Possible link between zinc intake and colon cancer.
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Animals↗
Biomedical subjects
M K Song
Publications and source records attributed to M K Song.
Reciprocity between tissue calmodulin and cAMP levels: modulation by excess zinc.
Signal transduction of many intracellular events is initiated by a minute influx of calcium ions into the cells, resulting in the formation of calcium-calmodulin complex and cAMP. Because zinc appears to have an inhibitory effect on a number of tissue reactions, it is postulated that this occurs through modulation of intracellular calcium influx. To test the hypothesis that the inhibitory effects of zinc are mediated through the calcium-calmodulin-cAMP pathway, zinc was administered by various routes to five groups of nude mice (control, intragastric, intraperitoneal, intradermal and oral groups), and calmodulin and cAMP concentrations were measured in the cytosol of epidermal cells. Calmodulin levels decreased significantly in the groups given intraperitoneal zinc (P < 0.025) and intradermal zinc (P < 0.001) injections. Significant elevations of cAMP levels were noted with intradermal zinc (P < 0.025). Overall, the relationship between calmodulin and cAMP appeared to be inversely logarithmic, with the lowest calmodulin levels associated with the highest cAMP concentrations. In addition, there was a significant trend towards a smaller calmodulin/cAMP ratio in all zinc-treated groups, except the mice fed dietary zinc. These results appear to correlate with tissue zinc levels obtained with these various forms of zinc administration. Our results therefore indicate that there is a reciprocity between epidermal calmodulin and cAMP levels, which may be modulated by external factors such as zinc.
Animals↗
Strain-dependent differences in vertebral bone mass, serum osteocalcin, and calcitonin in calcium-replete and -deficient mice.
The effects of dietary calcium intake on vertebral bone mass, composition, and turnover (calcium deposition and resorption) were determined in 10- and 14-week-old C57BL/6 (small) and SENCAR (large) mice. Total vertebral mass, percent ash, calcium, magnesium, and phosphorus were higher in SENCAR mice than in C57BL/6 mice at 10 weeks of age and after being fed 0.02% or 0.6% dietary calcium for 4 additional weeks. Relative calcium deposition was higher in C57BL/6 than in SENCAR mice, while relative calcium resorption was similar in both strains. The rate of resorption was higher in mice fed 0.02% dietary calcium than in those fed 0.6% dietary calcium. Thus, C57BL/6 mice gained vertebral calcium, while it remained unchanged or declined in SENCAR mice under conditions of both calcium depletion and calcium repletion. Serum osteocalcin (an index of bone formation) was higher in C57BL/6 mice than in SENCAR mice. Mathematically significant correlations between osteocalcin levels and vertebral calcium resorption and the net vertebral calcium loss were observed only in SENCAR mice. The serum calcitonin concentration was correlated with the amount of vertebral calcium resorbed in SENCAR mice, but not in C57BL/6 mice. Thus, vertebral resorption and formation are more tightly coupled in 10- to 14-week-old SENCAR mice than in C57BL/6 mice. In addition, remodeling appears to dominate vertebral calcium dynamics in SENCAR mice, while growth dominates in C57BL/6 mice during this period. Rodents have frequently been dismissed as potential models of bone aging based on the expectation that continued growth, rather than remodeling, dominates skeletal dynamics. These data clearly demonstrate that increases in body mass ("growth") are not invariably associated with continued vertebral growth. In this murine model, both heredity and dietary calcium intake modulate vertebral bone mass, turnover dynamics, and composition at sexual maturity. These differences in the development and regulation of vertebral bone mass in small C57BL/6 and large SENCAR mice suggest that animal, as well as clinical, models provide useful insights into the cellular and hormonal mechanisms of somatotype-dependent vertebral growth.
Analysis of Variance↗
Stimulation of inositol phosphate formation in cultured human retinal pigment epithelium.
