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PubMed1985

Inhibition of parathyroid hormone secretion and parathyroid hormone-independent diminution of tubular calcium reabsorption by WR-2721, a unique hypocalcemic agent.

Hypocalcemia has been observed in patients receiving WR-2721 [S-,2-(3-aminopropylamino)-, ethylphosphorothioic acid]. WR-2721 is a compound that, after being dephosphorylated, provides protection of normal tissues against radio- and chemotherapy. The hypocalcemic response was accompanied by a decrease in the plasma level of parathyroid hormone (PTH) and by hypomagnesemia. Our present studies in rats on the mechanism of the hypocalcemic effect of WR-2721 indicate that: (a) The phosphorylated and dephosphorylated form of WR-2721 induced an equal dose-dependent decrement in plasma calcium. (b) In intact rats a maximal hypocalcemic dose of WR-2721 reduced urinary cyclic AMP excretion from 70.5 +/- 6.3 to 38.2 +/- 3.1 pmol/ml glomerular filtration rate (GFR), a level comparable to that observed (35.9 +/- 5.2 pmol/ml GFR) in thyroparathyroidectomized (TPTX) rats. (c) WR-2721 given to TPTX rats did not significantly interfere with the calcemic effect of bovine PTH 1-34 infused at 2.5 IU/h. Likewise, the drug did not impair the PTH actions on the renal Ca and inorganic phosphate (Pi) handling, and on the urine cyclic AMP excretion. (d) In TPTX rats made normocalcemic by low Pi diet, the hypocalcemic effect of WR-2721 was only about 25% of that observed in intact animals. However, it was associated with increased urine Ca per milliliter GFR, indicating a PTH-independent inhibitory effect on tubular Ca reabsorption. (e) In WR-2721-treated intact rats, prevention of hypomagnesemia by infusing magnesium chloride did not reduce hypocalcemia. In conclusion, the hypocalcemic effect of WR-2721 is not dependent upon the presence of a phosphate group in the molecule and is not causally related to hypomagnesemia. WR-2721 appears to be a unique hypocalcemic pharmacologic agent with strong inhibitory activity on PTH secretion and additional PTH-independent action on renal Ca reabsorption.

Amifostine↗
PubMed2002

TL emission spectra from differently doped LiF:Mg detectors.

There are two widely applied types of thermoluminescent detectors based on LiF:Mg luminophor: Lif:Mg,Ti and highly sensitive LiF:Mg,Cu,P. The role of luminescence centres in these materials is usually attributed to defects connected with, respectively, titanium and phosphorus dopants. In order to check how composition of dopants introduced into the LiF lattice influences emission spectra, measurements on a series of variously doped LiF:Mg samples were performed. Apart from LiF:Mg,Cu,P and LiF:Mg,Ti detectors with different concentration of activators, an experimental sample being a kind of a 'hybrid' between both standard materials was also prepared. It was synthesised with concentrations of magnesium and copper identical to those used for LiF:Mg,Cu,P preparation. but instead of phosphorus it was doped with titanium (LiF:Mg,Cu,Ti). The measurements of the emission spectra were performed by using a liquid nitrogen cooled CCD 1024E detector with an SP150 spectrograph. During the measurements the samples were placed inside a cryostat in a vacuum. Resulting data were numerically deconvoluted for individual peaks with respect to the wavelength and the temperature. The glow curve shape of this material resembles that of LiF:Mg,Cu,P, while sensitivity is at the level of LiF:Mg,Ti. Preliminary results indicate that emission of the LiF:Mg,Cu,Ti sample is similar to that of LiF:Mg,Cu,P rather than to LiF:Mg,Ti, showing a maximum for wavelengths well below 400 nm.

Copper↗
PubMed1999

Medical management of secondary hyperparathyroidism in uremia.

