quercus ilex, Arbutus unedo and Phillyrea latifolia. Soil water availability was partially reduced, about 15% as predicted for this area for the next decades by GCM and ecophysiological
models, by plastic strips intercepting rainfall and by ditch exclusion of water runoff. The stem diameter increment was highly
correlated with annual rainfall in all species, and drought treatment strongly reduced the diameter increment of Q. ilex (41%) and specially of A. unedo (63%), the species showing higher growth rates. Stem mortality rates were highly correlated with previous stem density, but
drought treatment increased mortality rates in all species. Q. ilex showed the highest mortality rates (9% and 18% in control and drought plots, respectively), and P. latifolia experienced the lowest mortality rates (1% and 3% in control and drought plots, respectively). Drought strongly reduced the
increment of live aboveground biomass during these 5 years (83%). A. unedo and Q. ilex experienced a high reduction in biomass increment by drought, whereas P. latifolia biomass increment was insensitive to drought. The different sensitivity to drought of the dominant species of the holm oak
forest may be very important determining their future development and distribution in a drier environment as expected in Mediterranean
areas for the next decades. These drier conditions could thus have strong effects on structure (species composition) and functioning
(carbon uptake and biomass accumulation) of these Mediterranean forests. 相似文献
120.
Zanolla Marianela Carmona Raquel Mata Leonardo De la Rosa Julio Sherwood Alison Barranco Carlos Navarro Muñoz Antonio Román Altamirano María 《Journal of applied phycology》2022,34(1):1-17
Journal of Applied Phycology - Asparagopsis (Bonnemaisoniaceae, Rhodophyta) species are distributed in most temperate and tropical waters of the world, where they are considered an iconic invader.... 相似文献