Several hormones, neurotransmitters, and neuropeptides were screened for the ability to stimulate inositol phosphate formation in cultured human retinal epithelial (RPE) cells. Carbachol, vasopressin and thrombin were found to be effective. Treatment of RPE cells with all three agents produced increases in inositol monophosphate, inositol bisphosphate and inositol trisphosphate in the presence of 10 mM LiCl. Carbachol stimulated a 4-fold increase in the total of inositol phosphates at 1 mM. Studies with cholinergic antagonists showed a rank order of 4 DAMP greater than QNX greater than pirenzepine greater than methoctramine, suggesting the presence of M3 muscarinic receptors. Vasopressin gave a 2.5-fold stimulation at 10 microM. Agonists of vasopressin were also tested and gave differential responses. Studies using a V1 agonist (PIOVP) and a V2 agonist (DAVP) showed DAVP matching the level of stimulation elicited by vasopressin whereas treatment with PIOVP only reached 50% of the vasopressin response. These data suggested the presence of V2 receptors in the RPE cells. Several proteases were tested for their ability to stimulate RPE inositol phosphates. Thrombin caused a 7-fold increase in inositol phosphate formation at 1 U/ml, whereas trypsin and plasmin elicited smaller responses (approximately 2-fold). The thrombin effect was blocked by the thrombin-specific inhibitor, hirudin, but not by other protease inhibitors. Several mediators of inflammation such as bradykinin, histamine and serotonin were also tested, and they were ineffective in stimulating inositol phosphate turnover in the RPE cells.
Angiotensin II↗
Excessive chromium intake in children receiving total parenteral nutrition.
Various expert bodies have recommended that the daily parental intake of chromium in children receiving total parenteral nutrition (TPN) should be 0.20 micrograms/kg. To test whether this recommendation is appropriate, we assessed chromium intake, serum chromium concentrations, and renal function in 15 children receiving TPN. The median duration of TPN use was 9.5 (range 1.3-14) years. The children's glomerular filtration rate (GFR), measured by plasma clearance of indium-111-DTPA was lower than that of non-TPN controls (70 [SD 17] vs 110 [10] ml/min per 1.73 m2). The daily chromium intake averaged 0.15 (0.09) micrograms/kg daily but the serum chromium concentration was 20 (4 to 42) times higher than that of the controls (2.1 [1.2] vs 0.10 [0.03] micrograms/l; p less than 0.0001). GFR was significantly inversely correlated with serum chromium concentration (r = -0.60, p less than 0.02), daily chromium intake (r = -0.69, p less than 0.01), cumulative parenteral chromium intake (r = -0.72, p less than 0.01), and TPN duration (r = -0.52, p less than 0.05). We discontinued chromium supplementation of TPN solutions and reassessed the children a year later. Contaminating chromium concentrations were 1.0-1.8 micrograms/l in TPN solutions and 0.9 micrograms/l in fat emulsions. Drinking water contained 4.3-5.7 micrograms/l. Thus, the chromium intake without supplementation was only 0.05 (0.01) micrograms/kg daily. The mean serum chromium concentration fell to 0.50 (0.30) micrograms/l but was still significantly higher than that in the controls (p less than 0.01). The GFR did not change significantly (65 [14] ml/min per 1.73 m2). No patient has shown signs of chromium deficiency. Although our patients were receiving less than the recommended chromium intake during supplementation, their high serum concentrations suggested excessive intake. The recommended parenteral chromium intake for children should be lowered.
Adolescent↗
Prostaglandin interacts with steroid sex hormones in the regulation of intestinal zinc transport.