The prevention and treatment of the secondary hyperparathyroidism of chronic renal failure by medical means relies on a number of different possible approaches, which should be tailored to each patient's individual needs. Schematically, prevention should start early during the course of chronic renal failure (ie, when plasma intact parathyroid hormone is normal or only slightly elevated). Small calcium supplements prevent the development of a calcium deficit and may prevent parathyroid hormone oversecretion. The various therapeutic options that are available at present include: oral or intravenous vitamin D and vitamin D derivatives, in particular the 1alpha-hydroxylated vitamin D compounds; oral calcium supplements (calcium carbonate and calcium acetate) to avoid calcium depletion and also to bind phosphate in the intestinal lumen; aluminum-containing phosphate binders, the use of which should be restricted; oral magnesium salts (magnesium carbonate and magnesium hydroxide), which often are not well tolerated; general measures, such as dietary restriction of phosphate intake; and, in the case of resistance to all these approaches, the possibility of attempting ultrasound-guided ethanol injection of grossly hyperplastic parathyroid glands. Finally, it is encouraging to know that new drugs are in development, including calcium-free, aluminum-free, nonabsorbable oral phosphate binders, potentially nonhypercalcemic vitamin D derivatives, and calcimimetics. Some of them already have entered the stage of clinical evaluation, and preliminary results are promising.

Aluminum Compounds↗
PubMed2002

Role of impurities in the thermoluminescence of LiF:Mg,Cu,P.

The thermoluminescent properties of lithium fluoride doped with magnesium, copper and phosphorous are reviewed. This material shows specific advantages over LiF (TLD-100) in that is has higher sensitivity, less energy dependence and no supralinear behaviour with dose. However, it suffers from an irreversible loss in sensitivity when heated above 270 degrees C. Possible causes for this loss in sensitivity are discussed and experimental results are shown that indicate potential roles for the Cu, P and O impurities in this process. The present work focuses on the understanding of the impurity contents, inclusions, cluster formation and valence changes in this material by using differential scanning calorimetry (DSC) and glow discharge mass spectroscopy (GDMS). This research concludes that phosphorus inclusions are formed and a valence change of the Cu ions occurs after annealing above 270 degrees C, which degrades the TL sensitivity of LiF:Mg,Cu,P phosphors. It is also shown that a high content of oxygen in the material and control of the oxygen content during processing are critical to maintaining the sensitivity of these phosphors.

Calorimetry, Differential Scanning↗
PubMed1990

Studies on rat liver nuclear DNA damaged by chemical carcinogen (3'-Me DAB) and AP DNA endonuclease. II. Kinetic properties of AP DNA endonucleases in rat liver chromatin.

An experiment was designed to investigate the reaction mechanism of AP (apurinic or apyrimidinic) DNA endonucleases (APcI, APcII, APcIII) purified from rat liver chromatin. Sulfhydryl compounds (2-mercaptoethanol, dithiothreitol) brought about optimal activities of AP DNA endonucleases and N-ethylmaleimide or HgCl2 inhibited the enzyme activities, indicating the presence of sulfhydryl group at or near the active sites of the enzymes. Mg2+ was essential and 4mM of Mg2+ was sufficient for the optimal activities of AP DNA endonucleases. Km values of APcI, APcII and APcIII for the substrate (E. coli chromosomal AP DNA) were 0.53, 0.27 and 0.36 microM AP sites, respectively. AMP was the most potent inhibitor among adenine nucleotides tested and the inhibition was uncompetitive with respective to the substrate. The Ki values of APcI, APcII and APcIII were 0.35, 0.54 and 0.41mM, respectively. The degree of nick translation of AP DNAs nicked by APcI, APcII and APcIII with Klenow fragment in the presence and absence of T4 polynucleotide kinase or alkaline phosphatase were the same, suggesting that all 3 AP DNA endonucleases excise the phosphodiester bond of AP DNA strand to release 3-hydroxyl nucleotides and 5-phosphomonoester nucleotides.

Animals↗
PubMed2005

Layered inorganic-organic clay-like nanocomposites rearrange to form silsesquioxanes on acid treatment.

