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101.
Synthesis of a peptidocalix[4]arene library and identification of compounds with hydrolytic activity
A 120 member library of peptidocalix[4]arenes was synthesized and screened for catalysis of the hydrolysis of p-nitrophenyl acetate. His-Ser-His-calix[4]arene was found to catalyze this reaction with v(0)=3.24 x 10(-8)M/s, an increase of 1520% above background and 30% above the tripeptide (His-Ser-His) alone. 相似文献
102.
Mazzini GS Schaf DV Oliveira AR Gonçalves CA Belló-Klein A Bordignon S Bruch RS Campos GF Vassallo DV Souza DO Portela LV 《Life sciences》2005,77(8):882-889
S100B is an astrocytic protein assessed in cerebrospinal fluid and serum as a biochemical marker of cerebral injuries. However, increasing evidences suggest the influence of extra cerebral sources on its serum levels. Since it was reported that the injured myocardium expresses S100B, we investigated whether the isolated heart releases this protein. The rat hearts were excised and perfused by the Langendorff technique of isolated heart perfusion. After stabilization, 10 hearts (ischemic group) were submitted to 20 minutes of ischemia and 30 minutes of reperfusion, and 5 hearts (control group) were submitted to 50 minutes of perfusion. The perfusion fluid was collected at pre-ischemia, and 0, 5, 10, 15 and 30 min after ischemia (or equivalent in controls) for S100B and cardiac troponin T (a heart injury marker) assays. In the ischemic group, S100B and troponin T levels increased significantly at time 0 min: S100B values [mug/L, median (IQ25/IQ75)] increased from < or = 0.02 (< or = 0.02/0.03) to 0.38 (0.22/0.84), while troponin T values [mug/L, median (IQ25/IQ75)] increased from 0.31 (0.15/0.45) to 2.84 (2.00/3.63). Our results point to the ischemic heart as an extra cerebral source of S100B. 相似文献
103.
Blaney Davidson EN Scharstuhl A Vitters EL van der Kraan PM van den Berg WB 《Arthritis research & therapy》2005,7(6):R1338-R1347
Osteoarthritis (OA) is a common joint disease, mainly effecting the elderly population. The cause of OA seems to be an imbalance
in catabolic and anabolic factors that develops with age. IL-1 is a catabolic factor known to induce cartilage damage, and
transforming growth factor (TGF)-beta is an anabolic factor that can counteract many IL-1-induced effects. In old mice, we
observed reduced responsiveness to TGF-beta-induced IL-1 counteraction. We investigated whether expression of TGF-beta and
its signaling molecules altered with age. To mimic the TGF-beta deprived conditions in aged mice, we assessed the functional
consequence of TGF-beta blocking. We isolated knee joints of mice aged 5 months or 2 years, half of which were exposed to
IL-1 by intra-articular injection 24 h prior to knee joint isolation. Immunohistochemistry was performed, staining for TGF-beta1,
-2 or -3, TGF-betaRI or -RII, Smad2, -3, -4, -6 and -7 and Smad-2P. The percentage of cells staining positive was determined
in tibial cartilage. To mimic the lack of TGF-beta signaling in old mice, young mice were injected with IL-1 and after 2 days
Ad-LAP (TGF-beta inhibitor) or a control virus were injected. Proteoglycan (PG) synthesis (35S-sulfate incorporation) and PG content of the cartilage were determined. Our experiments revealed that TGF-beta2 and -3 expression
decreased with age, as did the TGF-beta receptors. Although the number of cells positive for the Smad proteins was not altered,
the number of cells expressing Smad2P strongly dropped in old mice. IL-1 did not alter the expression patterns. We mimicked
the lack of TGF-beta signaling in old mice by TGF-beta inhibition with LAP. This resulted in a reduced level of PG synthesis
and aggravation of PG depletion. The limited response of old mice to TGF-beta induced-IL-1 counteraction is not due to a diminished
level of intracellular signaling molecules or an upregulation of intracellular inhibitors, but is likely due to an intrinsic
absence of sufficient TGF-beta receptor expression. Blocking TGF-beta distorted the natural repair response after IL-1 injection.
In conclusion, TGF-beta appears to play an important role in repair of cartilage and a lack of TGF-beta responsiveness in
old mice might be at the root of OA development. 相似文献
104.
