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At least 505 records · Page 28Linked to original sources
PubMed1976

A model of promoter recognition along the two helical grooves of DNA.

A speculative model based on published sequences to explain the specific binding of RNA polymerase of E. coli to promoters is suggested: (see article). A fragment 24 base pairs long to the left of the initiation site must not contain the G's in the positions indicated by the circles and must contain T's (or G's) in the positions marked by the squares. In most known cases mutual disposition of the circle and square patterns is as shown above. In one case (the fd G3 promoter) the pattern of squares is shifted by 4 base pairs to the right relative to the pattern of universal non-G's (circles).

Base Sequence↗
PubMed1984

Enzyme-linked immunosorbent assays for antibodies to poly(A), poly dAT and histones: possibly useful tools for the evaluation of prognosis and disease activity in systemic lupus erythematosus.

In a prospective study 222 sera from 56 patients with systemic lupus erythematosus (SLE) were tested for antibodies to poly(A), poly dAT and histones using enzyme-linked immunosorbent assay (ELISA). Patients with active disease had significantly more often antibodies to poly(A), poly dAT and histones than patients with inactive disease. There was a positive correlation between the activity score of the disease and the levels of poly(A)-antibodies of IgG and IgM class, poly dAT-antibodies and antibodies to histones. Patients with SLE-nephritis had a higher level of poly dAT and IgG class poly(A) antibodies than patients without nephritis. Interestingly, patients with an SLE-nephritis had lower levels of IgM-poly(A)-antibodies than those without nephritis. Attempts to use the ELISAs in predicting the SLE exacerbations were unsuccessful. However, the assays can be used as parameters in the estimation of the disease activity.

Adolescent↗
PubMed1989

New in vivo model to assess venous endothelial cell functions. Effect of defibrotide.

In the past few years there has been increasing interest in the role of the vascular endothelium as an active modulator of biological responses. Endothelial cells exert antithrombotic activity by the release of prostacyclin [23] and adenine nucleotides [16], the availability on the cell surface of heparin-like substances [3], and thrombomodulin-mediated activation of protein C [8]. In addition, endothelium is involved in the regulation of fibrinolysis by releasing soluble factors, such as tissue plasminogen activator (tPA; [10]) and plasminogen activator inhibitor (PAI; [22, 11]), as well as in the control of vascular responsiveness by the production of smooth muscle relaxing and contracting factors. Endothelial cells have also been shown to synthesize and to express procoagulant activities [18]. Many data on endothelial cell functions has been obtained from two experimental models, namely endothelial cell cultures and perfused segments of animal and human vessels. Both are subject to methodological criticism since they only represent in part in vivo conditions, and the necessary experimental manipulations and laboratory procedures greatly modify the naturally occurring cellular functions. In order to overcome such difficulties as far as possible, a new in vivo model has been employed to provide easily assessable and reliable data on the properties of endothelial cells in man. A venous segment was isolated functionally by cannulating a dorsal vein in the hand and a cubital vein in the same arm. Changes observed ex vivo in blood from the cubital vein following infusion into the hand vein of an active drug, can mainly be attributed to its local effect on the venous wall. At the same time, a cubital vein in the other arm was cannulated in order to provide information to distinguish systemic from regional effects.

6-Ketoprostaglandin F1 alpha↗
PubMed1988

Acute effects of defibrotide, an experimental antithrombotic agent, on fibrinolysis and blood prostanoids in man.

