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61.
Styczyński J Wysocki M Debski R Balwierz W Rokicka-Milewska R Matysiak M Balcerska A Kowalczyk J Wachowiak J Sońta-Jakimczyk D Chybicka A 《Acta biochimica Polonica》2002,49(1):221-225
Glufosfamide (beta-D-glucosyl-ifosfamide mustard) is a new agent for cancer chemotherapy. Its pharmacology is similar to commonly used oxazaphosphorines, but it does not require activation by hepatic cytochrome P-450 and preclinically demonstrates lower nephrotoxicity and myelosuppression than ifosfamide. The aim of the study was a comparison of the drug resistance profiles of glufosfamide and other oxazaphosphorines in childhood acute leukemias. Leukemic cells, taken from children with ALL on diagnosis (n = 41), ALL on relapse (n = 12) and AML on diagnosis (n = 13) were analyzed by means of the MTT assay. The following drugs were tested: glufosfamide (GLU), 4-HOO-ifosfamide (IFO), 4-HOO-cyclophosphamide (CYC) and mafosfamide cyclohexylamine salt (MAF). In the group of initial ALL samples median cytotoxicity values for GLU, IFO, CYC and MAF were 15.5, 33.8, 15.7 and 7.8 microM, respectively. In comparison with initial ALL samples, the relative resistance for GLU and IFO in relapsed ALL samples was 1.9 (p = 0.049) and 1.3 (ns), and in initial AML samples 31 (p < 0.001) and 5 (p = 0.001), respectively. All oxazaphosphorines presented highly significant cross-resistance. Glufosfamide presented high activity against lymphoblasts both on diagnosis and on relapse. 相似文献
62.
Crystal structures of two homologous pathogenesis-related proteins from yellow lupine 总被引:4,自引:0,他引:4
Pathogenesis-related class 10 (PR10) proteins are restricted to the plant kingdom where they are coded by multigene families and occur at high levels. In spite of their abundance, their physiological role is obscure although members of a distantly related subclass (cytokinin-specific binding proteins) are known to bind plant hormones. PR10 proteins are of special significance in legume plants where their expression patterns are related to infection by the symbiotic, nitrogen-fixing bacteria. Here we present the first crystal structures of classic PR10 proteins representing two homologues from one subclass in yellow lupine. The general fold is similar and, as in a birch pollen allergen, consists of a seven-stranded beta-sheet wrapped around a long C-terminal helix. The mouth of a large pocket formed between the beta-sheet and the helix seems a likely site for ligand binding. The shape of the pocket varies because, in variance with the rigid beta-sheet, the helix shows unusual conformational variability consisting in bending, disorder, and axial shifting. A surface loop, proximal to the entrance to the internal cavity, shows an unusual structural conservation and rigidity in contrast to the high glycine content in its sequence. The loop is different from the so-called glycine-rich P-loops that bind phosphate groups of nucleotides, but it is very likely that it does play a role in ligand binding in PR10 proteins. 相似文献
63.
Acid phosphatase (AP) and diphosphonucleoside phosphatase/phosphodiesterase (PPD1) were purified from yellow lupin (Lupinus luteus L.) immature green seeds (40 days after blooming), dry seeds (40 days later) and dry seeds stored for 160 days. Both enzymes are known to differ in the type of N-glycosylation: the first has an N-glycosylation pattern typical for a vacuolar protein, while the second enzyme has a pattern typical for an extracellular or membrane-bound protein. N-Glycans were released from each of the enzyme preparations, fluorescence labeled, separated and identified by HPLC (GlycoSep N and GlycoSep H columns). Changes in the level of each N-glycan during seed maturation and dormancy were compared. The results show that N-glycan processing in the case of AP and PPD1-two proteins residing in the same plant organ, but possibly in different compartments-is not synchronized and performed not only in metabolically active maturing seeds, but also in metabolically inactive dormant seeds. 相似文献
64.
65.