1. The effects of prostaglandins (PGs) E1 and E2, testosterone, 17 beta-estradiol and indomethacin on the intestinal zinc transport rates of male and female rats were compared. 2. PGE1 stimulated Jms (the zinc flux rate from mucosa-to-serosa) of jejunal segments from male rats but inhibited Jms of those from female rats in Ussing chamber experiments. 3. 17 beta-Estradiol inhibited Jms of jejunal segments from male rats, while testosterone stimulated it in those from female rats. However, testosterone inhibited Jms of segments isolated from male rats and 17 beta-estradiol that of those from female rats, while in segments from ovariectomized rats, both of these steroid hormones stimulated Jms. 4. When PGE2 was added to an indomethacin containing medium, Jms significantly increased whereas Jsm (the zinc flux rate from serosa-to-mucosa) decreased further.
Alprostadil↗
Prostaglandin metabolism in relation to the bowel habits of women.
A relationship between the menstrual cycle, changes of bowel habits and concentrations of plasma prostaglandin (PG)E2, PGF2 alpha, 6-keto-PGF1 alpha and thromboxane (TX)B2 in 3 groups of 8 women with different bowel habit were determined. The concentrations of PGE2, PGF2 alpha and TXB2 were significantly higher in the group who had bowel habits smoother than usual at menses compared to those who had experienced constipation throughout cycle or at menses. However, no differences between at mid-cycle and at menses were observed in the groups who had experienced constipation. These results suggest that constipation of young women is related to the inherited inability of patients to synthesize and secrete PGs in plasma and possibly in small intestine.
Adolescent↗
Retinal pigment epithelium-stromal interactions modulate hyaluronic acid deposition.
Hyaluronic acid (HA) is a major component of the extracellular matrix (ECM) and is particularly prominent in various structures of the eye. Choroidal mesenchymal fibroblasts (CHM) and fetal retinal pigment epithelial (fRPE) cells were cultured individually and in cocultivation, as a paradigm for ocular stromal-epithelial interactions. Such interactions are thought to be a key mechanism for the modulation of the ECM and of HA deposition in the region of Bruch's membrane and related structures. In cocultivation, increased levels of HA production were observed, more than the sum of the two cell types grown individually. Conditioned medium from fRPE cultures placed over CHM cells was able to enhance production in such cells several-fold, demonstrating that cell-cell contact was not needed for this enhanced production. On the other hand, when conditioned medium from CHM fibroblasts was added to the fetal RPE cells, no increase in HA production was observed. A soluble HA-stimulating factor apparently released by fRPE cells in a paracrine manner enhanced HA production in CHM cells. The fRPE cell-conditioned media was unable to exert this effect on the fRPE cells themselves. The fRPE cells may lack the appropriate receptor. Alternatively, they may not have the biosynthetic machinery for augmented HA production.
Cell Communication↗
Focal endothelial cell degeneration and proliferative endarteritis in trauma-induced early lesions of necrobiosis lipoidica diabeticorum.
Microangiopathy is an essential component in diabetic vascular pathology. We report ultrastructural observations of ballooning degeneration involving isolated endothelial cells of cutaneous capillaries, while leaving adjacent endothelial cells relatively intact in six diabetic patients with early lesions of necrobiosis lipoidica induced by trauma. Focal proliferation of endothelial cells encroaching upon the vascular lumina (obliterative endarteritis) was also observed. Lectin studies on biopsy specimens of older lesions of necrobiosis lipoidica revealed paucity of dermal blood vessels. These observations enable us to gain further insight into the pathophysiological mechanisms that underlie diabetic microvascular disease.
Aged↗
Electron microscopic and immunocytochemical studies of the sequence of events in psoriatic plaque formation following tape-stripping.
Electron microscopic and immunocytochemical studies were performed on sequential biopsies following the tape-stripping of the uninvolved skin in 12 patients with psoriasis. In the biopsies taken after 5 min for up to 7 days during the pre-psoriatic phase, there were initial lymphocyte-Langerhans cell interactions as well as interactions between lymphocytes and keratinocytes. In biopsies taken after 6-8 weeks during the proliferative phase there were lymphocyte-macrophage interactions. In the 24-h and 7-day biopsies there were close contacts between epidermal lymphocytes and keratinocytes via microvilli, with blebbing of the keratinocyte plasma membranes and granular cytoplasmic changes around these microvilli. Few basal keratinocyte herniations were noted during this phase. The 6-8-week biopsies of Köbner-positive patients were characterized by a marked increase in lymphocyte-macrophage interactions via similar microvillous processes with associated electronlucent areas suggestive of cytotoxicity.
