PubMed Health⌕ Search

Biomedical subjects

M J Fryer

Publications and source records attributed to M J Fryer.

16 recordsLinked to original sources
PubMed2002

Rationale for clinical trials of selenium as an antioxidant for the treatment of the cardiomyopathy of Friedreich's ataxia.

A pure selenium deficiency is harmful to the heart and causes a fatal dilated congestive cardiomyopathy in animals (white muscle disease) and in man (Keshan disease). Both of these syndromes are selenium-responsive. A deficiency of the micronutrient has also been reported in patients with Friedreich's ataxia and there are histological similarities between Friedreich's cardiomyopathy and Keshan disease. A low selenium status results in reduced selenium-dependent glutathione peroxidase activity. This essential antioxidant enzyme protects membrances from oxidative deterioration, a function it shares in common with vitamin E. As iron-induced mitochondrial lipid peroxidation is central to the pathology of Friedreich's ataxia, the administration of selenium supplements should normalize the antioxidant activity of myocardial glutathione peroxidase and slow the progression of the life-shortening cardiomyopathy associated with this illness.

Animals↗
PubMed1998

The possible role of nitric oxide and impaired mitochondrial function in ataxia due to severe vitamin E deficiency.

Ataxia due to prolonged vitamin E (RRR-alpha-tocopherol) deficiency still remains the only human neurodegenerative disorder that can be positively attributed to insufficient levels of an essential antioxidant. In affected nerve cells during vitamin E deficiency there is an increase in peroxidation of mitochondrial membranes and a progressive reduction in respiration-dependent axonal transport processes, ultimately resulting in cell death. The possibility of inhibition of electron transport and the increased generation of oxygen radicals that may arise due to prolonged exposure to the toxic nitric oxide radical within mitochondria of vitamin E-deficient neurones is discussed as a pathway to nerve cell death that is characteristically seen in the syndrome.

Ataxia↗
PubMed1993

Evidence for the photoprotective effects of vitamin E.

The antioxidant vitamin E (alpha-tocopherol) may protect both animal and plant cell membranes from light-induced damage. The various biochemical and biophysical modes of protection are considered. An examination is made of the evidence that vitamin E plays an important prophylactic role against a number of serious light-induced diseases and conditions of the eye (cataractogenesis and retinal photodeterioration) and skin (erythrocyte photohemolysis, photoerythema, photoaging and photocarcinogenesis) that are mediated by photooxidative damage to cell membranes.

Animals↗
PubMed1991

Desensitization of rat osteoblast-like cells (ROS 17/2.8) to parathyroid hormone uncouples the adenosine 3',5'-monophosphate and cytosolic ionized calcium response limbs.

We have investigated the effects of PTH-induced desensitization on second messenger interactions in the rat osteosarcoma cell line ROS 17/2.8. Adenylate cyclase activation was assessed by accumulation of immunoassayable cAMP, and cytosolic calcium ion ([Ca2+]i) concentrations were measured in adherent perifused cells loaded with the Ca2(+)-sensitive bioluminescent protein aequorin. Preexposure to rat PTH-(1-34) [rPTH-(1-34); 10(-8) M for 48 h, then 10(-7) M for 24 h] dramatically reduced (by 85%) the cAMP response to fresh challenge [2 min; 10(-9)-10(-7) M rPTH-(1-34)], but the peak PTH-induced rise of [Ca2+]i was not diminished significantly (0-20%). Nevertheless, we did observe other changes in the PTH-induced [Ca2+]i response. Exposure of treated cells to (Bu)2cAMP nearly abolished the [Ca2+]i response to PTH (greater than 80% reduction), but had much less effect on the PTH-stimulated [Ca2+]i increment of the naive cells (less than 35% reduction). Treated cells also had a blunted [Ca2+]i response to PTH in the presence of low extracellular calcium (greater than 60% reduction), but in the naive cells, low extracellular Ca2+ did not significantly diminish the peak PTH-induced [Ca2+]i rise, although low extracellular Ca2+ dramatically reduced the area under this [Ca2+]i transient (greater than 50%). Low extracellular Ca2+ had no influence on the peak [Ca2+]i responses of treated cells to bradykinin or prostaglandin F2 alpha. Although the peak PTH-stimulated [Ca2+]i rise of treated cells in normal Ca2+ medium was not significantly attenuated, the time to half-maximum [Ca2+]i concentration was significantly increased (greater than 100%), and the area under the [Ca2+]i transient was diminished. These alterations in the [Ca2+]i response of treated cells were not observed upon challenge with bradykinin or prostaglandin F2 alpha. Thus, 1) the cAMP and [Ca2+]i responses of ROS 17/2.8 cells to rPTH-(1-34) are not obligatorily coupled; 2) the response of naive cells to PTH includes both the release of Ca2+ from intracellular stores and the entry of extracellular Ca2+; and 3) pretreatment of these cells with rPTH-(1-34) augments the dependence on Ca2+ entry during hormone rechallenge. We propose that the preserved PTH-stimulated [Ca2+]i rise in treated cells results partly from loss of cAMP-mediated inhibition of extracellular Ca2+ entry.

