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PubMed1994

Modulation of resistance to anticancer drugs by inhibition of metallothionein synthesis.

The expression of metallothionein (MT) in certain tumor cells has been associated with resistance to anticancer drugs. In the present study, we examined the effects of inhibition of MT synthesis on resistance to anticancer drugs of human bladder tumor which were inoculated in nude mice. The results show that pretreatment of tumor-bearing mice with zinc salts increased MT content, both in normal and tumor tissues, with a marked reduction in the antitumor activity of cisplatin, Adriamycin, and melphalan. Injection of propargylglycine, an inhibitor of cystathionase, decreased MT induction by zinc in the tumor and diminished the resistance to these drugs. These results suggest a role for MT in drug resistance in tumors, and injection of propargylglycine may provide a potential means to overcome drug resistance caused by elevation of MT levels in certain tumors.

Alkynes↗
PubMed1994

Dependence of increased linear bone growth on age at oMT1a-oGH transgene expression in mice.

We have previously shown that growth hormone (GH) accelerates the rate and extends the duration of linear bone growth in a GH-transgenic mouse model. To determine if this GH effect was temporally regulated, bone lengths and growth plate widths were determined in transgenic mice carrying an ovine metallothionein 1a-ovine growth hormone (oMT1a-oGH) transgene. Transgene expression was initiated in oMT1a-oGH hemizygous transgenic mice by addition of 25 mM ZnSO4 to the water at 21 d of age; littermate control mice were also ZnSO4 supplemented. These mice were maintained on ZnSO4 until 70 d of age at which time the mice were killed and the ulna, humerus, and tibia were collected. Additional transgenic and control mice were stimulated at 21 d and the ZnSO4 stimulus withdrawn after 21 d of treatment and killed at 70 d or stimulated at 28 d with the stimulus withdrawn after 28 d and killed at 70 d. Continuously stimulated transgenic mice had longer bones than those of comparable control mice. The increased bone length in the transgenics was correlated with wider growth plates. Transgene expression initiated at 21 d of age increased bone length to the same or greater extent than that observed for mice with transgene expression initiated at 28 d but maintained for a longer interval thereby indicating that the age of GH initiation is more critical in bone elongation than the duration of GH exposure. The elevated GH effects were independent of circulating thyroid hormones and attainment of puberty. Elevated GH also increased the widths of all growth plate zones to the same extent by increasing cell numbers, rather than enhancing matrix production or individual cellular area.

Aging↗
PubMed1994

A trial of oral zinc supplementation in psoriasis.

A controlled double-blind study of oral zinc supplementation was performed in twenty-five patients with chronic plaque psoriasis over twelve weeks to assess changes in both psoriasis (using the psoriasis area and severity index) and neutrophil zinc content. There were no statistically significant differences in the psoriasis area and severity index during the trial between the placebo- and zinc-treated group, nor in the zinc levels. There was therefore no evidence of a benefit from zinc supplementation in patients with this disease.

Administration, Oral↗
PubMed1994

Captopril inhibits neutrophil synthesis of leukotriene B4 in vitro and in vivo.

The aim of this investigation was to determine the effects of metalloproteinase inhibitors on leukotriene (LT) A4 hydrolase in human neutrophil cytosol and to examine the effects of captopril on intact neutrophils in vitro and in vivo. Cytosolic fractions were assayed for LTA4 hydrolase and 5-lipoxygenase activity in the presence or absence of inhibitors. Only bestatin, 1,10-O-phenanthroline, captopril and fosinoprilat demonstrated significant effects. The IC50 of captopril and fosinoprilat for LTA4 hydrolase activity were 500 microM and 1 mM, respectively. No inhibition of 5-lipoxygenase activity in cytosolic fractions was detected. The effect of captopril was only minimally reversed by ZnSO4. The IC50 of captopril for inhibition of LTB4 synthesis in intact neutrophils was 63 microM. Furthermore, 5-HETE production in intact cells was diminished 25.3 +/- 8.5% in the presence of 1 mM captopril. Oral captopril inhibited stimulated LTB4 release by subsequently isolated neutrophils by 48.1 +/- 5.6% and 5-HETE release by 43.2 +/- 5.5%. Thus, captopril is an inhibitor of LTB4 synthesis in neutrophils in vitro and in vivo. However, there are differences between the potency of this drug as assessed in cytosol and intact cell studies. This study significantly extends previous reports in that it demonstrates that captopril is a more potent inhibitor of LTB4 synthesis in intact neutrophils than in cytosol and in that it demonstrates an inhibitory effect of captopril on synthesis of LTB4 by neutrophils exposed to captopril in vivo.

