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PubMed1985

Patterns of structural change in DNA during tissue necrosis indicated by benzoylated DEAE-cellulose chromatography.

Structural change in liver DNA, isolated following administration of a necrogenic dose of carbon tetrachloride to rats, was examined by benzoylated DEAE-cellulose (BD-cellulose) chromatography. Greatest increase in the amount of DNA exhibiting single stranded character was detected 48 h after treatment, at which time massive necrosis was evident histologically. By 72 h after dosing, normal hepatic architecture had been restored and gross structural change in DNA could no longer be detected. The extent of single stranded regions in DNA isolated at various times after carbon tetrachloride intoxication was assessed by caffeine gradient elution of respective samples from BD-cellulose. By this criterion, structural damage to DNA was again most marked 48 h after treatment at which time single stranded regions extending over several kilobases were apparent. At earlier times such lesions were considerably shorter. Single stranded regions of discrete length detected 72 h after administration of the hepatotoxin appeared to be associated with cell division. Structural damage to DNA coincident with toxic injury was further characterized using BD-cellulose, by caffeine gradient elution of preparations subjected to denaturation before chromatography. The data indicate that production of single stranded regions is a major feature of DNA degradation during tissue necrosis. Whilst such degradation might otherwise confound interpretation of structural analyses based only upon strand breakage, the size of these regions suggests a basis for distinguishing between them and lesions specifically associated with repair, replication and transcription of DNA.

Animals↗
PubMed1988

Structural changes in glycogen phosphorylase induced by phosphorylation.

A comparison of the refined crystal structures of dimeric glycogen phosphorylase b and a reveals structural changes that represent the first step in the activation of the enzyme. On phosphorylation of serine-14, the N-terminus of each subunit assumes an ordered helical conformation and binds to the surface of the dimer. The consequent structural changes at the N- and C-terminal regions lead to strengthened interactions between subunits and alter the binding sites for allosteric effectors and substrates.

Adenosine Monophosphate↗
PubMed1988

Relation between cardiac hypertrophy and forearm vascular structural changes before and during long-term antihypertensive treatment.

In patients with hypertension, structural changes develop in the heart and in the systemic arteries that have a significant role in the maintenance and gradual worsening of the hypertensive disease. Blood pressure, basal and post-ischemic "maximal" forearm blood flow (strain-gauge venous occlusive plethysmography), and echocardiographic left ventricular mass index were measured in 28 hypertensive patients (WHO class I or II, 23 men and five women, aged 26 to 59 years). Minimal vascular resistance (mean arterial pressure/peak blood flow) was taken as an index of vascular structural changes. The same measurements were made in a group of 14 patients before and after long-term antihypertensive treatment: in eight patients after six and 12 months of treatment with captopril (50 mg twice a day, plus 25 mg of hydrochlorothiazide per day if necessary) and in six patients after six months of treatment with nitrendipine (20 mg per day, plus 50 mg of atenolol per day if necessary). A significant but weak direct correlation was found between the degree of left ventricular hypertrophy and mean arterial pressure (r = 0.41) or minimal vascular resistance (r = 0.31). Thus, patients were categorized according to whether they had left ventricular hypertrophy or impaired blood flow; the results suggested that left ventricular hypertrophy may be detected earlier than increased minimal vascular resistance. After six months of treatment, both captopril and nitrendipine significantly reduced left ventricular mass index and minimal vascular resistance. Left ventricular mass index was normalized in 50 percent of the patients, whereas minimal vascular resistance was normalized in one patient only. After 12 months of treatment, left ventricular mass index was normalized in all patients; minimal vascular resistance was on the average further reduced but normalized in only one additional patient. Thus, regression of cardiovascular structure also seems to occur earlier in the heart.

Adult↗
PubMed1992

The functional and structural changes of the glomerulus throughout the course of murine lupus nephritis.