Animals↗
PubMed1991

Parathyroid hormone (PTH)-induced intracellular Ca2+ signalling in naive and PTH-desensitized osteoblast-like cells (ROS 17/2.8): pharmacological characterization and evidence for synchronous oscillation of intracellular Ca2+.

We showed recently that the initial peak cytosolic ionized calcium ([Ca2+]i) response to PTH (2-min exposure) is preserved relative to the cAMP response in osteoblast-like rat osteosarcoma cells (ROS 17/2.8) desensitized by 72-h exposure to PTH. We attempted in the present studies to determine the mechanisms for preservation of the [Ca2+]i response and to explore the effects of longer PTH rechallenges. The [Ca2+]i response to a 20-min perifusion with rat PTH [rPTH-(1-34)] was monitored by aequorin luminescence in both naive and PTH-desensitized ROS 17/2.8 cells. The responses of both naive and desensitized cells consisted of two phases: an initial peak, followed by an intermediate plateau that was sustained in the presence of PTH. We observed in the naive cell populations synchronous oscillations in [Ca2+]i concentration during this second phase (amplitude, 10-60 nM; frequency, 1-3/100 sec). These oscillations were maintained through extracellular calcium (EC Ca2+) entry; the initial peak was the result of Ca2+ release from intracellular stores. In desensitized cells, these two phases could not be clearly separated with respect to Ca2+ source, but, as we showed before, exhibited an enhanced dependence on EC Ca2+ entry for the response to PTH. Nevertheless, in the desensitized cells, the sustained [Ca2+]i response was diminished in magnitude and showed little oscillatory behavior. Brief exposure to neomycin sulfate, an inhibitor of phosphoinositide turnover, attenuated the PTH-induced [Ca2+]i rise in both naive and desensitized cells. Protein kinase-C activity did not appear to be required for either phase of the PTH-induced [Ca2+]i response. Exposure to cholera toxin attenuated the [Ca2+]i response to hormone in both naive and desensitized cells, more markedly in the latter. Cholera toxin treatment dramatically increased basal cAMP levels in both cell preparations; PTH-stimulated cAMP production was unchanged in naive cells, but increased nearly 4-fold in desensitized cells. We propose that the preserved PTH-induced peak [Ca2+]i rise in desensitized cells results primarily from the diminished regulation of EC Ca2+ entry by the cAMP response limb. The attenuated sustained oscillatory behavior observed in desensitized cells upon rechallenge with hormone may be the result of reduced phosphoinositide turnover and reduced Ca2+-stimulated Ca2+ release. Thus, the [Ca2+]i response to PTH in osteoblast-like cells is complex and modulable and seems to provide a number of ways to regulate intracellular metabolism under various conditions. We speculate that this plasticity of the [Ca2+]i response to PTH is related to the pleiotropic actions of the hormone on cells of the osteoblast lineage.

Animals↗
PubMed1990

Structure-function relationships for full-length recombinant parathyroid hormone-related peptide and its amino-terminal fragments: effects on cytosolic calcium ion mobilization and adenylate cyclase activation in rat osteoblast-like cells.