Amphotericin B (AmB) is a polyene antibiotic frequently applied in the treatment of fungal infections. According to the general understanding, the mode of action of AmB is directly related to the molecular organization of the drug in the lipid environment, in particular to the formation of pore-like molecular aggregates. Electronic absorption and fluorescence techniques were applied to investigate formation of molecular aggregates of AmB in the lipid environment of liposomes and monomolecular layers formed at the argon-water interface. It appears that AmB dimers, stabilized by van der Waals interactions, are present in the membrane environment along with the aggregates formed by a greater number of molecules. Linear dichroism measurements reveal that AmB is distributed between two fractions of molecules, differently oriented with respect to the bilayer. Molecules in one fraction remain parallel to the plane of the membrane and molecules in the other one are perpendicular. Scanning Force Microscopy imaging of the surface topography of the monolayers formed with AmB in the presence of lipids reveals formation of pore-like structures characterized by the external diameter close to 17 A and the internal diameter close to 6 A. All the findings are discussed in terms of importance of the molecular organization of AmB in the pharmacological action, as well as of the toxic side effects of the drug. 相似文献
66.
Edson L da Silva Mariusz K Piskula Norio Yamamoto Jae-Hak Moon Junji Terao 《FEBS letters》1998,430(3):903
The oxidative susceptibility of plasma obtained from rats after intragastric administration of quercetin was studied to know whether or not quercetin acts as an in vivo antioxidant after metabolic conversion. Quercetin was raised in the rat blood plasma essentially as glucuronide and/or sulfate conjugates. The plasma obtained from rats after quercetin administration was more resistant against copper sulfate-induced lipid peroxidation than the control plasma on the basis of the accumulation of cholesteryl ester hydroperoxides and the consumption of α-tocopherol. The results strongly suggest that some conjugated metabolites of quercetin act as effective antioxidants when plasma is subject to metal ion-induced lipid peroxidation. 相似文献
67.
Anders ?stin Mariusz Kowalyczk Rishikesh P. Bhalerao G?ran Sandberg 《Plant physiology》1998,118(1):285-296
The metabolism of indole-3-acetic
acid (IAA) was investigated in 14-d-old Arabidopsis plants grown in
liquid culture. After ruling out metabolites formed as an effect of
nonsterile conditions, high-level feeding, and spontaneous
interconversions, a simple metabolic pattern emerged. Oxindole-3-acetic
acid (OxIAA), OxIAA conjugated to a hexose moiety via the carboxyl
group, and the conjugates indole-3-acetyl aspartic acid (IAAsp) and
indole-3-acetyl glutamate (IAGlu) were identified by mass spectrometry
as primary products of IAA fed to the plants. Refeeding experiments
demonstrated that none of these conjugates could be hydrolyzed back to
IAA to any measurable extent at this developmental stage. IAAsp was
further oxidized, especially when high levels of IAA were fed into the
system, yielding OxIAAsp and OH-IAAsp. This contrasted with the
metabolic fate of IAGlu, since that conjugate was not further
metabolized. At IAA concentrations below 0.5 μm, most of
the supplied IAA was metabolized via the OxIAA pathway, whereas only a
minor portion was conjugated. However, increasing the IAA
concentrations to 5 μm drastically altered the metabolic
pattern, with marked induction of conjugation to IAAsp and IAGlu. This
investigation used concentrations for feeding experiments that were
near endogenous levels, showing that the metabolic pathways controlling
the IAA pool size in Arabidopsis are limited and, therefore, make good
targets for mutant screens provided that precautions are taken to avoid
inducing artificial metabolism.The plant hormone IAA is an important signal molecule in the
regulation of plant development. Its central role as a growth regulator
makes it necessary for the plant to have mechanisms that strictly
control its concentration. The hormone is believed to be active
primarily as the free acid, and endogenous levels are controlled in
vivo by processes such as synthesis, oxidation, and conjugation. IAA
has been shown to form conjugates with sugars, amino acids, and small
peptides. Conjugates are believed to be involved in IAA transport, in
the storage of IAA for subsequent use, in the homeostatic control of
the pool of the free hormone, and as a first step in the catabolic
pathways (Cohen and Bandurski, 1978; Nowacki and Bandurski, 1980;
Tuominen et al., 1994; Östin et al., 1995; Normanly, 1997). It is
generally accepted that in some species conjugated IAA is the major
source of free IAA during the initial stages of seed germination (Ueda