The glomerular functional and structural changes in a murine model (MRL-lpr/lpr) of progressive lupus nephritis were studied. Animals were grouped into three age categories. (I, 14 wk; II, 20 wk; and III, 26 wk). GFR fell with age (257 +/- 43, 178 +/- 50, and 150 +/- 40 microL/min for Groups I through III, respectively). Similarly, the ultrafiltration coefficient (Kf) measured on isolated glomeruli fell with time (0.030 +/- 0.006, 0.023 +/- 0.006, and 0.013 +/- 0.002 nL/s/mm Hg, respectively). Both indomethacin and a selective thromboxane receptor antagonist L-670,596 significantly improved GFR in Group II animals to values seen in Group I animals. Neither agent had any effect to increase GFR in older group III animals. L-670,596 had no effect on Kf in Group II or III animals. Glomerular morphometric evaluation demonstrated a progressive rise in glomerular tuft volume, mesangial matrix expansion, proliferation in cells, and a reduction in open capillary loops and epithelial filtration slits with age. However, because of the increase in glomerular volume, calculated surface area remained well preserved over the three respective groups (61 +/- 18, 76 +/- 15, and 71 +/- 13 microns2 x 10(3)). Therefore, the fall in Kf is likely due to a fall in hydraulic permeability (Lp). The ultrastructural component of the glomerular capillary wall that correlated best with Lp was the epithelial filtration slit number per micrometer of glomerular basement length (r = 0.73; P < 0.0001), which suggests that the structural correlate Kf is in the filtration slit length (FSL). Despite the cell proliferation and mesangial matrix expansion in early disease (Group II), the overall FSL remains stable because of a slight increase in filtration surface area and a slight reduction in epithelial slits per micrometer of glomerular basement membrane. The fall in GFR appears to be hemodynamically mediated by thromboxane A2. In older Group III animals, the fall in GFR appears to be due to a 40% reduction in FSL rather than being hemodynamically based. Thus, the early improvement in function with pharmacological agents is deceptive because considerable disease may be present because of adaptive structural changes. Eventually, with disease progression, compensating hemodynamic and structural factors fail to maintain GFR within normal limits.

6-Ketoprostaglandin F1 alpha↗
PubMed1985

Structural changes in alpha-2- and ovomacroglobulins studied by gel chromatography and electron microscopy.

The structural change that occurs in alpha-2-macroglobulin upon its interaction with methylamine or chymotrypsin was studied by high-performance gel chromatography and electron microscopy. The result enabled us to estimate the Stokes radius of the protein as 8.8 nm and 7.9 nm before and after binding with the proteinase, respectively. The methylamine-treated protein also had the Stokes radius of 7.9 nm. Similar studies on the chicken and crocodilian ovomacroglobulins showed that these homologues of alpha 2-macroglobulin had Stokes radii of 9.2-9.3 nm and 8.5-8.7 nm before and after binding with chymotrypsin. Their Stokes radii did not change as a result of the methylamine treatment. Electron micrographs of the native and altered forms of the three proteins are presented. This study introduces a simple and quantitative method to study the structural change of alpha 2-macroglobulin and its homologues.

Alligators and Crocodiles↗
PubMed1978

Structural changes at the active site of pyruvate kinase during activation and catalysis.

The distance between the obligatory monovalent and divalent cations at the active site of pyruvate kinase (rabbit muscle) has been used to monitor structural changes at various successive intermediates in the catalytic reaction and to relate structure and activity of substrate analogs. Determinations of distance were obtained from measurements of the longitudinal relaxation rate (1/T1) of the methyl protons of methyl ammonium ion, which was affected by the activating divalent cation Mn2+ in the various enzyme complexes. A frequency dependence of the 1/T1 effects with several complexes indicats that the observed relaxation rate changes are modulated by changes in the cation-cation distances. The results are interpreted as a sequence of structural changes at the active site which occur upon substrate binding, catalysis, and product release. Substrate analogs which are good analogs of phosphoenolpyruvate by kinetic criteria induce structural changes analogous to the substrate. An attempt is made to correlate the cation-cation distance changes to other structural changes reported for pyruvate kinase.

Animals↗
PubMed1990

The age at onset of diabetes influences functional and structural changes in the pituitary-thyroid axis of streptozocin-diabetic male rats.

