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PubMed1976

Prevention of induced atherosclerosis by diversion of bile or blockade of intestinal lymphatics in dogs.

The prevention of induced hypercholesterolemia and atherosclerosis was studied by means of intestinal lymphatic blockade and of bile diversion in the dog. Hypercholesterolemia and atherosclerosis were produced by high cholesterol feeding after induction of hypothyroidism with radio-iodine plus thiouracil. Complete diversion of bile, by shunting all bile into the urinary bladder, effectively prevented hypercholesterolemia and atherosclerosis; in contrast, blockade of the intestinal lymphatics failed to prevent the consequences of the atherogenic regimen, because of the development of collateral lymphatic channels.

Animals↗
PubMed1996

Influence of the low thyroid state in diabetes mellitus on cardiac function and inotropic responsiveness to alpha 1-adrenoceptor stimulation: comparison with the role of hypothyroidism alone.

The hypothyroid state accompanying diabetes mellitus has been suggested to be partly responsible for the diabetes-induced metabolic, hemodynamic, and pharmacological cardiovascular changes. We assessed the effectivity of streptozotocin (STZ) to induce diabetes mellitus and a hypothyroid state. Furthermore, we investigated the influence of diabetes and hypothyrodism on cardiac function and the inotropic responsiveness to the alpha 1-adrenoceptor agonist cirazoline in isolated perfused hearts. Fasted or nonfasted Wistar rats were made diabetic with STZ 20, 40 or 60 mg/kg intravenously (i.v.). Another group was made hypothyroid by addition of 6-n-propyl-2-thiouracil (PTU) to their drinking water. Rats receiving PTU became hypothyroid, whereas rats receiving STZ became simultaneously diabetic and hypothyroid. Basal functional parameters obtained in isolated perfused hearts were not influenced by diabetes, whereas maximal contractility was reduced in hearts obtained from hypothyroid animals. Cardiac inotropic responses to cirazoline were increased in diabetic rats, whereas responses in hypothyroid rats were not different from those in hearts obtained from control animals. Although diabetes mellitus and hypothyroidism are associated with various similar metabolic and haemodynamic parameters, the increased inotropic response to alpha 1-adrenoceptor stimulation as observed in isolated perfused hearts of diabetic rats cannot be explained by the decrease in serum thyroxine levels.

Adrenergic alpha-Agonists↗
PubMedDate not supplied

Reversible depigmentation of human melanoma cells by halistanol trisulphate, a novel marine sterol.

The pigmented human melanoma cell line, MM418, became demelanized when treated continuously with a nontoxic level of halistanol trisulphate (HTS), a C29 steroidal detergent isolated from a marine sponge. Nontoxic levels of halistanol or of a range of anionic, cationic and neutral detergents had no such effect. Control MM418 cells varied greatly in size, appearance and pigmentation; HTS-treated cells were smaller than controls, had a uniform, generally bipolar appearance, and lacked pigment. HTS induced only minor changes in cell ultrastructure, with fewer mature melanosomes being found in treated cells. Suppression of melanin synthesis was apparent within 24 h of addition of HTS, as judged by inhibited incorporation of the false precursor, 5[125I]-2-thiouracil. Reversal of inhibition occurred within the same period after removal of HTS. Tyrosinase activity gradually decreased to 25% of the control value during a 19-day treatment with HTS, and expression of two carbohydrate-dependent tyrosinase epitopes, 5C12 and 2B7, was abolished. Expression of one other melanosomal protein and of vimentin was not affected. The results suggest that HTS inhibits maturation of tyrosinase to a form associated with melanin synthesis.

Animals↗
PubMed1996

Thiourea as a melanoma targeting agent.

It has previously been shown that various thiourea derivatives are incorporated into nascent melanin, and a few of these substances, e.g. 2-thiouracil and its radioiodinated analogue, have been used for selective targeting of melanotic melanoma. Possible localization of thiourea itself in melanoma, however, has not been investigated so far. We have therefore performed the present autoradiographic and impulse counting study on the disposition of 14C-thiourea in mice transplanted with B16 melanoma. The results demonstrated a pronounced, but partly heterogeneous, uptake of radioactivity in the melanoma tissue, with the highest concentration 4 h after the injection. Four days after the administration of a single dose, the retention of label was still high in certain tumoral areas. The lung was the only normal tissue with a similarly high uptake of radioactivity. Additional experiments in vitro showed that the incorporation of thiourea into melanin was dose-dependent. The binding to performed melanin was found to be low, which strongly indicates that the incorporation of thiourea into melanin mainly is due to interaction with intermediates of the melanin synthetic pathway.