Defibrotide is a polynucleotide extracted from mammalian lung, which shows antithrombotic and anti-ischaemic activity in animals, probably related to stimulation of fibrinolysis and/or enhancement of prostacyclin production. The effect of a single infusion of defibrotide on fibrinolysis and the levels of certain prostanoids in man has been investigated in a cross-over double-blind placebo-controlled study. Evaluation of changes in fibrinolysis was difficult because of the spontaneous activation observed after placebo. However, the fast-acting plasminogen activator inhibitor was decreased only at end of the defibrotide infusion, suggesting a moderate profibrinolytic effect superimposed on the spontaneous activation. There was a marked and prolonged elevation of the plasma level of 6-keto-PGF1 alpha, the stable metabolite of prostacyclin. In collagen stimulated whole blood, both 6-keto-PGF1 alpha and prostaglandin E2 production were also greatly increased, with no consistent indication of inhibition of thromboxane B2. It is suggested that defibrotide stimulates prostacyclin and prostaglandin E2 production by leucocytes or via platelet/leukocyte interactions. The effects observed here should be useful in guiding subsequent clinical trials.

6-Ketoprostaglandin F1 alpha↗
PubMed1985

Selective stimulation of coronary vascular PGI2 but not of platelet thromboxane formation by defibrotide in the platelet perfused heart.

Defibrotide is a partially depolymerized DNA fraction, having a molecular weight of about 20,000 and possessing antithrombotic and fibrinolytic activities. The present study was designed to investigate the action of defibrotide on PGI2 and thromboxane formation as well as left ventricular pressure and coronary vascular resistance in the platelet-perfused in vitro heart (Schrör et al. 1981). Defibrotide (0.1 mg/ml) administration resulted in a longlasting and significant elevation, seven-fold above control within 80 min, of PGI2 release from the platelet-perfused heart preparation while thromboxane and PGE2 release remained unaffected. This effect was only seen in presence of platelets but not in platelet-free perfused heart preparations. Urokinase, at an equieffective fibrinolytic concentration (10 IU/ml, euglobulin clot-lysis time) did not influence PGI2 generation. Treatment of the platelets with acetylsalicylic acid prevented the stimulatory action of defibrotide on vascular PGI2 as well as the transient decrease in coronary vascular resistance seen after administration of the agent. The data suggest that defibrotide is a selective stimulus for coronary vascular PGI2 formation. The mechanism of action is unknown, but appears to require platelets as an essential cofactor. The PGI2 stimulation by defibrotide appears not to be associated with its fibrinolytic action.

Animals↗
PubMed1993

Defibrotide versus heparin in the prevention of coronary reocclusion after thrombolysis in acute myocardial infarction.

A multicenter controlled study versus heparin was conducted to explore the activity of defibrotide, a polydesoxyribonucleotide drug, in preventing reocclusion after urokinase thrombolysis in patients with acute myocardial infarction (AMI). The study involved 137 consecutive patients with AMI and a time from the onset of symptoms < or = 6 hours, treated with urokinase (1,000,000 U intravenous bolus followed by 1,000,000 U slow-drip infusion over 12 hours). Immediately after thrombolysis, patients were allocated to treatment with defibrotide (group D: day 0, 3.6 g by intravenous infusion in 12 hours; days +1 to +6, 800 mg tid intravenously; days +7 to +10/+12, 400 mg tid intramuscularly), or heparin (group H: day 0, 1000 IU/hour infused over 12 hours; days +1 to +10/+12, 5000 IU tid subcutaneously). Coronary angiography was done, whenever possible, at +10/+12 days. The following parameters were assessed: (a) noninvasive estimate of myocardial reperfusion, through the analysis of CPK time-activity curves; (b) incidence of infarct-related artery (IRA) patency (TIMI scores 2-3) at coronary angiography. A total of 125 patients had a complete enzymatic curve (63 in group D and 62 in group H) and 106 had coronary angiography as well. IRA patency (the main end point) was observed in 63% of group D versus 43% of group H patients (p = 0.07). No statistically significant differences were found in the proportion of patients with indirect signs of early reperfusion (63% in group D versus 52% in group H patients).(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1976

Photochemically induced cross-links between DNA and alcohol dehydrogenase or salmine, respectively.

