CSF soluble proteins and vigabatrin.
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Aminocaproates↗
Biomedical subjects
L Persson
Publications and source records attributed to L Persson.
L-ornithine-induced inactivation of mammalian ornithine decarboxylase in vitro.
Partially purified ornithine decarboxylase, isolated from the liver of thioacetamide-treated rats, is stable in the absence of added low-molecular-mass thiols or other reducing agents. However, under these conditions, the enzyme is rapidly inactivated upon incubation with L-ornithine or L-2-methylornithine. The inactivation process follows first-order kinetics, and saturation kinetics are observed. Rapid recovery of activity is observed after subsequent addition of dithiothreitol. As distinct from L-ornithine, D-ornithine, putrescine, spermidine, or spermine do not produce inactivation of ornithine decarboxylase. Very similar results are obtained with pure ornithine decarboxylase isolated from androgen-stimulated mouse kidney, stabilized with a rat liver extract.
Animals↗
Evidence for the existence of ornithine decarboxylase-immunoreactive neurons in the rat brain.
By means of polyclonal antibodies against purified mouse kidney ornithine decarboxylase (ODC) and using the biotin-avidin immunoperoxidase procedure in combination with image analysis the cellular localization and distribution of ODC immunoreactivity (ODC IR) have been demonstrated in the rat brain. ODC IR was located in a large number of neuronal populations. A nuclear ODC IR was always present but in many neurons also a cytoplasmic localization of ODC IR was demonstrated (dendrites, axons and putative terminals). Based on the present findings central neurons may be mapped out not only on the basis of their transmitter contents but also on the basis of their contents of trophic factors.
Animals↗
Localization of ornithine decarboxylase in the chick embryo during organogenesis.
The localization of ornithine decarboxylase (ODC), a key enzyme in polyamine biosynthesis and thus in cell growth, was determined in the 4.5-day-old chick embryo, using two independent methods of analysis. ODC protein was identified by indirect immunofluorescence with a monospecific ODC antibody, and catalytically active ODC was identified by autoradiography with alpha-(5-3H) difluoromethylornithine. Both methods revealed a basically similar distribution of ODC within the embryo. Among the organs, the brain exhibited the highest ODC levels. ODC levels were also high in spinal cord, mesonephric tubules and heart. Similar levels, but confined to limited areas, were found in liver tissue, head mesenchyme, and the oral and pharyngeal regions. Organs that exhibited high ODC levels are all engaged in rapid growth, as well as in extensive tissue remodeling and differentiation.
Animals↗
Somatomedins in tumour cyst fluid, cerebrospinal fluid, and tumour cytosol in patients with glial tumours.
In the present study, the levels of the growth-promoting hormones, somatomedins, were analysed in tumour cyst fluid, CSF, and tumour cytosol, collected from 22 unselected patients with intracranial tumours. All samples contained somatomedin activity. 5/7 CSF samples, taken from patients with tumour mass visible on CT, showed elevated concentrations. 6/9 cyst fluid samples, taken from patients with glioma were elevated compared with normal serum somatomedin levels. Tumour cytosol, taken from 7 patients with malignant glioma contained somatomedins in an elevated level compared with values previously analysed from normal adult brains. These preliminary findings demonstrate for the first time the presence of somatomedins in brain tumours and suggest the use of somatomedins as a possible brain tumour marker.
Adult↗
Dopaminergic regulation of polyamine synthesis in the rat pituitary gland.
The biosynthesis of polyamines, a group of growth-related amines, varied in the rat pituitary gland with the different stages of the estrous cycle. The activity of ornithine decarboxylase (ODC), which catalyzes the rate-limiting step in the biosynthesis of polyamines, was greatly increased in the pituitary gland during the evening of proestrus. Ovariectomy resulted in a disappearance of this cyclic change in polyamine synthesis, whereas estrogen treatment of the ovariectomized rats gave rise to daily afternoon peaks in pituitary ODC activity. Like the prolactin cells, pituitary polyamine biosynthesis appeared to be regulated by dopamine. The induction of ODC activity in the pituitary gland during proestrus or after estrogen treatment was almost completely repressed by bromocriptine, a dopaminergic compound. The dopamine antagonist haloperidol, on the other hand, was a potent inducer of pituitary ODC activity. Neither pituitary DNA synthesis nor prolactin secretion, which both are induced by estrogen, were affected by inhibition of polyamine synthesis, suggesting a biological function of the pituitary polyamines unrelated to these events.