Animals↗
PubMed1966

Auxin stimulation of ethylene evolution.

The stimulation of ethylene production from seedling tissue of Phascolus vulgaris, Helianthus annuus and Zea mays by growth regulators was inhibited by actinomycin D and puromycin and to a lesser extent by 2-thiouracil and p-fluorophenylalanine. It is concluded that the mechanism of action of growth regulators on the enhancement of ethylene production is the formation of enzymes involved in ethylene biogenesis.

Journal Article↗
PubMed1968

The induction of biplanar growth in fern gametophytes in the presence of RNA base analogues.

The RNA base analogues, 5-fluorouracil, 2-thiouracil, and 8-azaguanine, inhibit the growth of Dryopteris borreri, but do not prevent the transition from filamentous to biplanar growth. Transition, which occurs only when the filament has developed to 4 or 5 cells, may be considerably delayed, due to inhibition of filamentous growth, but it always occurs when the critical cell number of the filament is reached. Furthermore, the inhibitors show only a marginal differential effect on biplanar compared to filamentous growth when the growth rates are determined from kinetic studies. It is suggested that the selective effects previously reported may result from the experimental techniques used, coupled with the actual growth characteristics of the gametophyte.

Journal Article↗
PubMed1995

Endothelin-1 as a new melanogen: coordinated expression of its gene and the tyrosinase gene in UVB-exposed human epidermis.

We previously demonstrated that human keratinocytes produce and secrete endothelins (ET), which can be strong mitogens for human melanocytes. Ultraviolet B (UVB) exposure highly stimulated the paracrine linkage of endothelins between keratinocytes and melanocytes, indicating that they are keratinocyte-derived intrinsic mitogens in UVB-induced pigmentation. In this study, the role of ET-1 as a melanogen in UVB melanogenesis was investigated in vitro and in vivo. In the conditioned medium of keratinocytes exposed to UVB, melanin synthesis by human melanocytes, as measured by 14C-thiouracil incorporation, was significantly accentuated. This stimulatory effect was reduced by anti-ET-1 to the level of that in the non-UVB-exposed control, suggesting an essential role of ET-1 as an intrinsic melanogen in UVB-induced melanogenesis. In a parallel study, the addition of 10 nM ET-1 induced an increase in tyrosinase activity in cultured human melanocytes and was accompanied by elevated levels of tyrosinase and tyrosinase-related protein-1 mRNA expression as shown by Northern blotting. Reverse transcription-polymerase chain reaction of RNA isolated from the epidermis of human skin exposed to UVB revealed that, whereas in non-exposed sites ET-1, IL-1 alpha, and tyrosinase mRNA signals were scarcely detected, UVB-irradiation, with a dose of twice the minimal erythema dose, caused a significant increase in the expressions of the three genes 5 d after irradiation. These findings suggest that ET-1 is an important mediator for UVB-induced pigmentation in the epidermis in vivo.

Base Sequence↗
PubMed1992

Allergic contact dermatitis releases soluble factors that stimulate melanogenesis through activation of protein kinase C-related signal-transduction pathway.

Phenylazo-naphthol (PAN) allergy induces visibly well-defined and late-appearing hyperpigmentation of brownish yellow guinea pig skin in clear contrast to dinitrochlorobenzene (DNCB) allergy, which has very low incidence of hyperpigmentation. Skin extract from PAN allergy at 20-29 d post-challenge exhibited marked melanogenic stimulatory effects (3H2O release and 14C-thiouracil incorporation) when added to cultured guinea pig melanocytes. The time course in the appearance of melanogenic factor was definitely consistent with the induction pattern of visible pigmentation. By contrast, the addition of DNCB-challenged skin extract demonstrated no significant stimulating effect on melanogenesis in either assay system on any of the post-challenge days tested. Assay of intracellular inositol 1,4,5-trisphosphate formed through incubation with the melanocytes demonstrated that the PAN-allergy skin extract at day 28, which contains definite melanogenic factors, stimulated the formation of inositol 1,4,5-trisphosphate that occurs around 50 seconds in contrast to no or little increase with extracts obtained at days 0 and 1 post-challenge. Gel chromatographic analysis revealed that the PAN-allergy skin extract at day 28 contained a newly generated melanogenic fraction with a molecular weight of approximately 9000 Da which was also capable of stimulating DNA synthesis and activating the signal-transduction process (inositol trisphosphate formation) when added to guinea pig melanocytes. Both stimulations of melanogenesis and DNA synthesis by the 9000 Da fraction were completely abolished by the prior and simultaneous addition of protein kinase C (PKC) inhibitor (H-7) or its down-regulatory agent, phorbol 12,13-dibutyrate (PdBu). Taken together, these results suggest that PAN allergy provides a new mechanism of hypermelanization in which endogenous factors synthesized within skin induce the activation of signal-transduction pathways such as phosphoinositide turnover through ligands-receptor binding, resulting in the stimulation of melanocytes possibly through the activation of PKC.