Arachidonate 5-Lipoxygenase↗
PubMed1993

Modulation of the neuroendocrine system and immune functions by zinc supplementation in children with Down's syndrome.

Plasma levels of TSH, T4, T3, and reversal T3 (rT3) were measured in 51 children with trisomy of the chromosome 21 and in 15 controls. Levels of TSH were higher in children with DS than in controls and rT3 levels were decreased. However, T3 and T4 levels were in the normal range. Plasmic zinc and thymulin, a zinc-dependent thymic hormone, were also decreased. After dietary supplementation with ZnSO4, levels of plasmic zinc, thymulin, TSH and rT3 were restored. A follow up of DS children one year after the cessation of zinc therapy showed that plasma levels of zinc decreased and TSH lightly increased. Zinc deficiency may play a crucial role in the pathogenesis of thyroid gland disfunction which leads to the autoimmune hypothyroidism often observed in this syndrome.

Down Syndrome↗
PubMedDate not supplied

[Relation between neurogenesis and electrical responses of olfactory receptors].

Structural and functional changes in olfactory epithelium of laboratory mice were studied following the treatment of nasal cavity with zinc sulphate. Different concentrations of zinc sulphate caused olfactory epithelium cells destruction, moreover the degree of this destruction depended on concentration. Direct dependence between morphological regeneration and the EOG amplitude increase was observed after the treatment with 1% zinc sulphate. The epithelium regeneration after the treatment with higher concentration (3 and 5%) was slower and the EOG amplitude fell behind the increase of the olfactory epithelium thickness. The application of different olfactory stimuli allowed to establish that the rate of reactions re-establishment differed with the odorous.

Animals↗
PubMed1994

[Studies on the anticonvulsive activity of pyrazolidinones].

The anticonvulsive activity of three kinds of pyrazolidinones: 5-benzyl-substituted-3-pyrazolidinones; 5-benzyl-1-alkyl substituted and 1-alkyl substituted-3-pyrazolidinones were studied. Fourteen substitutes of these three kinds of pyrazolidinones were found to be potent anticonvulsants. In doses less than TD50, they were found to be able to protect mice and rats from seizures produced by maximal electroshock seizure (MES), such action appeared rapidly and lasted for a short period. II-f was shown to be the most potent anti-MES agent among these three kinds of pyrazolidinones. It also showed therapeutic effect in treating experimental epilepsy produced by intrahippocampal injection of zinc sulfate in rabbits and audiogenic seizures in rats. The third kind of pyrazolidinones also showed anti-metrazol induced seizures in mice.

Acoustic Stimulation↗
PubMed1993

A study of the effect of oral zinc supplementation during pregnancy on pregnancy outcome.

Women in different trimesters of pregnancy (Group B; n = 106) were administered 200 mg zinc sulphate (elemental Zn 45 mg) orally/day from the day of reporting till delivery. Untreated group of 62 served as control. Levels of zinc in maternal serum, umbilical cord blood serum, and urine were estimated. Pregnancy outcome was assessed in terms of incidence of prematurity, IUGR, birth weight; apgar score and gestational age. Serum zinc levels in Gp. A declined significantly from 113.00 +/- 2.80 ug/dl in I trimester to 83.78 +/- 2.20 ug/dl in III (P < 0.001). Following zinc supplementation (Gp. B) serum zinc levels increased significantly from 109.70 + 3.23 micrograms/dl to 205.40 +/- 4.47 micrograms/dl (P < 0.001). Urinary excretion of zinc in Gp. A declined significantly with increase in the period of gestation. However in Gp. B, elimination of Zn increased significantly in proportion with the serum levels (P < 0.001) cord blood serum zinc level was normal irrespective of maternal serum Zn levels. Following oral Zn supplementation, levels increased significantly from below 127.0 micrograms/dl to above 158.0 micrograms/dl in Gp. B (P < 0.001). Maternal serum and cord blood serum zinc ratios were fairly constant in Gp. A as well as in Gp. B. Birth weight of babies born with Zn supplementation was significantly higher than control and was related to duration of oral zinc supplementation (P < 0.001). Gestational age of babies in Gp. B was significantly higher than respective controls when Zn supplementation was given for more than 3 months (P < 0.01), and was related to duration of zinc therapy (P < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Oral↗
PubMed1994

Effect of the acute promyelocytic leukemia PML/RAR alpha protein on differentiation and survival of myeloid precursors.