and Bandurski, 1969; Sandberg et al., 1987; Bialek and Cohen, 1989),
and there is also evidence that in some plants (but not all; see Bialek
et al., 1992), the young seedling is entirely dependent on the release
of free IAA from conjugated pools until the plant itself is capable of
de novo synthesis (Epstein et al., 1980; Sandberg et al., 1987).The function of conjugated IAA during vegetative growth is somewhat
less clear. It has been shown that conjugated IAA constitutes as much
as 90% of the total IAA in the plant during vegetative growth
(Normanly, 1997). However, the role of the IAA conjugates at this stage
of the plant''s life cycle remains unknown. Analysis of endogenous IAA
conjugates in vegetative tissues has revealed the presence of a variety
of different compounds, including indole-3-acetyl-inositol,
indole-3-acetyl-Ala, IAAsp, and IAGlu (Anderson and Sandberg, 1982;
Cohen and Baldi, 1983; Chisnell, 1984; Cohen and Ernstsen, 1991;
Östin et al., 1992). Studies of vegetative tissues have indicated
that IAAsp, one of the major conjugates in many plants, is the first
intermediate in an irreversible deactivation pathway (Tsurumi and Wada,
1986; Tuominen et al., 1994; Östin, 1995). Another mechanism that
is believed to be involved in the homeostatic control of the IAA pool
is catabolism by direct oxidation of IAA to OxIAA, which has been shown
to occur in several plant species (Reinecke and Bandurski, 1983;
Ernstsen et al., 1987).One area in the study of IAA metabolism in which our knowledge is
increasing is the analysis of the homeostatic controls of IAA levels in
plants. It has been possible, for instance, to increase the levels of
IAA in transgenic plants expressing iaaM and iaaH
genes from Agrobacterium tumefaciens. Analysis of these
transgenic plants has indicated that plants have several pathways that
can compensate for the increased production of IAA (Klee et al., 1987;
Sitbon, 1992). It is expected that future studies using now-available
genes will provide further insight into IAA metabolism. For example, a
gene in maize encoding IAA-Glc synthetase has been identified, and
several genes (including ILR1, which may be involved
in hydrolysis of the indole-3-acetyl-Leu conjugate) have been cloned
from Arabidopsis (Szerszen et al., 1994; Bartel and Fink,
1995). Furthermore, Chou et al. (1996) identified a gene that
hydrolyzes the conjugate IAAsp to free IAA in the bacterium
Enterobacter aggloremans.Because of its small genome size, rapid life cycle, and the ease of
obtaining mutants, Arabidopsis is increasingly used as a
genetic model system to investigate various aspects of plant growth and
development. IAA signal transduction is also being investigated
intensively in Arabidopsis in many laboratories (Leyser, 1997). Mutants
with altered responses to externally added auxins or IAA conjugates
have been identified in Arabidopsis. The identified mutants are either
signal transduction mutants such as axr1-4 (Lincoln et al.,
1990), or have mutations in genes involved in auxin uptake or
transport, such as aux1 and pin1 (Okada et al.,
1991; Bennett et al., 1996). A few mutants that are unable to regulate
IAA levels or are unable to hydrolyze IAA conjugates, sur1-2
and ilr1, respectively, have also been identified (Bartel
and Fink, 1995; Boerjan et al., 1995). To our knowledge, no mutant that
is auxotrophic for IAA has been identified to date, which may
reflect the redundancy in IAA biosynthetic pathways or the lethality of
such mutants.In spite of the work reported thus far, many aspects of the metabolism
of IAA in Arabidopsis require further investigation, because few
details of the processes involved in IAA regulation are known. This
lack of knowledge puts severe constraints on genetic analysis of IAA
metabolism in Arabidopsis. For example, it is essential to have prior
knowledge of IAA metabolism to devise novel and relevant screens with
which to identify mutants of IAA metabolism. We have sought to address
this issue by identifying the metabolic pathways involved in catabolism
and conjugation under conditions that minimally perturb physiological
processes. In this investigation we studied the conjugation and
catabolic pattern of IAA by supplying relatively low levels of labeled
IAA and identifying the catabolites and conjugates by MS. Different
feeding systems were tested to optimize the application of IAA and to
avoid irregularities in metabolism attributable to culturing, feeding
conditions, or microbial activity. It is well documented that IAA
metabolism is altered according to the amount of exogenous auxin
applied; therefore, we placed special emphasis on distinguishing
between catabolic routes that occur at near-physiological
concentrations and those that occur at the high auxin concentrations
commonly used in mutant screens. 相似文献
68.