Animals↗
PubMed1978

Sporadic non-toxic goitre: an investigation of the hypothalamic-pituitary-thyroid axis.

Thyrotrophin releasing hormone (TRH) tests have been carried out on sixty-two patients with sporadic non-toxic nodular goitre. 61% gave a subnormal thyroid stimulating hormone (TSH) response but had normal plasma thyroxine (T4) and triiodothyronine (T3) levels. T3 administration suppressed 131I uptake by the thyroid adequately in 74% of these and there was normal stimulation of thyroid uptake by exogenous TSH. Prolactin (PRL) rose normally after TRH in all the TRH non-responders. Normal TSH response to TRH was restored by partial thyroidectomy and in some cases by propyl thiouracil administration. Possible reasons for these findings are discussed. It is concluded that these cases were truly euthyroid.

Goiter, Nodular↗
PubMed1986

Familial dysalbuminaemic hyperthyroxinaemia: studies of albumin binding and implications for hormone action.

The abnormal intermediate-affinity T4 binding to albumin which is characteristic of familial dysalbuminaemic hyperthyroxinaemia (FDH) is dependent on buffer, temperature, and ionic composition. Scatchard analysis of T4-binding to isolated albumin preparations from FDH subjects showed that half the circulating albumin showed the higher-affinity T4 binding site, assuming one site per molecule. Using dextran-charcoal separation at 4 degrees C the T4 affinity (Kd) of purified albumin from FDH subjects was 7.5 nmol/l in phosphate and 17 nmol/l in Tris-Cl- buffer. T4 binding to FDH albumin was inhibited by a range of substances in the order: 8-anilino-1-naphthalene sulphonic acid greater than merthiolate greater than propylthiouracil greater than methyl-thiouracil greater than carbimazole greater than salicylate greater than barbitone. Binding of T4 was competitively inhibited by low concentrations of dithiothreitol (DTT). The effect of DTT 0.1-0.5 nmol/l was reversed by removal of DTT by dialysis. Competition with a range of iodothyronines indicated that the 3', 5'-iodine atoms are most important for binding to this site. Serum binding of salicylate, frusemide, fenclofenac and barbituric acid, and a range of steroid hormones was similar in FDH and normal sera. Serum levels of sex hormone binding globulin (SHBG), were not significantly different from sex-matched controls. Nuclear [125I]-T3 binding sites in circulating lymphocytes from two FDH subjects showed affinities (Kd) of 59 and 79 pmol/l (normal 67 +/- 7 pmol/l, n = 6). These findings suggest that the highly specific binding anomaly of FDH is due to a disulphide-dependent structural change in albumin.(ABSTRACT TRUNCATED AT 250 WORDS)

Blood Protein Disorders↗
PubMed2005

Effect of the thyroid on faecal shedding of E. coli O157:H7 and Escherichia coli in naturally infected yearling beef cattle.

AIMS: To determine if thyroid function affects faecal shedding of Escherichia coli O157:H7. METHODS AND RESULTS: Eight yearling cattle (n = 4 per treatment group), previously identified as shedding E. coli O157:H7, received either 0 or 10 mg 6-N-propyl-2-thiouracil (PTU) kg(-1) BW day(-1) for 14 days to reduce serum concentrations of the thyroid hormones, T(3) and T(4). Animals were monitored daily for changes in faecal shedding of E. coli O157:H7 and E. coli (EC) for the 14-day treatment period and an additional 7 days post-treatment. Body weight was measured weekly and serum concentrations of T(3) and T(4) were determined every 3 days. No differences in faecal shedding of E. coli O157:H7 were observed during the 14-day treatment period. However, compared with control animals, a greater percentage of PTU-treated cattle ejected E. coli O157:H7 on day 16 (100 vs 25%) and 18 (75 vs 0%) of the post-treatment period. Serum T(3) was lower in PTU-treated cattle during the 14-day treatment period and greater on day 18 of the post-treatment period. CONCLUSION: Cattle with chemically altered thyroid hormones had similar shedding patterns of faecal E. coli O157:H7 and EC during the 14-day treatment period. However, faecal shedding of E. coli O157:H7 tended to be greater, and serum concentrations of T(3), were greater for PTU-treated cattle immediately following the termination of PTU treatment. SIGNIFICANCE AND IMPACT OF THE STUDY: Short-term chemical inhibition of thyroid hormones had minimal effects on faecal shedding of E. coli O157:H7 in naturally infected cattle. However, a hyperthyroid state as observed postdosing might play a role in the seasonal shedding of E. coli O157:H7 in cattle.