Andrew EM Newton DJ Dalton JE Egan CE Goodwin SJ Tramonti D Scott P Carding SR 《Journal of immunology (Baltimore, Md. : 1950)》2005,175(3):1741-1750
Gammadelta T cells play important but poorly defined roles in pathogen-induced immune responses and in preventing chronic inflammation and pathology. A major obstacle to defining their function is establishing the degree of functional redundancy and heterogeneity among gammadelta T cells. Using mice deficient in Vgamma1+ T cells which are a major component of the gammadelta T cell response to microbial infection, a specific immunoregulatory role for Vgamma1+ T cells in macrophage and gammadelta T cell homeostasis during infection has been established. By contrast, Vgamma1+ T cells play no significant role in pathogen containment or eradication and cannot protect mice from immune-mediated pathology. Pathogen-elicited Vgamma1+ T cells also display different functional characteristics at different stages of the host response to infection that involves unique and different populations of Vgamma1+ T cells. These findings, therefore, identify distinct and nonoverlapping roles for gammadelta T cell subsets in infection and establish the complexity and adaptability of a single population of gammadelta T cells in the host response to infection that is not predetermined, but is, instead, shaped by environmental factors. 相似文献
105.
Soybean (Glycine max (L.) Merr.) root nodules contain the enzymes of the ascorbate-glutathione cycle as an important defense against activated forms of oxygen. A key enzyme in this cycle--monodehydroascorbate reductase (MR)--was purified 646-fold and appeared as a single band on SDS-PAGE with silver or Coomassie blue staining. Purified MR contained 0.7 mol FAD/mol enzyme and had a specific activity of 288 mumol NADH oxidized.min-1.mg protein-1. The enzyme was a single subunit occurring as two isozymes (MR I and MR II) with Mr values of 39,000 and 40,000. Isoelectric focusing revealed that each isozyme consisted of two forms with pl values of 4.6 to 4.7. Ferricyanide and 2,6-dichlorophenol-indophenol were effective as electron acceptors. The purified enzyme did not possess leghemoglobin reductase activity. Inhibition by p-chloromercuribenzoate indicated the involvement of a thiol group in MR activity. The Km values were 5.6, 150, and 7 microM for NADH, NADPH, and monodehydroascorbate, respectively. The pH optimum was 8 to 9. The N-terminal sequence of 10 amino acids of MR II had little homology to known protein sequences. 相似文献
106.
Yan Lu Zhao Wang Chien-Ming Li Jianjun Chen James T. Dalton Wei Li Duane D. Miller 《Bioorganic & medicinal chemistry》2010,18(2):477-495
A series of (2RS,4R)-2-arylthiazolidine-4-carboxylic acid amide (ATCAA) was synthesized. Antiproliferative activity against melanoma and prostate cancer cells compared with control cells (fibroblast and RH7777, respectively) was evaluated. Compound 3id showed the best selectivity and growth-inhibition activity against three melanoma cell lines (B16-F1, A375, and WM-164). Compounds 15b and 3ac had good selectivity and potency against four prostate cancer cell lines (DU 145, PC-3, LNCaP, and PPC-1). The structure–activity relationship (SAR) of the side chain, the thiazolidine ring, and phenyl substituents is discussed. Cell cycle analysis showed that the percentage of cancer cells undergoing apoptosis (sub-G1 phase) increased after treatment with 1b and 3ad, which also strongly inhibited melanoma colony formation. In vivo studies on nude mice bearing A375 melanoma tumors showed that compound 1b inhibited tumor growth in a dose-dependent manner. At a dose of 10 mg/kg, 1b significantly inhibited melanoma tumor growth and showed higher efficacy than did dacarbazine at 60 mg/kg. 相似文献
107.
Recent observations suggest that a spreading disease is increasingly contributing to hard coral mortality in the Solitary Islands Marine Park, NSW, Australia. This study determined coral disease prevalence and rate-of-spread through individual affected colonies and investigated the effect this epizootic had on coral populations at sites adjacent to South West Solitary Island. Quantitative data were collected between 2002 and 2004 using photographic and video methods, and visual census along radial arc belt transects. Disease similar to the reported white syndrome and white plague was apparent, spreading through hard coral species from the genera Turbinaria, Acropora, Goniastrea, Pocillopora, Stylophora and Porites. Coral disease prevalence varied between survey dates with mean prevalence increasing from 8.55% during March 2003 to 13.58% in June and declining to 7.75% in September and 6.21% during March 2004. There was a significant difference in mean prevalence between the affected species (p<0.001) and an overall difference between survey dates (p=0.001). Additionally, the rate-of-spread of coral disease through coral colonies determined using repeated, seasonal, still photographs followed similar patterns, with disease progression differing between affected species (p=0.004), and between survey dates (p<0.001). Analysis of the video-transects indicated significant difference in disease prevalence over larger spatial scales (100s of m). However, disease frequency did not vary significantly between 2002 and 2003. 相似文献
108.