Adult↗
Influence of ardacin supplementation on feedlot performance and digestive function of cattle.
A feedlot growth-performance trial and a metabolism trial were conducted to evaluate a dose response to ardacin (a glycopeptide antibiotic). Treatments consisted of an 88% concentrate finishing diet supplemented to contain (DM basis) 0, 8.25, 16.5., or 33 mg ardacin/kg. The growth-performance trial (129 d) involved 120 heifers and 120 steers in a randomized complete block design. There were no interactions (P less than .10) between sex and response to ardacin. Average daily gain increased (P less than .05) and DM conversion decreased (P less than .01) with increasing levels of ardacin supplementation. At the 33 mg/kg level of supplementation, ADG and DM conversion were improved 10.6 and 5.6%, respectively. Four Holstein steers (344 kg) with cannulas in the rumen and proximal duodenum were used to evaluate treatment effects on characteristics of digestion. There were cubic effects of ardacin on ruminal starch digestion (P less than .05), microbial N synthesis (MNS, P less than .10), and microbial efficiency (MNEFF, grams of MNS/kilogram of OM fermented). For the 16.5 and 33 mg/kg levels of supplementation, ruminal starch digestion was increased 4.9%, and MNS and MNEFF were decreased 12.9 and 15.6%, respectively. Postruminal and total tract digestion of N increased linearly (P less than .10) with ardacin supplementation. Total tract digestion of OM, ADF, and starch were not affected (P greater than .10). Ardacin did not influence (P greater than .10) ruminal pH or molar VFA proportions. It is concluded that supplementation of a finishing diet with 33 mg ardacin/kg will enhance ADG and DM conversion of feedlot steers and heifers.
Aminoglycosides↗
Propagation of fetal human RPE cells: preservation of original culture morphology after serial passage.
The permissive effects of extracellular matrix (ECM) on in vitro growth and differentiation of fetal human retinal pigment epithelial (RPE) cells have been studied. Factors which enhanced the effect of ECM to support cell division were also examined, including growth factors, culture media, and serum requirement. Under the specific culture conditions we have defined, it is possible to propagate these RPE cells at low density (less than 20 cells/mm2) with excellent growth properties for greater than 72 doublings (fourteen passages) in serial culture. Later-passaged cells maintained the morphological appearance of early-passaged cultures. ECM produced by bovine corneal endothelial cells was by far the most predominant factor in promoting rapid cell proliferation and viability over repeated passaging. Basic fibroblast growth factor (bFGF) exerted a substantial effect on the rate of cell division at different serum concentrations on plastic dishes. In addition, this factor showed profound synergistic effect when RPE cells were maintained on ECM, both in the preservation of cell morphology and also in long term viability. Other growth factors, such as epidermal growth factor (EGF) and transforming growth factor-beta (TGF-B), were also tested, but EGF effects were less prominent than those observed with bFGF, and TGF-B had an inhibitory effect at high concentrations. The ability to obtain a relatively large number of human RPE cells in vitro which preserve the appearance of early passage cells may provide useful opportunities to study the physiological properties and pathological alterations involving this important cell type.
Cell Division↗
Ruminal fermentation pattern, bacterial population and ruminal degradation of feed ingredients as influenced by ruminal ammonia concentration.