PTH-related peptide (PTHrP) may be a major cause of the humoral hypercalcemia of malignancy. The circulating form of PTHrP is unknown, but mRNA analysis of tumor tissue suggests that multiple forms of PTHrP may exist. Therefore, we examined the ability of the full 141-amino acid protein as well as 2 amino-terminal fragments, PTHrP-(1-34) and PTHrP-(1-74), to increase cytosolic calcium ion concentrations ([Ca2+]i; assessed by aequorin luminescence) and stimulate cAMP accumulation in osteoblast-like rat osteosarcoma cells (ROS 17/2.8). PTH and all PTH-related peptides examined increased [Ca2+]i and cAMP in a concentration-dependent manner. The [Ca2+]i response to PTHrP-(1-34) closely resembled that to rat PTH-(1-34); both peptides produced biphasic responses. However, the responses to the longer PTHrP fragments generally were not biphasic. There were no significant differences among the three PTHrP forms in increasing [Ca2+]i or stimulating cAMP accumulation, although PTHrP-(1-74) was consistently weaker than the other two PTHrP peptides. PTHrP-(1-34) was more potent than rPTH-(1-34), which, in turn, was more potent than human PTH-(1-34) in increasing [Ca2+]i. However, PTHrP-(1-34) was not consistently more potent than either human PTH-(1-34) or rat PTH-(1-34) in stimulating cAMP accumulation. The inhibitory PTH analog bovine PTH-(3-34) attenuated both cAMP and [Ca2+]i responses to PTHrP-(1-34), but bovine PTH-(7-34) only reduced the [Ca2+]i response. Our data are generally consistent with PTHrP's acting through the PTH receptor, but differences in the effects of inhibitory PTH analogs on PTH and PTHrP action suggest as yet unexplained complexities, such as the existence of a PTH/PTHrP receptor family.

Adenylyl Cyclases↗
PubMed1988

Differential effects of parathyroid hormone and its analogues on cytosolic calcium ion and cAMP levels in cultured rat osteoblast-like cells.

While the stimulatory effect of parathyroid hormone (PTH) on osteoblast-like cell adenylate cyclase is well known, the effect of PTH on cytosolic calcium ion ([Ca2+]i) mobilization is controversial, one group finding no effect but others reporting various increases. We investigated the effects on [Ca2+]i of synthetic rat PTH fragment 1-34 (rPTH(1-34)) and two bovine PTH analogues that inhibit PTH's stimulation of adenylate cyclase (bovine 8,18Nle, 34Tyr-PTH(3-34) and 34Tyr-PTH(7-34]. [Ca2+]i was measured before, during, and after exposure to PTH analogues in perifused, attached osteoblast-like rat osteosarcoma cells (ROS 17/2.8) that had been scrape-loaded with the luminescent photoprotein aequorin. Resting [Ca2+]i was 0.094 +/- 0.056 microM (mean +/- S.D., n = 103) and rose in a time- and dose-specific way after exposure to rPTH(1-34). At 10(-10) M rPTH(1-34), [Ca2+]i rose 100% within 30 s to a plateau; higher concentrations of PTH yielded increasing initial peaks of [Ca2+]i followed by lower plateaus. At 10(-6) M, the initial peak was 5-fold basal, or 0.64 +/- 0.07 microM. Both analogues of PTH were at least partial agonists for [Ca2+]i mobilization and did not reduce peak [Ca2+]i when co-perifused with rPTH(1-34). However, the analogues did reduce significantly rPTH(1-34)-induced cAMP accumulation and did not increase cAMP accumulation by themselves. Thus, rPTH(1-34) strongly mobilizes [Ca2+]i in ROS 17/2.8 cells, at near-physiologic concentrations. Failure of the PTH analogues to block the effect of PTH on [Ca2+]i while inhibiting the effect on cAMP accumulation suggests separate pathways for PTH activation of adenylate cyclase and mobilization of calcium.

Adenylyl Cyclases↗
PubMed1988

Specific effect of putative 5-HT1A agonists, 8-OH-DPAT and gepirone, to increase hypertonic saline consumption in the rat: evidence against a general hyperdipsic action.