Severe structural changes leading to marked alterations in secretory activity are known to occur in the pituitary-thyroid axis 1 month after induction of postpuberal streptozocin (SZ)-diabetes. However, SZ-diabetic rats of different age groups have not been compared, nor has the maturity of the pituitary and thyroid glands at the onset of diabetes been correlated with the type and evolution of functional and structural changes. We thus induced diabetes in 1-month (prepuberal of 3-month (postpuberal) old male rats and compared diabetic with control groups 4 and 8 months after SZ or saline injection. We determined: 1) pituitary and thyroid weights, 2) the basal plasma TSH, T3, and T4 concentrations, and 3) several morphometrical measurements in the pituitary and thyroid glands. After 4 months, 1) the pituitary and thyroid weights were decreased, 2) plasma TSH and T3 were unchanged, plasma T4 was reduced. and 3) the number of thyrotropes, degenerative changes of follicle cells, and colloid area were increased, the follicle cell height as well as the number of fused cold follicles decreased, and the follicle area was unchanged in diabetic compared with control rats. The lesions were more conspicuous in pre- than in postpuberal diabetic animals. After 8 months, plasma TSH, T3, and T4 were decreased in diabetic compared with control rats. Except for the increased colloid area, all other lesions were similar, though more severe in prepuberal diabetic rats after 8 than 4 months. Few changes were found in postpuberal diabetic rats.(ABSTRACT TRUNCATED AT 250 WORDS)

Aging↗
PubMedDate not supplied

[Photo damage to the eye in exposure to the radiation from a Nd:YAG Q-switching laser: the physicochemical structural changes to the crystalline lens and the vitreous body].

Structural changes in the lens and vitreous body exposed to short-pulse Nd:YAG Q-switching laser were under study. The laser was focussed in the lens nucleus or vitreous center plane. A pulse energy was 7.1-9.3 mJ, with a total of 75-100 pulses. Cataract development was induced via the formation of cavities with the guidance spot focal plane localized in the lens nucleus plane. When the focus was in the vitreous body and the laser operated in a similar energy mode, great numbers of small cavities rapidly formed, this evidencing a shock wave propagation. Specific and structural conformational changes in the lens and vitreous protein molecules were detected by nitrate quenching of the triptophane amino acid residue fluorescence. Laser exposure was found to reduce triptophanile availability for nitrates, this evidencing protein complexes aggregation (collapse); besides, laser exposure essentially increased the amino acid residue quenching constants, which fact pointed to a decreased density of the vitreous collagen and lens crystalline negative charges (increased hydratation). These findings permit a conclusion that the shifts connected with injury to the vitreous body, with macular edema, or with detachment of the retina after exposure to Nd:YAG laser may be due to collapse of the vitreous gel liquified components.

Animals↗
PubMed1992

Assembly-associated structural changes of bacteriophage T7 capsids. Detection by use of a protein-specific probe.

To detect changes in capsid structure that occur when a preassembled bacteriophage T7 capsid both packages and cleaves to mature-size longer (concatameric) DNA, the kinetics and thermodynamics are determined here for the binding of the protein-specific probe, 1,1'-bi(4-anilino)naphthalene-5,5'-di-sulfonic acid (bis-ANS), to bacteriophage T7, a T7 DNA deletion (8.4%) mutant, and a DNA-free T7 capsid (metrizamide low density capsid II) known to be a DNA packaging intermediate that has a permeability barrier not present in a related capsid (metrizamide high density capsid II). Initially, some binding to either bacteriophage or metrizamide low density capsid II occurs too rapidly to quantify (phase 1, duration < 10 s). Subsequent binding (phase 2) occurs with first-order kinetics. Only the phase 1 binding occurs for metrizamide high density capsid II. These observations, together with both the kinetics of the quenching by ethidium of bound bis-ANS fluorescence and the nature of bis-ANS-induced protein alterations, are explained by the hypothesis that the phase 2 binding occurs at internal sites. The number of these internal sites increases as the density of the packaged DNA decreases. The accompanying change in structure is potentially the signal for initiating cleavage of a concatemer. Evidence for the following was also obtained: (a) a previously undetected packaging-associated change in the conformation of the major protein of the outer capsid shell and (b) partitioning by a permeability barrier of the interior of the T7 capsid.