The effects of ruminal ammonia concentration on bacterial numbers, fermentation pattern and degradation of feed ingredients in the rumen were examined with three nonlactating Holstein cows fitted with ruminal cannulas. Cows were fed twice daily a complete mixed diet (90% whole plant oat silage and 10% concentrate mixture) containing 11.1% CP on a DM basis. Ammonium bicarbonate (NH4HCO3) was infused continuously into the rumen at levels of 0, 95, 190 or 280 g/d. Infusion of NH4HCO3 linearly increased (P less than .05) the concentrations of ruminal ammonia and blood urea N. Total VFA concentrations and mixed bacterial numbers also were increased (P less than .05) by NH4HCO3 infusion. Infusions of NH4HCO3 increased (P less than .05) butyrate and decreased (P less than .05) isobutyrate and isovalerate proportions. Infusion of NH4HCO3 increased (P less than .05) rate of degradation of soybean meal DM but did not (P greater than .05) influence degradation characteristics of fish meal and barley grain. In conclusion, supplementation of N by continuous infusion of NH4HCO3 appeared to stimulate bacterial growth and fermentation but it did not influence extent of ruminal degradation of selected feed ingredients.
Ammonia↗
Thyroid hormone-mediated transcriptional activation of the rat liver malic enzyme gene by dehydroepiandrosterone.
Dehydroepiandrosterone (DHEA), a naturally occurring steroid secreted from the adrenal, has been reported to decrease the body weight gain in rodents without suppressing food intake and to stimulate malic enzyme activity in liver (Tepperman, H. M., de la Garza, S. A., and Tepperman, J. (1968) Am. J. Physiol. 214, 1126-1132). Herrin, we demonstrate that DHEA induces hepatic malic enzyme activity by increasing the rate of transcription of the malic enzyme gene. This transcriptional activation of the malic enzyme gene is dose dependent, i.e. the treatment of euthyroid male rats with daily doses of 17.5 and 35 mg of DHEA/100 g of body weight for 7 days elevated the rate of malic enzyme gene transcription in liver above the basal levels 4-5- and 8-9-fold, respectively. The levels of nuclear malic enzyme RNA, cytoplasmic malic enzyme mRNA, and enzyme activity were increased correspondingly. Malic enzyme stimulation by DHEA was liver specific, i.e. malic enzyme activity in brain, heart, kidney, and testis was unchanged. Thyroid hormone is required for the induction of hepatic malic enzyme activity by DHEA since in hypothyroid animals, DHEA was without effect. However, stimulatory effects of thyroid hormone and DHEA on malic enzyme expression are additive in euthyroid rat livers at both levels of gene transcription and enzyme activity.
Animals↗
Role of zinc in treatment of experimental acute pancreatitis in mice.
A study on the effect of zinc feeding on the survival rate as well as the levels of trypsinogen, alpha 2-macroglobulin, zinc, calcium, and magnesium in the plasma, pancreata, and livers of BALB/c mice fed a choline-deficient diet supplemented with 0.5% DL-ethionine (CDE diet) was undertaken. Feeding them a zinc-excess diet significantly increased the survival rate of mice with pancreatitis induced by CDE diet feeding. Trypsinogen concentrations in plasma and pancreas increased in mice fed a CDE diet and further increased in mice fed a zinc-deficient diet. The plasma alpha 2-macroglobulin levels in mice fed a zinc-deficient diet decreased compared to those fed a zinc-adequate or a zinc-excess diet. In mice with pancreatitis, zinc and calcium concentrations of pancreata increased and magnesium concentrations decreased compared to those of normal controls. The calcium concentrations in both livers and pancreata increased, but magnesium concentrations in these tissues decreased. These results suggest that altered mineral metabolism in the pancreas may have contributed to the pathophysiology of the mice with acute pancreatitis and that zinc supplementation in the diet may be therapeutic for pancreatitis.
Acute Disease↗
Altered biliary prostaglandins and cholesterol gallstones: an in vivo study.