The formation of talc-like compounds by the condensation of organotrialkoxy silanes with magnesium hydroxide has been recently reported. These represent layered hybrid nanomaterials that have a layer thickness of around 1 nm, have organic moieties covalently linked to the layer surfaces, and are called "organoclays." We show that such compounds are sensitive to acid treatment. When a phenylclay is treated with hydrochloric acid, magnesium leaches out, destroying the layered structure. The extent to which magnesium is leached out is a function of the time of the acid treatment and the concentration of the acid used. Magnesium leaches out rapidly when the concentration of acid used to treat the phenyl-clay is higher, and the extent of structural magnesium that is leached out is also higher for higher acid concentrations. Removal of the magnesium rearranges the structure of the phenyl-clay to form oligomeric phenylsilsesquioxanes. FTIR and NMR suggest that the silsesquioxanes formed by acid treatment of the phenyl-clay comprise a mixture of ladderlike and cagelike structures.

Journal Article↗
PubMed2001

Inhibition of stress-activated protein kinase in the ischemic/reperfused heart: role of magnesium tanshinoate B in preventing apoptosis.

The activation of stress-activated protein (SAP) kinase may lead to an induction of apoptosis that is responsible for part of the cardiomyocyte death in reperfusion injury. The objective of the present study was to investigate the mechanism by which magnesium tanshinoate B (MTB), a bioactive compound isolated from Danshen, prevents apoptosis in cardiomyocytes in the ischemic/reperfused heart. Isolated adult rat hearts were perfused by the Langendorff mode with medium containing MTB prior to the induction of normothermic global ischemia. At the end of the 30-min ischemic period, the heart was reperfused with the same medium with or without MTB for an additional 20 min. In the MTB-treated ischemic/reperfused heart, the number of apoptotic nuclei was reduced by 2.5-fold in comparison to that in untreated ischemic/reperfused controls [23 +/- 4 vs 57 +/- 7 (mean +/- SD) TUNEL-positive cells, respectively, N = 3-4, P < 0.001]. SAP kinase activity was elevated 1.7-fold in ischemic/reperfused rat hearts [35.6 +/- 3.8 vs 21.2 +/- 3.3 (control) (mean +/- SEM) relative densitometric units, N = 4-6, P < 0.05]. Treatment with MTB abolished this elevation in SAP kinase activity (25.0 +/- 5.2 relative densitometric units), which was also decreased by 40% in the nucleus. When the heart was subjected to ischemia alone, there was no significant change in SAP kinase activity in the presence or absence of MTB. MTB did not appear to affect the p38 mitogen-activated protein kinase activity in this model system. In conclusion, MTB was shown to have cardioprotective activity against apoptosis, probably through the inhibition of SAP kinase activity.

Animals↗
PubMed1994

Neurogenic peptides and the cardiomyopathy of magnesium-deficiency: effects of substance P-receptor inhibition.

Dietary deficiency of magnesium (Mg) in rodents results in cardiomyopathic lesion formation. In our rat model, these lesions develop after 3 weeks on the Mg-deficient diet; significant elevation of several cytokines, IL-1, IL-6 and TNF alpha also occurs. In probing the mechanisms of lesion formation, we obtained data supporting the participation of free radicals (Freedman AM et al.: Bioch Biophys Res Commun 1990; 170: 1102). Recently, we identified an early elevation of circulating substance P and proposed a role of neurogenic peptides during Mg-deficiency (Weglicki WB, Phillips TM: AM J Phys 1992;262:R734). The present study was designed to evaluate the contribution of neurogenic peptides to the pathogenesis of Mg-deficiency. In the blood, substance-P and calcitonin gene related peptide (CGRP) are elevated during the first week on the diet. During the second week, circulating histamine, PGE2 and TBAR-materials were elevated and red cell glutathione was reduced, all prior to the elevation of the inflammatory cytokines during the third week. When the rats were treated with the substance P-receptor blocker [CP-96,345], the levels of substance P and CGRP remained elevated; however, increases in histamine, PGE2, TBAR-materials, and the decrease in red cell glutathione were inhibited; also, the development of cardiac lesions was inhibited significantly. These data support a central role for neurogenic peptides, especially substance P, in the development of cardiomyopathic lesions during Mg-deficiency.