Katarzyna Danis-Wlodarczyk Tomasz Olszak Michal Arabski Slawomir Wasik Grazyna Majkowska-Skrobek Daria Augustyniak Grzegorz Gula Yves Briers Ho Bin Jang Dieter Vandenheuvel Katarzyna Anna Duda Rob Lavigne Zuzanna Drulis-Kawa 《PloS one》2015,10(5)
We here describe two novel lytic phages, KT28 and KTN6, infecting Pseudomonas aeruginosa, isolated from a sewage sample from an irrigated field near Wroclaw, in Poland. Both viruses show characteristic features of Pbunalikevirus genus within the Myoviridae family with respect to shape and size of head/tail, as well as LPS host receptor recognition. Genome analysis confirmed the similarity to other PB1-related phages, ranging between 48 and 96%. Pseudomonas phage KT28 has a genome size of 66,381 bp and KTN6 of 65,994 bp. The latent period, burst size, stability and host range was determined for both viruses under standard laboratory conditions. Biofilm eradication efficacy was tested on peg-lid plate assay and PET membrane surface. Significant reduction of colony forming units was observed (70-90%) in 24 h to 72 h old Pseudomonas aeruginosa PAO1 biofilm cultures for both phages. Furthermore, a pyocyanin and pyoverdin reduction tests reveal that tested phages lowers the amount of both secreted dyes in 48-72 h old biofilms. Diffusion and goniometry experiments revealed the increase of diffusion rate through the biofilm matrix after phage application. These characteristics indicate these phages could be used to prevent Pseudomonas aeruginosa infections and biofilm formation. It was also shown, that PB1-related phage treatment of biofilm caused the emergence of stable phage-resistant mutants growing as small colony variants. 相似文献
69.
70.
Zuzanna Setkowicz Agata Ga?dzińska Joanna J. Osoba Karolina Karwowska Piotr Majka Jaros?aw Orze? Bartosz Kossowski Piotr Bogorodzki Krzysztof Janeczko Mariusz Wyle?o? Stefan P. Gazdzinski 《PloS one》2015,10(10)
BackgroundObesity is a worldwide epidemic with more than 600 million affected individuals. Human studies have demonstrated some alterations in brains of otherwise healthy obese individuals and elevated risk of neurodegenerative disease of old age; these studies have also pointed to slightly diminished memory and executive functions among healthy obese individuals. Similar findings were obtained in animal models of obesity induced by high fat diet. On the other hand, low carbohydrate high fat diets are currently promoted for losing weight (e.g., Atkin’s style diets). However, the long-term effects of such diets are not known. Additionally, high fat diets leading to (mild) ketonemia were shown to improve brain function in elderly humans and in some animal models.AimTo evaluate the hypothesis that long-term use of a high fat diet was associated with decreases in spatial memory, smaller hippocampi and hippocampi metabolite concentrations in Wistar rats.MethodsTwenty five male Wistar rats were put on high fat diet (HFD; 60% calories from fat, 30% from carbohydrates) on their 55th day of life, while 25 control male rats (CONs) remained on chow. Adequate levels of essential nutrients were provided. Both groups underwent memory tests in 8-arm radial maze at 3rd, 6th, 9th, and 12th month. 1H magnetic resonance spectroscopy was employed to measure concentrations of tNAA (marker of neuronal integrity) at one month and one year, whereas MRI was used to evaluate hippocampal volumes.ResultsObese rats (OBRs) consumed similar amount of calories as CONs, but less proteins. However, their protein intake was within recommended amounts. Throughout the experiment OBRs had statistically higher concentrations of blood ketone bodies than CONs, but still within normal values. At post-mortem assessment, OBRs had 38% larger fat deposits than CONs (p<0.05), as evaluated by volume of epididymis fat, an acknowledged marker of fat deposits in rats. Contrary to our expectations, OBRs had better scores of memory behavioral tasks than CONs throughout the experiment. At one year, their hippocampi were by 2.6% larger than in CONs (p = 0.05), whereas concentration of tNAA was 9.8% higher (p = 0.014).ConclusionLong-term HFD in our study resulted in better memory, larger hippocampal volumes, as well as higher hippocampal metabolite concentrations, possibly due to increased levels of blood ketone bodies. The results should be interpreted with caution, as results from animal models do not necessarily directly translate in human condition. 相似文献