Model experiments with two structurally different proteins (alcohol dehydrogenase and salmine) show that glycine, alanine, and tyrosine are by far more frequently involved in photochemically induced cross-link formations with DNA than is cysteine. The yields for cross-link formation of thymidine with salmine (cysteine-free) are about as high as those with alcohol dehydrogenase (athiol protein).

Alcohol Oxidoreductases↗
PubMed1993

Stimulation of in vitro proliferation of murine lymphocytes by synthetic oligodeoxynucleotides.

To elucidate the properties of mitogenic nucleic acids, the ability of oligodeoxynucleotides to stimulate the in vitro proliferation of murine lymphocytes was investigated. The compounds tested were a series of oligodeoxynucleotides, synthesized with either phosphodiester or phosphorothioate chemistry and containing (dG) and (dC) alone or together. Among oligodeoxynucleotides tested, phosphorothioates were more active than phosphodiesters and stimulated thymidine incorporation under the same conditions as mitogenic non-mammalian DNA. Mitogenesis was unaffected by depletion of T cells, suggesting B cells as the predominant cell type stimulated. These results indicate that mitogenic nucleic acids need not have an extended polymeric structure and raise the possibility that antisense compounds have immunologic activity, at least in animal models.

Animals↗
PubMed1984

Conformational flexibility of poly (dG-m5dC) under very low salt conditions.

The methylated DNA polymer poly (dG-m5dC) which exhibits a B helical conformation in solutions containing 20 mM NaCl, undergoes a gradual and reversible transition to the Z conformation as the NaCl concentration is lowered. The midpoint of this transition occurs around 5-6 mM NaCl. The conformational flexibility of this polymer at such low NaCl concentrations opens up the possibility of studying the effects of other perturbants with negligible interference from salt concentration effects.

Circular Dichroism↗
PubMed1994

Steady-state kinetic studies with the polysulfonate U-9843, an HIV reverse transcriptase inhibitor.

The tetramer of ethylenesulfonic acid (U-9843) is a potent inhibitor of HIV-1 RT* and possesses excellent antiviral activity at nontoxic doses in HIV-1 infected lymphocytes grown in tissue culture. Kinetic studies of the HIV-1 RT-catalyzed RNA-directed DNA polymerase activity were carried out in order to determine if the inhibitor interacts with the template primer or the deoxyribonucleotide triphosphate (dNTP) binding sites of the polymerase. Michaelis-Menten kinetics, which are based on the establishment of a rapid equilibrium between the enzyme and its substrates, proved inadequate for the analysis of the experimental data. The data were thus analyzed using steady-state Briggs-Haldane kinetics assuming that the template: primer binds to the enzyme first, followed by the binding of the dNTP and that the polymerase is a processive enzyme. Based on these assumptions, a velocity equation was derived which allows the calculation of all the specific forward and backward rate constants for the reactions occurring between the enzyme, its substrates and the inhibitor. The calculated rate constants are in agreement with this model and the results indicated that U-9843 acts as a noncompetitive inhibitor with respect to both the template:primer and dNTP binding sites. Hence, U-9843 exhibits the same binding affinity for the free enzyme as for the enzyme-substrate complexes and must inhibit the RT polymerase by interacting with a site distinct from the substrate binding sites. Thus, U-9843 appears to impair an event occurring after the formation of the enzyme-substrate complexes, which involves either an event leading up to the formation of the phosphoester bond, the formation of the ester bond itself or translocation of the enzyme relative to its template:primer following the formation of the ester bond.

Binding Sites↗
PubMed1988

Abundance and degree of dispersion of genomic d(GA)n.d(TC)n sequences.