Previous reports indicate that 5-HT1A agonists, in addition to benzodiazepines, increase the consumption of hypertonic saline in rehydrating rats. Experiment 1 investigated the effects of 8-OH-DPAT (10-100 micrograms/kg) and gepirone (0.1-3.0 mg/kg) on consumption of water and of saline over a range of concentrations (0.45%-2.8%) in a 30 min drinking test. The two 5-HT1A agonists dose-dependently increased ingestion of two hypertonic salt solutions, but produced little or no increase in the drinking of water, hypotonic or isotonic saline. Experiment 2 demonstrated that 8-OH-DPAT and gepirone did not enhance water consumption in animals given a water preload, or markedly increase drinking quinine-adulterated water. Taken together, the results indicate a selective dose-related effect of the two drugs to increase hypertonic saline drinking; they did not have a general hyperdipsic effect across all salt and water conditions, and they did not increase intake simply because of a low baseline level of consumption. Hence, 5-HT1A agonist act much more selectively than benzodiazepines in their effects on drinking responses.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1986

Accumulation of cyclic 3',5'-adenosine monophosphate in cultured neonatal human dermal fibroblasts exposed to parathyroid hormone and prostaglandin E2.

We sought to determine whether cultured human dermal fibroblasts respond to parathyroid hormone (PTH) with accumulation of cyclic 3',5'-adenosine monophosphate (cAMP) reproducibly enough for such cells to be useful in characterizing states of altered end-organ response to PTH. Thus, we cultured fibroblasts from 15 human neonatal foreskins and tested fibroblast cAMP responses to addition of synthetic human PTH-(1-34), bovine PTH-(1-34), and native bovine PTH-(1-84) at concentrations of 10(-6) to 10(-10) M. Accumulation of cAMP (cells plus medium) was significantly enhanced by PTH in only 10 of 37 experiments. In cells that had a significant cAMP response to PTH, the ratio of treated to control cAMP values ranged only from 1.27 to 2.18. No study showed a clear-cut dose-response relationship. In six of six experiments, the cells responded to prostaglandin E2 (1 microgram/ml) with markedly increased accumulation of cAMP (9.7 to 110.9-fold the basal value). We conclude that cultured human dermal fibroblast cAMP responses to PTH with use of the current methods are too small and inconsistent for that tissue to be useful in studies of reduced end-organ responsiveness to PTH such as pseudohypoparathyroidism. Nevertheless, states of hyperresponsiveness to PTH might still be detectable by this method.

1-Methyl-3-isobutylxanthine↗
PubMed1985

Structural requirements for parathyroid hormone action in mature bone. Effects on release of cyclic adenosine monophosphate and bone gamma-carboxyglutamic acid-containing protein from perfused rat hindquarters.

To determine the structural requirements for parathyroid hormone (PTH) activity in mature bone, we perfused the surgically isolated hindquarters of adult male rats with either native bovine PTH-(1-84) [bPTH-(1-84)] or the synthetic amino-terminal fragment, bovine PTH-(1-34) [bPTH-(1-34)]. Changes in the release of cyclic AMP (cAMP) and bone Gla protein (BGP) were monitored as evidence of bone-specific response to PTH; tissue specificity of the cAMP response was confirmed through in vitro examination on nonskeletal tissue response to PTH. Biologically active, monoiodinated 125I-bPTH-(1-84) was administered to determine if mature murine bone cleaves native hormone. We found that perfused rat bone continuously releases BGP, and that both bPTH-(1-84) and bPTH-(1-34) acutely suppress this release. In addition, both hormones stimulate cAMP release from perfused rat hindquarters. When examined on a molar basis, the magnitude of the cAMP response was dose-dependent and similar for both hormones, with doses yielding half-maximal cAMP responses. The response for bPTH-(1-34) was 0.5 nmol and for bPTH-(1-84) was 0.7 nmol. Moreover, biologically active 125I-bPTH-(1-84) was not metabolized in our hindquarter perfusion system. These findings indicate that PTH-(1-84) does not require extraskeletal or skeletal cleavage to an amino-terminal fragment in order to stimulate cAMP generation in, or suppress BGP release from, mature rat bone.

Animals↗
PubMedDate not supplied

Vitamin E may slow kidney failure owing to oxidative stress.

Progression to kidney failure in a number of major renal diseases is now thought to be significantly worsened by oxidative stress at the biochemical level. Evidence is accumulating that the rate of deterioration could, in many cases, be slowed down to a more acceptable level by the simple expedient of dietary supplementation with the antioxidant, vitamin E. Evidence for the potential use of vitamin E as an adjunctive therapy to help prolong kidney function in conditions that are accelerated by oxidative stress is discussed.

Animals↗