Anilino Naphthalenesulfonates↗
PubMed1985

Structural changes in rat hepatocytes following ingestion of sugar solutions.

The present investigation describes the structural changes in rat hepatocytes following the ingestion of 3% solutions of the dietary sugars sucrose, fructose, fructose/glucose, or glucose. The most striking changes occurred in rats that drank large amounts of sucrose where large areas of rarefied hyaloplasm isolated islands of cellular organelles. Similar but less dramatic effects were seen in hepatocytes of animals that drank moderate amounts of sucrose, fructose, or a combination of glucose and fructose. In contrast, the hepatocytes of animals that drank the 3% glucose solution did not display the rarefied hyaloplasm or disorientation of cellular organelles and resembled the hepatocytes of control animals. It is proposed that ingestion of large amounts of fructose results in a build-up of fructose-1-phosphate in the liver, thereby disturbing the osmotic equilibrium of hepatocytes and causing the structural changes noted.

Animals↗
PubMed1984

Evidence for similar structural changes on binding of platinum anti-tumor agents to DNA and nucleosomes.

The influence of Pt(II) compounds on the 31P NMR spectra of natural DNA, synthetic polynucleotides, and nucleosomes was investigated. With Pt complexes which are anti-tumor agents, a new peak or shoulder centered at approximately 1.2 ppm downfield from the untreated DNA signal was observed. When Pt compounds known not to be anti-tumor agents were studied, no such new signal was observed. The most reasonable explanation for the downfield resonance is that it is a consequence of a structural change induced in the DNA by the anti-tumor agent. Since the effect of the Pt compounds on nucleosomes was similar, the same structural change is probably occurring in DNA in solution and in nucleosomes. A nonalternating dG . dC polymer, but not alternating G . C or any A . T polymers, exhibited a similar spectral change and this finding suggests that the structural change in the DNA arises primarily from reaction of Pt anti-tumor agents with adjacent G residues.

Animals↗
PubMed1992

Inhibition of structural changes in the simian virus 40 core origin of replication by mutation of essential origin sequences.

Mutation of the simian virus 40 (SV40) origin of replication (ori) has revealed the presence of three critical domains needed for DNA replication. The outer two domains, the AT tract and early palindrome element (EP), colocalize with DNA regions that become structurally altered in the presence of the SV40 large tumor antigen (T antigen) and ATP. Mutations within each domain were examined for their effect on the distortion of ori DNA by T antigen, as assayed by the sensitivity of DNA to KMnO4 oxidation. We have found that mutations in the AT tract that inhibit SV40 DNA replication also inhibit the distortion of the AT tract. Similarly, mutations in the EP inhibited the generation of structural changes in this element by T antigen. Although AT-tract mutations or mutations on the late side of ori affected structural changes only in the AT tract, certain EP mutations or mutations on the early side of ori also inhibited AT-tract distortion. Mutation of the flanking regions did not significantly affect either the affinity of T antigen for ori or the rate of binding to ori. We conclude from these results that the primary function of the flanking ori domains is to undergo structural changes required during the initiation of SV40 DNA replication. Moreover, our results suggest that the efficiency of replication initiation is significantly affected by the degree to which the flanking elements undergo a structural transition.

Antigens, Polyomavirus Transforming↗
PubMed1991

Regression of cardiovascular structural changes after long-term antihypertensive treatment with the calcium antagonist nitrendipine.