Animals↗
PubMed2004

Inter-relationships between the secretory dynamics of thyrotrophin-releasing hormone, thyrotrophin and prolactin in periovulatory mares: effect of hypothyroidism.

We used our nonsurgical technique for collecting pituitary venous blood to relate the dynamics of thyrotrophin-releasing hormone (TRH) secretion to the secretion patterns of both prolactin and thyrotrophin in periovulatory mares, either euthyroid (n = 5) or made hypothyroid by treatment with propyl-thiouracil (n = 5). Pituitary venous blood was collected continuously and divided into 1-min aliquots for 4 h. To test the effect of dopamine on the relationship between secretion patterns, sulpiride, a selective D2 receptor antagonist, was given i.m. after 2 h of sampling. Thorough testing of the model and blood collection procedure revealed no sites of TRH loss. Hypothyroidism increased the mean secretion rates of TRH (P = 0.04) and thyrotrophin (P < 0.0001) but not prolactin. Sulpiride increased prolactin secretion rates in hypothyroid (P < 0.0001) and control (P = 0.007) mares, but did not alter TRH or thyrotrophin secretion rates. In both groups of mares, all three hormones were secreted episodically but not rhythmically. In both groups, the secretion pattern of TRH was almost always significantly related to that of thyrotrophin, as assessed by cross correlation and cross approximate entropy (ApEn) analysis. However, the degree of linear correlation was weak, with only 14% (hypothyroid) or 8% (controls) of the variation in thyrotrophin secretion rates attributable to TRH. Prolactin and TRH secretion patterns before sulpiride were coupled on cross ApEn analysis in both groups, and the minute-to-minute secretion rates of the two hormones were correlated in four hypothyroid and three euthyroid mares. Overall, the small, but significant, degree of association between TRH and prolactin was similar to that between TRH and thyrotrophin. In hypothyroid mares, sulpiride increased (P = 0.02) the synchrony between TRH and prolactin patterns. We conclude that in horses: (i) little TRH degradation occurs during passage through the pituitary or in blood after 1 h at 37 degrees C; (ii) TRH is not the major factor controlling minute-to-minute fluctuations in either thyrotrophin or prolactin; and (iii) reducing two strongly inhibitory inputs (i.e. dopamine and thyroid hormones) may magnify the stimulatory effect of TRH on prolactin secretion.

Animals↗
PubMed1995

Effect of orally administered antithyroid thioureylenes on PCNA and P53 expression in psoriatic lesions.

BACKGROUND: Antithyroid thioureylenes are effective agents in the oral and topical treatment of patients with chronic plaque psoriasis. METHOD: The effect of oral treatment with 6-n-propyl 2-thiouracil (propylthiouracil, PTU) and 2-mercapto 1-methyl imidazole (methimazole, MMI) on proliferating cell nuclear antigen (PCNA), and p53 protein expression was studied in patients with stable plaque psoriasis. RESULTS: Following treatment with PTU and MMI, PCNA staining in psoriatic epidermis was significantly decreased. P53 was minimally expressed in untreated lesions, and treatment with PTU and MMI did not enhance p53 expression in the psoriatic lesions. CONCLUSIONS: Since PCNA is a marker of cellular proliferation and p53 inhibits cellular cycling, some of the beneficial effects of PTU and MMI in psoriasis may depend on the ability of the drugs to impair cellular turnover, perhaps by binding to the triiodothyronine (T3) receptor. These effects may be in addition to the previously described effects of PTU and MMI as immune modulators and free radical scavengers.

Administration, Oral↗
PubMed1981

tRNA thiolated pyrimidines as targets for near-ultraviolet-induced synthesis of guanosine tetraphosphate in Escherichia coli.