Animals↗
Regulation of ovarian ornithine decarboxylase by human chorionic gonadotrophin.
Treatment of 29-day-old female Sprague-Dawley rats with human chorionic gonadotrophin (hCG) produced a large and rapid increase in the activity of ornithine decarboxylase. Measurements that use a specific radioimmunoassay showed that the increased activity could be accounted for by a parallel change in the amount of ornithine decarboxylase protein. The increased protein content was caused by an increased rate of synthesis, since the half-life of ornithine decarboxylase was not changed by the hormone treatment. The content of mRNA for ornithine decarboxylase was determined by hybridization with a cDNA probe, and it was found that the increased amount of protein was correlated with a change in the amount of mRNA. These results indicate that treatment with hCG induces ornithine decarboxylase in the rat ovary by increasing the production or the stability of the mRNA for this enzyme. The increased amount of ornithine decarboxylase led to an increase in putrescine in the ovary but did not increase the content of the polyamines spermidine and spermine. These findings show that, despite its rapid and large scale induction, ornithine decarboxylase is not the rate-limiting step that determines the content of these polyamines in this tissue. They also suggest that putrescine itself may play an important role in the ovary.
Animals↗
Ornithine decarboxylase activity and polyamine content in normal renal tissue and in renal carcinoma.
Ornithine decarboxylase (ODC) activity and contents of putrescine, spermidine and spermine were determined in cortical and medullary tissue and clear cell tumours in human kidneys. Medullary ODC activity was 75 +/- 9% (n = 6; p less than 0.05) of the respective cortical value. The ODC activity in renal tumours varied considerably but did not differ significantly from the respective cortical values. Similar concentrations of putrescine were found in cortex and medulla, but a 5-fold increase was found in the tumours (p less than 0.02). Significantly lower values (p less than 0.01) of spermidine and spermine were found in medulla when compared to cortex. No significant change was found for these amines in the carcinomas when compared with corresponding cortical tissue.
Adult↗
Fracture of hip prostheses due to inadequate welding.
Twenty-five patients underwent total hip arthroplasty using a copy of a well-known prosthesis during the period 1974-1976. Five of the prostheses fractured through the neck after 5-12 years. There were no prodromal symptoms and no trauma preceded the fractures. Technical analysis revealed that inadequate welds were responsible.
Aged↗
Translational regulation of ornithine decarboxylase by polyamines.
The activity of ornithine decarboxylase (ODC), the first and rate-limiting enzyme in the polyamine biosynthetic pathway, is dramatically increased in proliferating cells. In addition to transcriptional regulation of ODC, the present study shows that the enzyme is regulated at the translational level by putrescine and spermidine. ODC synthesis is inhibited by an increase and stimulated by a decrease in their cellular content. Spermidine is a more potent negative regulator than is putrescine. The effects of polyamines on ODC synthesis were not attributable to changes in the cellular content of ODC mRNA, thus demonstrating regulation at the translational level.
Animals↗
Synergistic antileukemic effect of two polyamine synthesis inhibitors. Host survival and cell-cycle kinetic analysis.
alpha-Difluoromethylornithine (DFMO), an enzyme-activated irreversible inhibitor of ornithine decarboxylase, was used alone and in combination with multiple doses of methylglyoxal-bis(guanylhydrazone) (MGBG) to treat mice with systemic L1210 leukemia. Used as a single agent (administered p.o. as a 3% solution in tap water), DFMO exerted a weak therapeutic effect against this tumor. The therapeutic effect of MGBG (administered i.p. at 50 mg/kg/day) was only slightly better. However, 1-3 days of pretreatment with DFMO strongly potentiated the effect of MGBG treatment. Thus, mice treated with the combination exhibited an increase in life span of up to 138%. The prolonged survival of leukemic mice treated with a combination of DFMO and MGBG was associated with inhibition of polyamine synthesis and a marked decrease in the spermidine and spermine content of the tumor cells as compared to untreated controls. As a consequence, there was a continuous decrease in the S- and G2-phase fractions with a concomitant increase in G1. Used singly, DFMO and MGBG had no significant effect on the cell-cycle distribution. The effects of the combination of DFMO and MGBG on the cell-cycle distribution are consistent with the contention that polyamine deficiency primarily interferes with initiation of DNA synthesis. However, the possibility that selective S-phase kill partly contributes to this change in cell-cycle distribution cannot be excluded.