Regression of cardiovascular structural changes is a main goal of antihypertensive treatment. Nitrendipine is a calcium antagonist of the dihydropiridine group that may be given once daily. In different animal models of experimental hypertension, nitrendipine was shown to reduce blood pressure (BP) and left ventricular (LV) mass, to prevent early mortality, and to limit the development of vascular lesions. It has also been proposed that nitrendipine is able to preserve tissue integrity and increase life span in malignant hypertension, because it prevents a deleterious calcium overload in the heart and arterial vessels. In humans, the effect of nitrendipine on LV mass has been evaluated in a limited number of studies with conflicting results. It has been shown that nitrendipine is able to increase the compliance of large arteries; its effect on vascular structural changes has never been reported. In this study, nitrendipine (20 mg o.d.) was given to 10 hypertensive patients. BP, (ambulatory BP monitoring) heart rate (HR), LV mass and function (TM echo, 2D guided), forearm minimal vascular resistance (min VR = BP/max blood flow--venous occlusion plethysmography--taken as an index of vascular STC), plasma renin activity (PRA), plasma catecholamines (NE and E), and aldosterone (ALD) were measured during placebo, after 2 and 6 months of treatment. BP was significantly reduced and HR was slightly increased. After 6 months of treatment a significant reduction of LV mass index (p less than 0.001) and of min VR (p less than 0.002) was observed.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1987

H3 phosphorylation-dependent structural changes in chromatin. Implications for the role of very lysine-rich histones.

Contrary to native H1/H5-containing chromatin where phosphorylation induces local structural changes affecting chromatin condensation, in stripped fibers phosphorylation of the totality of H3 molecules does not affect significantly chromatin conformation and DNA-protein interactions. Modification of H3 causes only a slight increase of flexibility of nucleosomal chains, despite important changes in histone topography revealed by immunochemical reactivity studies. We suggest that phosphorylation may only induce into the system the potential for dynamic change by modulating histone-histone interactions within and between nucleosomes, probably as a result of conformational change in the H3 protein. The signal for structural change would come from one or other factors (very lysine-rich histones, non-histones) that influence internucleosomal interactions at very specific locations in the chromatin, probably through protein-protein contacts. So, phosphorylation may modify a direct interaction between the N-terminal basic tail of H3 and very lysine-rich histones.

Birefringence↗
PubMed1983

Hemoglobin tertiary structural change on ligand binding. Its role in the co-operative mechanism.

Analysis of the tertiary structural alterations in hemoglobin induced by ligand binding demonstrates that an allosteric core composed of the heme, histidine F8, the FG corner and part of the F-helix plays an essential role in co-operativity. This conclusion is based on structural and spectroscopic data and theoretical studies of hemoglobin chains. The methodology employed in the calculations is presented with details of the empirical energy function. Energy minimized structures of the unliganded hemoglobin chains, which serve as reference systems for the analysis, are described. To determine the structural changes induced by ligand binding, the effects of Fe--N bond shortening and of heme translation and tilting perturbations are examined. Energy minimization in the presence of the perturbations serves to provide information concerning the globin structural modifications produced by them. The validity of the results is supported by comparisons with the X-ray data of Anderson, Pulsinelli, Baldwin and Chothia on tertiary changes in the hemoglobin subunits. Internal to the allosteric core, there appear to be two stable positions for its elements: one of these corresponds to the liganded and the other to the unliganded species. The unliganded geometry fits without strain into the deoxy tetramer, while the liganded one fits without strain into the oxy tetramer. On ligation of a subunit in the deoxy tetramer, the structural changes within the allosteric core are in the direction of those found in going from the unliganded deoxy to the liganded oxy system, although they are reduced by the presence of constraints due to the other subunits in the deoxy tetramer. In addition, the quaternary constraints in the deoxy tetramer prevent the large overall displacement of the allosteric core that occurs in the transition to the liganded oxy tetramer. The coupling between the changes internal to the allosteric core, produced on ligation and the overall displacement of the core that accompanies the quaternary transition, is an essential element of the co-operative mechanism. As shown in previous work (Gelin & Karplus, 1977), the proximal histidine serves as the link between the position of the heme and the F-helix; the asymmetric orientation of the histidine in the deoxy structure, coupled with contributions from other heme-protein interactions, appears to initiate the tertiary structural changes induced by ligand binding. The reduced oxygen affinity of hemoglobin results not from tension on the heme in the unliganded structure (there is none) but instead from strain in the liganded subunit of the tetramer within the deoxy quaternary structure.(ABSTRACT TRUNCATED AT 400 WORDS)

Allosteric Site↗
PubMed1982

The effects of chemical cross-linking agents on calcium-induced structural changes in skinned muscle fibers. Origin within thick filaments detected by optical diffraction methods.