Acute promyelocytic leukaemia is characterized by an expansion of haematopoietic precursors arrested at the promyelocytic stage (1). The differentiation block can be reversed by retinoic acid, which induces blast differentiation both in vitro (2) and in vivo (3-4). Acute promyelocytic leukaemia is also characterized by a 15;17 chromosome translocation (5) with breakpoints within the retinoic acid alpha receptor (RAR alpha) gene on 17 and within the PML gene, that encodes a putative transcription factor of unknown function (6-7), on 15 (8-10). As a consequence of the translocation a PML/RAR alpha gene is formed. It is transcriptionally active and encodes a PML/RAR alpha fusion protein detectable in all APL cases (11-14). We expressed the PML/RAR alpha protein in U937 myeloid precursor cell line and show that they: 1) lose the capacity to differentiate under the action of different stimuli (vitamin D3, transforming growth factor beta 1); ii) acquire enhanced sensitivity to retinoic acid; iii) exhibit a higher growth rate that is due to a reduction in apoptotic cell death. These results provide the first evidence of biological activity of PML/RAR alpha and recapitulate critical features of the promyelocytic leukemia phenotype.

Cell Differentiation↗
PubMed1993

Effects of subchronic exposure of rats to lead or zinc on alpha-adrenoceptor-mediated contractile responses in isolated vas deferens.

The effects of subchronic (30 days) drinking water exposure of rats to ZnSO4 or Pb(CH3COO)2 alone or in combination on the adrenergically-mediated contractile responses of isolated vas deferens were studied. The contractile effects of the alpha 1, alpha 2-adrenoceptor agonist noradrenaline (NA) and to the alpha 1-adrenoceptor agonist 1-phenylephrine (1-PhE) were decreased after zinc exposure, whereas after lead exposure or lead plus zinc exposure they were not changed. The contractile responses to field electrical stimulation (FES, 0.1 Hz, 1 msec, 80 V) were diminished in amplitude in all metal-treated preparations as compared to controls. The yohimbine-induced restoration of the clonidine inhibited contractions in response to FES was decreased in both lead- and zinc-treated preparations, the EC50 for yohimbine being 0.018 +/- 0.001 microM in control preparations, 0.073 +/- 0.019 microM in lead-treated preparations and 0.056 +/- 0.021 microM in zinc-treated preparations. The calcium-channel blocker verapamil was found to inhibit at low concentrations and to increase at higher concentrations the FES-induced contractile responses in preparations from zinc-exposed rats. The inhibitory effect of cumulatively applied nitrendipine on the FES-induced contractions was increased in both lead- and zinc-treated smooth muscles, but was not altered in the preparations from lead plus zinc-treated rats. Therefore, subchronic exposure to subtoxic doses of lead of zinc led to different changes in the adrenergically-mediated contractility of isolated vas deferens. The changes induced by zinc exposure were not observed after lead plus zinc exposure. All these findings might be of pharmacological, toxicological or clinical importance.

Adrenergic alpha-1 Receptor Antagonists↗
PubMed1993

Wilson disease.

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Ceruloplasmin↗
PubMedDate not supplied

The zinc-immunodeficiency relationship in old patients.

The influence of oral zinc sulphate therapy on the humoral immunity was investigated by dosages of serum immunoglobulins (Ig) and of plasma zinc levels in 12 patients with a mean age of 70 years, in comparison with other 11 patients treated with placebo and with a control group of 50 apparently healthy subjects. The results of this double-blind study demonstrated the zinc effect on the immunoregulation, as the Ig levels, and particularly those of the IgG class, initially high, were lowered in a statistically significant proportion. It is assumed that further clinical trials with various zinc concentrations could bring more information on this trace element participation in the humoral immunoregulation.

Aged↗
PubMed1995

Induction of apoptosis by sodium butyrate in the human Y-79 retinoblastoma cell line.