Adenosylmethionine Decarboxylase↗
Thymidine kinase in extracts of human brain tumours.
Deoxythymidine kinase (TK) is an enzyme involved in DNA synthesis. It can be used as a marker of cell proliferation. TK was measured in extracts of human brain tumours and non-neoplastic brain tissue. In astrocytomas the mean TK activity increased with increasing grade of malignancy. Oligodendrogliomas showed higher TK activity than astrocytomas. The highest activities were noted in menigiomas, of which the recurrent ones exceeded the primary in TK activity. In non-neoplastic brain tissue lower TK activity was found. It is concluded that TK can be measured in human brain tumour extracts, and is potentially of use for studies on tumour cell proliferation.
Astrocytoma↗
Enhancement of insulin-like growth factor 2 receptors in glioblastoma.
The somatomedins (IGF-1/IGF-2) are a family of growth-promoting hormones which have been identified in the human central nervous system where their specific receptors are distributed. The present study identified somatomedin receptors in glioblastoma and compared them with those found in normal brain. A significant enhancement in the binding of 125I-IGF-2 but not 125I-IGF-1 to glioblastoma membranes was found. A fourfold increase in IGF-2 receptor concentration was observed. These findings indicate enhanced expression of the IGF-2 receptor in glioblastoma.
Brain Chemistry↗
Contact allergy to 4,4'-dihydroxy-(hydroxymethyl)-diphenyl methanes: sensitizers in a phenol-formaldehyde resin.
A particular phenol-formaldehyde resin of the resol type (P-F-R-2) was shown in a previous study to be a good tracer of patients with contact allergy to phenol-formaldehyde resins. Eleven patients with sensitivity to P-F-R-2 participated in the study in which chromatographically separated fractions of P-F-R-2 were patch tested. This procedure was repeated until a positive reaction to a single substance was noted. In this study 3 new sensitizers are reported. Investigations by mass spectrometry and nuclear magnetic resonance spectrometry identified the compounds to be 4,4'-dihydroxy-3-(hydroxymethyl)-diphenyl methane (4,4'-H-3-HPM), 4,4'-dihydroxy-3,3'-di-(hydroxymethyl)-diphenyl methane (4,4'-H-3,3'-HPM), and 4,4'-dihydroxy-3,5-di-(hydroxymethyl)-diphenyl methane (4,4'-H-3,5-HPM). Six of the 11 patients reacted to at least one of these compounds. All 6 patients reacted to 4,4'-H-3,3'-HPM and 5 reacted simultaneously to 4,4'-H-3-HPM. Four patients reacted to all 3 compounds tested. By patch testing with serial dilutions (ethanol 99.5%) of the three 4,4'-H-HPM, positive reactions were noted down to 0.5 X 10(-6)%, 1.0 X 10(-6)%, and 1.3 X 10(-3)% w/v for 4,4'-H-3-HPM, 4,4'-H-3,3'-HPM, and 4,4'-H-3,5-HPM, respectively.
Allergens↗
Demonstration of contact sensitizers in resins and products based on phenol-formaldehyde.