Illumination with near-ultraviolet light triggers synthesis of ppGpp (guanosine 3'-diphosphate 5'-diphosphate) not only in growing Escherichia coli cells containing the putative chromophore 4-thiouridine in their tRNAs [Ramabhadran, T. V and Jagger, J. (1976) Proc. Natl Acad. Sci. USA, 73, 59--69], but also in nuv- cells which lack 4-thiouridine. The burst of ppGpp in nuv- cells is, however, induced exclusively by light of wavelengths shorter than 350 nm. Its maximum level is half that obtained in the parental strain. This ppGpp synthesis is also under the control of the relA gene, indicating that it is due to the accumulation of uncharged tRNAs. A candidate likely to trigger this effect is a 5-methylaminomethyl-2-thiouracil residues present in the first position of the anticodon loop of tRNAGlu, tRNALys and one tRNAGln isoacceptor. In conditions in vitro, this base is highly photoreactive at wavelengths shorter than 350 nm. Furthermore, near-ultraviolet-photomodified tRNAGlu and tRNALys become poor substrates of their acylation enzyme.

Escherichia coli↗
PubMed1978

The influence of dietary iodine and enviromental temperature on the activity of mitochondria in liver and kidney.

It was found that both effect of temperatures and diets influence metabolic changes in rabbits. In animals fed basal and PTU diets (propyl-thiouracil diets) at 34 degrees C for 4 weeks the metabolic response showed a marked reduction in feed intake and body weight, compared with animals fed at normal temperatures. In the animals fed the iodine diet, there was an increase in daily food consumption and weekly body weight gain at 34 degrees C. This indicates a rise in metabolic activity in this case. Studying the activity of kidney mitochondria of the three groups of animals using succinate as a substrate revealed that the P/O ratio tends to decrease in animals kept at 6 degrees C while the RCR value was not altered by changing conditions or produced by the different diets. At the temperature of 6 degrees C both the P/O ratios and the RCR values of liver mitochondria using succinate as a substrate decreased in the group of rabbits fed the basal and iodine diets, but were not significantly different in the group fed the PTU diet. In the experiment on kidney mitochondrial activity using alpha-ketoglutarate as a substrate it was found that both the P/O ratios and the RCR values from animals fed basal and PTU diets at 6 degrees C decreased slightly as compared with animals fed at 20 degrees C and 34 degrees C. In liver mitochondria, using alpha-ketoglutarate as a substrate a significant decrease in the P/O ratio and the RCR value was found for both rabbits fed the basal and the iodine diets at 6 degrees C. In the group of rabbits fed the PTU diet, the P/O ratio also decreased but the fall was not significant. These results suggested that the activity of succinate dehydrogenase in liver mitochondria increases in animals fed basal and iodine diets at 6 degrees C. The enzyme dehydrogenase involved in oxidation of alpha-ketoglutarate which is localized in the outer membrane of mitochondria seems to be affected by different temperatures and diets as compared with succinate dehydrogenase localized in the matrix. The kidney mitochondria activity is less sensitive than that of liver mitochondria. Mitochondrial respiration and phosphorylation due to the tightness of their coupling may respond differently depending on the degree of thyroid activity.

Animals↗
PubMed1992

Cyclic adenosine 3',5'-monophosphate content and bronchial smooth muscle contractility of hyper- and hypothyroid lungs.

1. Male Sprague-Dawley rats were made either hyper- or hypothyroid with thyroxine or 4-methyl-2-thiouracil, respectively. Bronchial smooth muscle (BSM) contractility and lung cyclic adenosine 3',5'-monophosphate (cAMP) content were measured in both conditions. 2. Bronchial smooth muscle contractility was significantly weaker in hyperthyroid rats, while the BSM contractility of hypothyroid rats was the same as controls. 3. The cAMP content of hyperthyroid rat lungs was similar to controls but was decreased in hypothyroid rats. 4. These studies demonstrated that both the hyper- and hypothyroid states affect respiration, although the mechanisms involved with different for each condition.

Animals↗
PubMed1979

Vitamin D sclerosis in rats.

The early fine structural changes in the arteries of rats induced by excess vitamin D3 perorally or parenterally were essentially similar, except the latter had a more prominent toxic effect to the vascular wall. The ultrastructural features, incidental to calcification, included the appearance of increased ground substance with a separation of collagenous and elastic fibrils, and degenerative changes in smooth muscle cells. Atherosclerosis was greatly accelerated at the sites of vascular injury when cholesterol, cholic acid and thiouracil were added to the basal diet. Calcification was initially observed in relation to elastic fibrils or degenerated cells in the upper and middle layers of the arteries, although there were few such deposits in the thickened intima of the coronary arteries. Calcium deposition could not be a direct effect of hypercalcemia, but the functional activity of smooth muscle cells did seem to promote the mineralization of calcium and phosphate. Furthermore, vitamin D-induced sclerosis did not prevent intimal thickening of the arteries when vitamin D3 was withdrawn.

Animals↗