The mode of cell death induced in the Y-79 human retinoblastoma cell line by sodium butyrate (SB), a short-chain fatty acid with potent inhibitory effects on the growth of many transformed cell lines, was investigated by fluorescence and transmission electron microscopy, agarose gel electrophoresis, and metabolic studies. While SB (< 1 mM) resulted in marked morphological differentiation, higher concentrations (1-4 mM) induced predominantly apoptotic involution in Y-79 in a concentration-dependent fashion after a latent period of 24 h. Dying cells displayed the characteristic morphology of apoptosis accompanied by DNA laddering with agarose gel electrophoresis. Extensive cell necrosis was apparent with 0.5 M SB. Induction of apoptosis and DNA laddering by SB was reduced by putative inhibitors of RNA and protein synthesis, but not putative endonuclease inhibitors. These results are important for understanding the mode of action of sodium butyrate as a potential cancer chemotherapeutic agent.

Apoptosis↗
PubMed1995

DNA fragmentation induced in lymphocytes by gamma irradiation or dexamethasone: inhibition by diethyldithiocarbamate (DTC), potentiated by zinc.

Apoptosis is a process of physiological cell death characterized by DNA fragmentation, chromatin condensation, loss of membrane asymmetry and cell lethality. In the present study, apoptosis induced in thymocytes by dexamethasone or gamma irradiation is evaluated by flow cytometry, gel electrophoresis and other techniques. Treatment of thymocytes with DTC or zinc shows that these products can inhibit radiation- or dexamethasone-induced apoptosis. Moreover, a synergistic effect is observed by using associations of both products (5 microM DTC + 50 microM ZnSO4): ZnSO4 potentiates the effect of DTC at concentrations for which the molecules used separately show a low efficacy. These results indicate that DNA fragmentation induced by dexamethasone or irradiation in thymocytes share some identical mechanisms.

Animals↗
PubMed1995

Relative zinc-binding capacity of metallothionein in hepatic cytosols of zinc-injected rats.

In order to determine the zinc-binding capacity of metallothionein in hepatic cytosols of zinc-injected rats, we examined the relationship between zinc contents in cytosols and metallothionein fraction in rat livers. Each rat was injected intraperitoneally once with 0.9% NaCl or zinc (10, 20, 40 or 60 mg zinc/kg b.w.) and was killed 14 h after injection. The distribution profiles of the hepatic cytosols of zinc-injected rats on a Sephadex G-75 column showed that the increased zinc was attributable to the metallothionein and high molecular weight proteins. Our results demonstrated that 63% of the increased zinc in hepatic cytosols of zinc-injected rats was bound to metallothionein and that 23% of the increased zinc was bound to high molecular weight proteins. These results suggest that the mechanisms of zinc accumulation in rat liver are different from those of cadmium accumulation.

Animals↗
PubMed1995

Zinc, hydrochlorothiazide and sexual dysfunction.

This study was designed to test the hypothesis that hydrochlorothiazide a diuretic used to treat hypertension depletes body zinc and thereby cause sexual dysfunction. Serum zinc and sexual dysfunction were measured in 39 middle aged hypertensive men who had been taking hydrochlorothiazide in average daily doses of between 25 and 50 mg daily for at least six months, and a control group of 27 unmedicated middle aged normotensive men. The medicated group had a higher incidence of sexual dysfunction (56 pc) as compared to 11 pc in the control group. The use of hydrochlorothiazide did affect serum zinc levels significantly in 20 patients. Sexual dysfunction occurred more often in older and overweight patients (p < 0.004). Three of the normotensive men experienced sexual dysfunction probably related to old age. Twenty two of the 39 on hydrochlorothiazide and experiencing sexual dysfunction were divided into two groups of 11 patients. Bloods were taken from the 27 normotensive and 22 hypertensive men receiving hydrochlorothiazide for the analyses of zinc. Subsequently one group of the patients were supplemented with zinc 500 mg daily for 30 days while the other group was supplemented with magnesium chloride 1 g daily for 30 days. The normotensive men were not treated. After 30 days, bloods were again taken from the three groups of analyses for zinc and magnesium. Serum zinc was significantly decreased (p < 0.05) by hydrochlorothiazide and a non significant decrease in serum magnesium (p = ns) was observed. After supplementation with zinc, the serum zinc levels returned to normal only in eight patients. There was improvement in the symptoms of sexual dysfunction in five patients. Two patients gained weight. Hydrochlorothiazide decreased serum zinc levels (p < 0.05) and was unchanged with magnesium supplementation but the serum magnesium returned to normal values. Improvement of symptoms of sexual dysfunction was positive in one patient. This study shows that low serum zinc levels may be associated with sexual dysfunction but the definitive role of zinc in the pathogenesis of sexual dysfunction will remain controversial.

Aged↗