12 phenol-formaldehyde resins were investigated with regard to the presence of 14 contact sensitizers by using high-pressure liquid chromatography. The allergens consisted of simple methylol phenols, dihydroxydiphenyl methanes, 4,4(1)-dihydroxy-(hydroxymethyl)-diphenyl methanes and 2,4(1)-dihydroxy-(hydroxymethyl)-diphenyl methanes. Four substances, 2,4-dimethylol phenol, 2,6-dimethylol phenol, 4,4(1)-dihydroxydiphenyl methane and 2,4(1)-dihydroxydiphenyl methane, were isolated from a resol resin and identified by mass-spectrometry and nuclear magnetic resonance spectrometry. The highest concentrations (up to 15% w/w) of allergens were noted for methylol phenols in resol resins based on phenol and formaldehyde. The corresponding novolak resins showed a high content of dihydroxydiphenyl methanes. There was great variation in concentration of the sensitizers between the resins. None of these sensitizers were demonstrated in the resin based on paratertiary-butyl phenol. Products based on phenol-formaldehyde resins were also investigated for the presence of allergens. Uncured impregnated paper for laminate production and uncured mineral wool contained the same concentrations of the sensitizers as some of the resins studied. The curing process decreased the content of all the allergens investigated in all products, but the sensitizers did not disappear, and they may thus be present in finished products.
Allergens↗
Distribution of ornithine decarboxylase in ovaries of rat and hamster during pro-oestrus.
The biosynthesis of polyamines is dramatically increased in the ovaries of rat and hamster during the evening of pro-oestrus. In an attempt to shed some light on the physiological function of this biosynthesis ornithine decarboxylase (ODC), which catalyzes the rate-limiting step in the biosynthesis of the polyamines, was immunohistochemically localized in the ovaries from rat and hamster during pro-oestrus. At dioestrus, only a few immunoreactive cells were found in the ovaries. During the evening of pro-oestrus, on the other hand, numerous immunoreactive cells were observed in the ovaries. These cells were confined to the internal thecal layer of Graafian as well as smaller follicles and to the interstitial tissue of the ovary. The granulosa cells appeared to be devoid of immunoreactive ODC. The hamster ovary, which during this time exhibited considerably higher levels of ODC activity than the ovaries from the rat, did accordingly contain more immunoreactive cells than the rat ovary.
Animals↗
Induction of spermidine/spermine N1-acetyltransferase by methylglyoxal bis(guanylhydrazone).
The anti-tumor agent methylglyoxal bis(guanylhydrazone) was found to be a competitive inhibitor of spermidine/spermine N1-acetyltransferase with a Ki of about 8 microM. Treatment of rats with this drug lead to a very large increase in the total amount of spermidine/spermine N1-acetyltransferase in liver, kidney and spleen. The total increase as measured using a specific antiserum amounted to 700-fold in liver and 100-fold in kidney within 18 h of treatment with 80 mg/kg doses. At least part of this induction was due to a pronounced increase in the half-life of the acetyltransferase which increased from 15 min to more than 12 h. The very large increase in the amount of the enzyme is likely to overwhelm the direct inhibition, and a net increase in the acetylation of polyamines by this enzyme would be expected to occur after treatment with methylglyoxal bis(guanylhydrazone). The acetylated polyamines are known to be rapidly degraded by polyamine oxidase producing putrescine. Direct evidence that a substantial part of the increase in the content of putrescine in the liver of rats treated with methylglyoxal bis(guanylhydrazone) occurs via the induction of this acetylase/oxidase pathway was obtained. These results indicate that methylglyoxal bis(guanylhydrazone) affects cellular polyamine levels not only by means of its inhibitory effect on S-adenosylmethionine decarboxylase and diamine oxidase but also by the induction of spermidine/spermine N1-acetyltransferase. They also raise the possibility that the enormous increase in this enzyme which occurs with higher doses may contribute to the very severe toxicity of methylglyoxal bis(guanylhydrazone).
Acetyltransferases↗
Ornithine decarboxylase inhibitors increase the cellular content of the enzyme: implications for translational regulation.
Ehrlich ascites tumor cells grown in the presence of inhibitors of ornithine decarboxylase (EC 4.1.1.17) exhibited an elevated content of this enzyme. The increase could not solely be explained by a decrease in the degradation rate of the enzyme. Instead a stimulation of enzyme synthesis, probably mediated via the polyamine-depleting properties of the inhibitors, is suggested. The enhancement of cellular ornithine decarboxylase content was not accompanied by any significant changes in the amount of ornithine decarboxylase mRNA, indicating a regulation at the level of translation.
Animals↗