We have reported earlier (Sabbadini, R.A., Rieser, G.D. and Paolini, P.J. (1979) Biochim. Biophys. Acta 578, 526-533) that physiological levels of calcium (pCa 6.95-5.49) can produce structural changes in thick filaments which are detectable as an intensity loss of the first-order optical diffraction lines from chemically skinned skeletal muscle fibers stretched beyond myofilament overlap. We now show that the calcium-induced intensity decrease results from structural changes within, rather than between, thick filaments. Glycerinated, detergent-treated fibers from frog semitendinosus muscle were incubated in 1-10 mM concentrations of dimethylsuberimidate (DMS), dithiobis(succinimidylpropionate) (DTSP) or dimethyl-3,3'-dithiobispropionimidate (DTBP) for 4 h. These substances are homobifunctional lysine-modifying cross-linking reagents known to restrict movement of S-1 heads and limit changes in the association of myosin rods within the core of the thick filament without affecting interfilament lattice spacing. Diffraction patterns from cross-linked cells in relaxing solution were identical to those in control cells, but Ca2+ (pCa 5.49) totally failed to produce the typical 50-70% attenuation of first-order line intensity. Cleavage of the disulfide bond in DTBP-treated cells with dithiothreitol fully restored the Ca2+ sensitivity. Lysine group modification with methylacetimidate, a monofunctional lysine modification reagent equivalent to DMS, did not block the Ca2+ sensitivity. We observed that intensity reductions can also be produced by numerous other agents and mechanisms, such as nonionic polymeric solutions of polyvinylpyrrolidone, which reduces the lattice spacing, and alkaline pH, which probably displaces the S-1 heads from a resting position close to the thick filament surface. However, the prevention of the Ca2+ effect by cross-linkers indicates that intrafilament rather than interfilament changes in structure are responsible for the light diffraction intensity decrease accompanying activation.

Animals↗
PubMed1990

Structural changes in the round window membrane following exposure to Escherichia coli lipopolysaccharide and hydrocortisone.

The present study focused on structural changes of the round window membrane (RWM) from agents that evoke transient or permanent impairment of the auditory brainstem response when applied into the RW niche. Escherichia coli (E. coli) lipopolysaccharide (LPS) in sterile water (SW) and a 2% suspension of hydrocortisone (CORT), micronized in SW, were instilled into the round window (RW) niche of Sprague-Dawley rats. The morphology of the RWM was analyzed 3 to 21 days after instillation of either substance. Both substances caused minor structural alterations at the light microscopic level. The RWM showed a slight thickening and an invasion of inflammatory cells. At the ultrastructural level, the CORT-treated specimens showed an increased epithelial height and numerous microvilli, whereas the epithelium of the LPS-treated specimens was extended and contained few microvilli resembling those in the normal RWM. We postulate that the RWM may undergo dynamic structural changes when exposed to various agents. The structural alterations per se can influence the passage of substances from the middle ear to the inner ear.

Animals↗
PubMed1981

Effect of structural change on acute toxicity and antiinflammatory activity in a series of imidazothiazoles and thiazolobenzimidazoles.

The effect of structural change on the biological activity of a series of imidazothiazoles and thiazolobenzimidazoles is described. It was found that compounds with polar substituents at the 2 or 3 position of the ring system are less acutely toxic while maintaining antiinflammatory activity. Other structural changes, such as the incorporation of a gem-dimethyl substituent in the 6 position, increase acute toxicity and eliminate antiinflammatory activity. The compound with the best activity/toxicity ratio contains an alkyl sulfonyl substituent on the thiazole ring. The thiazolobenzimidazole analogues are more potent than the imidazole analogues.

Animals↗