Animals↗
PubMed2004

Normal matrix mineralization induced by strontium ranelate in MC3T3-E1 osteogenic cells.

There is growing evidence that strontium ranelate (SR; S12911-2, PROTELOS; Institut de Recherches Internationales Servier, Courbevoie, France), a compound containing 2 atoms of stable strontium (Sr), influences bone cells and bone metabolism in vitro and in vivo. We previously reported that SR increases bone mass in rats and mice by stimulating bone formation and inhibiting bone resorption. We also showed that short-term treatment with SR enhances osteoblastic cell recruitment and function in short-term rat calvaria cultures. Because Sr incorporates into the bone matrix, it was of interest to determine whether SR may affect matrix mineralization in long-term culture. To this goal, osteogenic mouse calvaria-derived MC3T3-E1 osteoblastic cells were cultured for up to 14 days in the presence of ascorbic acid and phosphate to induce matrix formation and mineralization. Matrix formation was determined by incorporation of tritiated proline during collagen synthesis. Matrix mineralization was quantified by measuring the number and surface of mineralized nodules using a digital image analyzer. In this model, 1,25(OH)2 vitamin D (1 nmol/L) used as internal control, increased alkaline phosphatase (ALP) activity, an early osteoblast marker, on days 4, 10, and 14 of culture. Treatment with SR (1 mmol/L Sr(2+)) increased ALP activity at days 4 and 14 of culture. SR also increased collagen synthesis at days 4 and 10 of culture. In contrast, 1,25(OH)2 vitamin D (1 nmol/L) inhibited collagen synthesis at 4 to 14 days of culture. Long-term treatment with SR (0.1 to 1 mmol/L Sr(2+)) dose dependently increased Sr concentration into the calcified nodules, but did not alter matrix mineralization in long-term culture, as shown by the ratio of the surface of mineralized nodules to the number of mineralized nodules on day 14 of culture. These results show that long-term treatment with SR increases collagenous matrix formation by MC3T3-E1 osteoblasts without inducing deleterious effect on matrix mineralization.

Alkaline Phosphatase↗
PubMed1996

Lesions associated with mineral deposition in the lymph node and lung of the dog.

This report includes details of the clinical and pathologic features of 31 dogs with a range of systemic illness and granulomatous lymphadenopathy associated with the presence of birefringent crystalline material within lymph nodes. Similar crystalline material was found in the lymph nodes of dogs with lymphoma (n = 9) and as an incidental finding within the canine lung (n = 9). The mineral content of these crystals was determined by electron microprobe analysis and interpreted in light of the composition of known geological or human-made compounds. A wide range of elements was identified including silicon, sulfur, copper, calcium, and aluminium, with lesser proportions of phosphorus, sodium, potassium, iron, magnesium, titanium, nickel, and chromium. Many of these compounds may have originated from exogenous natural and human-made sources, but some compounds (notably phosphates and sulfates) are uncommon or not found in nature and may have been formed within the tissues of the body (biomineralization). The inflammatory response induced by the presence of these minerals within lymphoid tissue may trigger altered immunoregulation, accounting for the spectrum of disease observed.

Aluminum↗
PubMed1995

Effect of casein-based semi-synthetic food on renal acid excretion and acid-base state of blood in dogs.

