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51.
Sawicki B Czykier E Kasacka I Kasprzak A Zabel M 《Folia histochemica et cytobiologica / Polish Academy of Sciences, Polish Histochemical and Cytochemical Society》2002,40(2):183-184
The present study was aimed at hybridocytochemical (HCC) detection and interspecies comparison of mRNA for calcitonin (CT), calcitonin gene-related peptide (CGRP), neuropeptide Y (NPY) and somatostatin (SS) in thyroid C cells of two rodent families of wild Microtidae: pine voles and common voles and also of laboratory Muridae, Wistar rats. Studies were performed on adult males. The HCC method in situ and immunomax technique were used to detect mRNA. DNA oligonucleotide probes labeled with digoxigenin were used in the HCC method. The obtained results were compared to the results of immunocytochemical (ICC) examinations, where rabbit or mouse antibodies against human CT, SS, NPY and rat CGRP, as well as chromogranin A were performed. In the present study, HCC reaction has demonstrated the presence of mRNA for CT and CGRP in all thyroid C cells in all the species examined. However, mRNA for NPY and SS was observed in very few C cells in rat and in many more C cells in the two species of wild rodents. The distribution of the positive cells corresponded with that of ICC detected cells. 相似文献
52.
Idarubicin is an anthracycline antibiotic used in cancer therapy. Mitoxantrone is an anthracycline analog with presumed better antineoplastic activity and lesser toxicity. Using the alkaline comet assaywe showed that the drugs at 0.01-10 microM induced DNA damage in normal human lymphocytes. The effect induced by idarubicin was more pronounced than by mitoxantrone (P < 0.001). The cells treated with mitoxantrone at 1 microM were able to repair damage to their DNA within a 30-min incubation, whereas the lymphocytes exposed to idarubicin needed 180 min. Since anthracyclines are known to produce free radicals, we checked whether reactive oxygen species might be involved in the observed DNA damage. Catalase, an enzyme inactivating hydrogen peroxide, decreased the extent of DNA damage induced by idarubicin, but did not affect the extent evoked by mitoxantrone. Lymphocytes exposed to the drugs and treated with endonuclease III or formamidopyrimidine-DNA glycosylase (Fpg), enzymes recognizing and nicking oxidized bases, displayed a higher level of DNA damage than the untreated ones. 3-Methyladenine-DNA glycosylase II (AlkA), an enzyme recognizing and nicking mainly methylated bases in DNA, increased the extent of DNA damage caused by idarubicin, but not that induced by mitoxantrone. Our results indicate that the induction of secondary malignancies should be taken into account as side effects of the two drugs. Direct strand breaks, oxidation and methylation of the DNA bases can underlie the DNA-damaging effect of idarubicin, whereas mitoxantrone can induce strand breaks and modification of the bases, including oxidation. The observed in normal lymphocytes much lesser genotoxicity of mitoxantrone compared to idarubicin should be taken into account in planning chemotherapeutic strategies. 相似文献
53.
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
54.
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
55.
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
56.
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
57.
Nickel compounds are known human carcinogens, but the exact molecular mechanisms of nickel carcinogenesis are not known. Due to their abundance, histones are likely targets for Ni(II) ions among nuclear macromolecules. This paper reviews our recent studies of peptide and protein models of Ni(II) binding to histones. The results allowed us to propose several mechanisms of Ni(II)-inflicted damage, including nucleobase oxidation and sequence-specific histone hydrolysis. Quantitative estimations of Ni(II) speciation, based on these studies, support the likelihood of Ni(II) binding to histones in vivo, and the protective role of high levels of glutathione. These calculations indicate the importance of histidine in the intracellular Ni(II) speciation. 相似文献
58.
Nickel, cadmium, cobalt, and copper are carcinogenic to humans and/or animals, but the underlying mechanisms are poorly understood. Our studies have been focused on one such mechanism involving mediation by the metals of promutagenic oxidative damage to DNA bases. The damage may be inflicted directly in DNA or in the deoxynucleotide pool, from which the damaged bases are incorporated into DNA. Such incorporation is prevented in cells by 8-oxo-2'-deoxyguanosine 5'-triphosphate pyrophosphatases (8-oxo-dGTPases). Thus, inhibition of these enzymes should enhance carcinogenesis. We have studied effects of Cd(II), Cu(II), Co(II), and Ni(II) on the activity of isolated bacterial and human 8-oxo-dGTPases. Cd(II) and Cu(II) were strongly inhibitory, while Ni(II) and Co(II) were much less suppressive. After developing an assay for 8-oxo-dGTPase activity, we confirmed the inhibition by Cd(II) in cultured cells and in the rat testis, the target organ for cadmium carcinogenesis. 8-Oxo-dGTPase inhibition was accompanied by an increase in the 8-oxo-dG level in testicular DNA. 相似文献
59.
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
60.
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