Recent investigations suggest that biliary prostaglandin metabolism is altered during cholesterol gallstone formation. Most of the available data, however, has been obtained from in vitro studies. The purpose of the present study was to define the effects of cholesterol gallstone formation on in vivo biliary prostaglandin metabolism. Male prairie dogs were fed either a control chow for 21 days or a 1.2% cholesterol-enriched chow for 14-21 days. Cholecystectomy was performed and gallbladder tissue and bile were collected for analysis of prostaglandin concentrations using radioimmunoassay techniques. Gallbladder bile was examined for the presence of crystals and stones. No control animals but all cholesterol-fed animals developed either cholesterol crystals or gallstones (P less than 0.001). Concentrations of prostaglandin E2, prostaglandin F2 (PGF2 alpha), and the stable metabolic products of prostacyclin and thromboxane A2, 6-keto-PGF1 alpha and thromboxane B2 (TXB2), respectively, were decreased 60-85% in the gallbladder tissue of animals with crystals and gallstones compared to controls. Additionally, gallstone containing animals and those with crystals demonstrated a significant increase in the gallbladder bile concentrations of PGF2 alpha, 6-keto-PGF1 alpha, and TXB2. These findings lend support to previously reported in vitro studies suggesting that prostaglandin synthesis increases at an early stage of experimentally induced cholesterol gallstone formation.
Animals↗
Age-related alterations in duodenal calcium transport rate in rats.
To determine the age-related alterations in intestinal calcium transport under in vitro controlled conditions, we studied the calcium transport across duodenal segments of prepubertal (2 months), young adult (6 months) and aged (26 months) Fisher 344 male rats using the Ussing chamber technique. We also evaluated the effect of 10(-11) M 1,25-dihydroxycholecalciferol [1,25-(OH)2D3] in tissue bathing media. The calcium transport rate from mucosa-to-serosa (Jms) and from serosa-to-mucosa (Jsm) in 26-month-old rats (33.5 +/- 6.6 nmol/h per cm2 and 25.4 +/- 3.1 nmol/h per cm2, respectively) were significantly larger than that in 6-month-old animals (18.1 +/- 2.6 nmol/h per cm2 and 17.7 +/- 1.7 nmol/h per cm2 respectively). The Jms (46.1 +/- 12.0 nmol/h per cm2) and Jsm (50.8 +/- 7.2 nmol/h per cm2) in 2-month-old rats were significantly larger than the respective rates measured in 6-month-old animals. The addition of 1,25-(OH)2D3 minimized the age-related differences in mucosal calcium transport but did not significantly stimulate Jms. The magnitude of change in 1,25-(OH)2D3-stimulated Jsm in 6-month-old rats (17.7 +/- 1.7 vs. 29.4 +/- 2.2 nmol/h per cm2) was similar to that seen in 26-month-old rats (25.4 +/- 3.1 vs. 47.5 +/- 4.5 nmol/h per cm2). The results indicate that the maturational reduction in intestinal calcium transport capacity is followed by increased calcium fluxes in senescence.
Aging↗
Structural characterization of the rat malic enzyme gene.
We have identified and characterized lambda bacteriophage clones containing genomic DNA encoding rat malic enzyme [(S)-malate:NADP+ oxidoreductase (oxaloacetate-decarboxylating); EC 1.1.1.40]. The malic enzyme gene is unexpectedly large, spanning at least 95 kilobases. It is divided into 14 exons that range in size from 76 to 1513 base pairs. The sizes and boundaries of the exons were determined by Southern blotting and DNA sequencing. The sequences at the 5' and 3' ends of each intron conformed to the consensus sequence for mammalian introns. S1 nuclease and primer-extension assays showed that transcription of the malic enzyme gene initiates at multiple sites, the strongest one at position -31 relative to the ATG. "TATA and CCAAT box" homologies are not present in the proximal promoter region. Analysis of the 3' end of the gene showed that the utilization of alternate polyadenylylation signals in exon 14 results in two mRNAs with 3' untranslated regions of 345 and 1345 nucleotides, respectively.
Amino Acid Sequence↗