The abundance of d(GA)n.d(TC)n tracts was determined in genomes of rodents and primates. Dot blot hybridization assays revealed that such tracts constitute 0.40%, 0.30%, and 0.40%, respectively, of the rat, hamster, and mouse genomes, but only 0.07% and 0.05% of the human and monkey genomes. A plaque hybridization assay of rat and human genomic libraries showed that 37% and 16%, respectively, of the recombinant phages in these libraries contain d(GA)n.d(TC)n tracts. A survey of sequences stored in the GenBank data bank showed that a significant fraction of the stored rodent genes (about 2.0%) contain long d(GA)n.d(TC)n tracts (n greater than 30) with greater than 10% mismatching. The primate genes contain only shorter tracts (n less than 15) with less than 10% mismatching. In addition, the rodent and the primate genes contain tracts with larger degrees of mismatching. The chicken, which represents an entirely different branch of the evolutionary tree, was found to be as low in d(GA)n.d(TC)n tracts as the primates. It is suggested that a common ancestor of the rodents has acquired the ability to amplify d(GA)n.d(TC)n tracts.

Animals↗
PubMed1993

Functional and morphological effects of defibrotide on renal ischemia.

Defibrotide (Df) has been reported to protect various organs from ischemic damage. The aim of this study was to evaluate the effect of Df on renal function and morphology after warm kidney ischemia. Divided into two groups, 14 pigs underwent bilateral renal clamping for 90 min. One group (7 pigs) was treated with Df (32 mg/kg per h) for 6 h, whereas the control group received 5000 IU of heparin. Serum levels of blood urea nitrogen (BUN) and creatinine measured for 6 days were significantly higher in the control group (peak 26.8 +/- 16.7 vs 11.0 +/- 2.9 mmol/l and 501.2 +/- 351.4 vs 230.2 +/- 68.0 mumol/l P < 0.05). Renal biopsy evidenced a lesser extent of tubular and endothelial damage in Df-treated animals. In conclusion, Df provided relevant protection against renal ischemic injury.

Animals↗
PubMed2000

Successful therapy of transplant-associated veno-occlusive disease with a combination of tissue plasminogen activator and defibrotide.

A 36-year-old man underwent matched unrelated donor bone marrow transplantation for chronic myeloid leukaemia. He developed severe hepatic veno-occlusive disease as an early post-transplant complication. Tissue plasminogen activator was initially felt to be contraindicated since the patient had concomitant pericarditis. Defibrotide was therefore commenced as treatment for veno-occlusive disease. The pericarditis improved but the veno-occlusive disease continued to worsen (peak bilirubin 353 micromol/l). Tissue plasminogen activator followed by a heparin infusion was therefore administered. However, he proceeded to develop haemorrhagic cardiac tamponade that required drainage. Thrombolysis was therefore discontinued and treatment with defibrotide resumed after an interval of 48 h. The veno-occlusive disease gradually resolved and defibrotide was discontinued once the bilirubin had plateaued. He was discharged home on day +52 post-transplant.

Adult↗
PubMed1995

Rapid identification of polymorphic CA-repeats in YAC clones.

Positional cloning of rare disease genes depends on the availability of highly polymorphic markers near the disease loci. The most abundant class of polymorphic markers in the human genome is CA-repeats. We have developed a strategy for the rapid isolation of highly polymorphic CA-repeats from YAC clones. Total DNA of yeast clones containing partly overlapping YACs is digested with frequent cutter restriction enzymes, blotted and hybridized with a poly(CA/GT) probe under high stringency conditions that enable preferential detection of long CA-repeats. The repeats detected in this way are isolated by PCR using vectorette linkers, sequenced, and appropriate flanking markers are constructed for genotyping. All of the CA-repeats identified using this approach were highly polymorphic. This simple and rapid approach should allow the development of highly polymorphic markers at any genomic region cloned in YACs.

Blotting, Southern↗
PubMed2001

Morphological examination of the effects of defibrotide on experimentally induced bladder injury and its relation to interstitial cystitis.