Recent histories of six productive lakes in the Irish Ecoregion based on multiproxy palaeolimnological evidence 总被引:2,自引:2,他引:0
D. Taylor C. Dalton M. Leira P. Jordan G. Chen L. León-Vintró K. Irvine H. Bennion T. Nolan 《Hydrobiologia》2006,571(1):237-259
Palaeolimnological data from six mesotrophic, eutrophic and hypertrophic lakes in the Irish Ecoregion, in the form of microfossil
(cladocera, diatoms and pollen) and sediment chemistry data from radiometrically dated sediment cores, were used to reconstruct
past variations in lake water quality and catchment conditions. Basal sediments from sediment cores from the six sites ranged
in age from the late 18th century to the early 20th century. A weighted averaging partial least squares regression model was
developed to reconstruct past epilimnetic total phosphorus concentrations. The results indicate that all but one of the study
sites currently are in a far more productive state compared with the beginning of the sediment core record and that those
same five lakes have experienced accelerated enrichment post c. 1980. Two of the sites demonstrated long-term enrichment,
in one case beginning in the late 19th century, while both eutrophication and oligotrophication have occurred at three sites.
The results highlight the difficulties in applying a general temporal end-point for reference conditions and demonstrate that
productive lakes in the Irish Ecoregion have complex, locally specific and often long histories of enrichment. These may not
be responsive to reduced external loadings of phosphorus and, as a result, restoration could prove particularly challenging.
The results also provide evidence of the ways in which palaeolimnological techniques can assist implementation of the EU Water
Framework Directive.
Electronic supplementary material Electronic supplementary material is available for this article at
and accessible for authorised users. 相似文献
109.
Sekiya M Mulcahy G Irwin JA Stack CM Donnelly SM Xu W Collins P Dalton JP 《FEBS letters》2006,580(21):5016-5022
The parasitic helminth Fasciola hepatica secretes a 2-Cys peroxiredoxin (Prx) that may play important functions in host-parasite interaction. Recombinant peroxiredoxin (FhePrx) prevented metal-catalyzed oxidative nicking of plasmid DNA and detoxified hydrogen peroxide when coupled with Escherichia coli thioredoxin and thioredoxin reductase (k(cat)/K(m)=5.2 x 10(5)M(-1)s(-1)). Enzyme kinetic analysis revealed that the catalytic efficiency of FhePrx is similar to other 2-Cys peroxiredoxins; the enzyme displayed saturable enzyme Michaelis-Menten type kinetics with hydrogen peroxide, cumene hydroperoxide and t-butyl hydroperoxide, and is sensitive to concentrations of hydrogen peroxide above 0.5 mM. Like the 2-Cys peroxiredoxins from a related helminth, Schistosoma mansoni, steady-state kinetics indicate that FhePrx exhibits a saturable, single displacement-like reaction mechanism rather than non-saturable double displacement (ping-pong) enzyme substitution mechanism common to other peroxiredoxins. However, unlike the schistosome Prxs, FhePrx could not utilise reducing equivalents supplied by glutathione or glutathione reductase. 相似文献
110.
X-ray Crystal Structure and Specificity of the Plasmodium falciparum Malaria Aminopeptidase PfM18AAP
Sivaraman KK Oellig CA Huynh K Atkinson SC Poreba M Perugini MA Trenholme KR Gardiner DL Salvesen G Drag M Dalton JP Whisstock JC McGowan S 《Journal of molecular biology》2012,422(4):495-507
The malarial aminopeptidases have emerged as promising new drug targets for the development of novel antimalarial drugs. The M18AAP of Plasmodium falciparum malaria is a metallo-aminopeptidase that we show demonstrates a highly restricted specificity for peptides with an N-terminal Glu or Asp residue. Thus, the enzyme may function alongside other aminopeptidases in effecting the complete degradation or turnover of proteins, such as host hemoglobin, which provides a free amino acid pool for the growing parasite. Inhibition of PfM18AAP's function using antisense RNA is detrimental to the intra-erythrocytic malaria parasite and, hence, it has been proposed as a potential novel drug target. We report the X-ray crystal structure of the PfM18AAP aminopeptidase and reveal its complex dodecameric assembly arranged via dimer and trimer units that interact to form a large tetrahedron shape that completely encloses the 12 active sites within a central cavity. The four entry points to the catalytic lumen are each guarded by 12 large flexible loops that could control substrate entry into the catalytic sites. PfM18AAP thus resembles a proteasomal-like machine with multiple active sites able to degrade peptide substrates that enter the central lumen. The Plasmodium enzyme shows significant structural differences around the active site when compared to recently determined structures of its mammalian and human homologs, which provides a platform from which a rational approach to inhibitor design of new malaria-specific drugs can begin. 相似文献