Urinary acid excretion and blood acid-base state were determined in dogs fed a casein-based semi-synthetic food (SSF), to which different amounts of salts had been added, in comparison with feeding normal dog food. Net acid excretion (NAE) and inorganic acid excretion (IAE) increased during SSF feeding. IAE was higher than the acid load calculated from the sulphur and phosphorus content of the casein. This higher IAE appeared to be due to the presence of calcium and magnesium phosphate in the diet, because calcium and magnesium may be in part precipitated as carbonate, leaving phosphate to be absorbed as phosphoric acid. Acid excretion decreased by addition of CaO. When no neutral Na+ and K+ salts were added, the increase in NAE was accompanied by a metabolic acidosis. K+ was more effective in attenuating the acidosis than Na+. On the basis of these findings a diet can be made which imposes a known acid load, and provides stable baseline values. Hence, any additions that influence the acid-base balance can be properly studied. The data obtained in these and future studies utilising this diet may be of help in optimising the composition of nutrient solutions to be used in the care of critically ill patients.

Absorption↗
PubMed1977

The oxygen affinity of concentrated human hemoglobin solutions and human blood.

The log P50 of normal human blood at 37 degrees C, PCO2 = 0, 21, 42, AND 57 MM Hg in the absence and in the presence of 2,3-DPG and ATP, has been determined in the pH range 7.0 to 7.6. Similar data have been obtained for human hemoglobin isotonic solutions at different protein concentrations in the presence of various amounts of each of the cofactors which are known to affect hemoglobin oxygen affinity in blood. It has been found that the addition of KC1, organic phosphates, magnesium ions, and CO2 confers to a 32% human hemoglobin solution the same oxygen affinity (over the entire physiological pH range) of whole blood. Thus there is no room for significant effects caused by some other unidentified molecules or ions.

Adenosine Triphosphate↗
PubMed2001

Direct measurement of HDL cholesterol: method eliminating apolipoprotein E-rich particles.

It has been reported that the existing direct method of high density lipoprotein (HDL) cholesterol measures particles enriched with apolipoprotein E (apoE). The aim of our study was to investigate a new analytical protocol to directly measure HDL cholesterol that eliminates apoE-rich particles. The interactions of four lipoproteins (HDL(3), HDL(2), LDL, and VLDL + chylomicron) with surfactants, divalent cations, sugars, and lectins were investigated. By analyzing sera, HDL(3), and HDL(2), we examined the relationships among the measurements obtained by our protocol, a precipitation method using heparin-MnCl(2), and a commercially available kit for this direct method. A significant difference was found between the direct method and the heparin-MnCl(2) method, but not between our protocol and the heparin-MnCl(2) method. Multiple regression analysis showed that the difference between the direct method and the heparin MnCl(2) method is dependent on sources of apoE-rich HDL. In conclusion, our protocol enables a direct measurement of HDL cholesterol that eliminates apoE-rich particles.

Apolipoproteins E↗
PubMed1983

Interaction of manganese with NB41A neuroblastoma adenylate cyclase.

In vitro assay of the adenylate cyclase of NB41A neuroblastoma cells in the presence of increasing concentrations of MnCl2 suggested that the enzyme is modulated by both high- and low-affinity sites for manganese. MnCl2 in a concentration of 1 microM significantly stimulated adenylate cyclase activity, but increasing the concentration of manganese to 3 microM or 10 microM had no further effect. Raising MnCl2 to 0.1 or 1 mM, however, further stimulated enzyme activity. In addition to differences in affinity for manganese, the two classes of binding sites may be distinguished by differences in their interaction with other agents that affect adenylate cyclase activity. Millimolar manganese and magnesium appeared to compete for a common site on the enzyme and the effect of manganese in this range and the effect of guanyl nucleotide were synergistic. In contrast, the stimulation of activity by micromolar manganese appeared to be additive to the effects of either increasing magnesium or the addition of guanyl nucleotide to the assay media. Comparison of the substrate dependency of the reaction measured in the presence and absence of manganese suggests that the stimulation of adenylate cyclase activity involves increases in both the apparent Vmax of the reaction and the affinity for ATP. The results raise the possibility that the interaction of Mn2+ may play a role in the modulation of adenylate cyclase in vivo.

Acetic Acid↗