This morphological study aims to investigate the effects of defibrotide, a deoxyribonucleic acid derivative drug with cytoprotective, immunosuppressive and vasorelaxant effects, on protamine sulfate induced bladder injury. Wistar albino female rats were catheterized and intravesically infused with phosphate buffered solution (control group) or, either protamine sulfate (bladder injury group) or protamine sulfate+defibrotide (bladder injury+defibrotide group) dissolved in phosphate buffered solution. The morphology of the urinary bladder was investigated using light and electron microscopy. The number of mast cells in the mucosa, mucosal alterations, intercellular junctions, surface topography and the glycosaminoglycan (GAG) layer as well as microvillus formation on the luminal surface were evaluated. In the bladder injury group, ulcerated areas, irregularity of the GAG layer, increased number of mast cells, vacuole formation, dilated perinuclear cistern, formation of pleomorphic and uniform microvilli and dilatations in the intercellular spaces in the urothelium were observed. In the bladder injury+defibrotide group a relatively normal urothelial topography, GAG layer and a few mast cells in the mucosa, some dilatations between the intercellular areas, less uniform microvilli, regular perinuclear cistern and tight junctions were observed. These results show that defibrotide can inhibit PS induced bladder damage.

Animals↗
PubMed2001

4',6-diamidino-2-phenylindole (DAPI) interacts with rare structures of GC polymers.

The binding of 4',6-diamidino-2-phenylindole (DAPI) to double-stranded GC polymers either in the alternating or in homopolymer sequence was investigated using fluorescence techniques. We employed fluctuation correlation spectroscopy, which measures the diffusion coefficient of fluorescent particles, to demonstrate that the fluorescence was originating from relatively slowly diffusing entities. These entities display a very large heterogeneity of diffusing coefficients, indicating that molecular aggregation is extensive in our samples. We used frequency domain fluorometry to characterize the fluorescence lifetime of the species, while varying the GC polymer-dye coverage systematically. At very low coverage we observed a relatively bright fluorescent component with a lifetime value of approximately 4 ns. The stoichiometry of binding of this bright species was such that it can only arise from rare molecular structures, either unusual loops or large molecular aggregates. The amount and characteristics of this bright fluorescent component were different between the homo and the alternating polymer, indicating that the difference in sequence of the two polymers is responsible for the different aggregates which are then detected in the fluorescence experiment. At large GC polymer coverage we observed a relatively wide distribution of fluorescent species with short lifetime values, in the range between 0.12 and 0.2 ns. Given the stoichiometry of binding of this fluorescent component, we concluded that it could arise either from intercalative and/or non-specific binding to the DNA double-stranded molecules. We comment on the origin of the rare but brightly fluorescent binding sites and discuss the potential to detect such unusual DNA structures.

Binding Sites↗
PubMed1999

Helix-helix transitions in DNA: fibre X-ray study of the particular cases poly(dG-dC). poly(dG-dC) and poly(dA). 2poly(dT).

The helix-helix transitions which occur in poly(dG-dC). poly(dG-dC) and in poly (dG-m(5)dC). poly(dG-m(5)dC) are commonly assumed to be changes between the right-handed A- or B-DNA double helices and the left-handed Z-DNA structure. The mechanisms for such transconformations are highly improbable, especially when they are supposed to be active in long polynucleotide chains organised in semicrystalline fibres. The present alternative possibility assumes that rather than the Z-DNA it is a right-handed double helix (S-DNA) which actually takes part in these form transitions. Two molecular models of this S form, in good agreement with X-ray measurements, are proposed. They present alternating C(2')-endo and C(3')-endo sugar puckering like the "alternating B-DNA" put forward some years ago. Dihedral angles, sets of atomic coordinates and stereo views of the two S-DNA structures are given, together with curves of calculated diffracted intensities. Furthermore, we question the possibility of obtaining semicrystalline fibres with triple helices of poly(dA). 2poly(dT) in a way which renders X-ray diffraction efficient. It is suggested that, up to now, only double helices of poly(dA). poly(dT) can actually be observed by fibre X-ray diffraction measurements.

DNA↗