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At least 19 recordsLinked to original sources
PubMed1978

Use of the L-proline analog, L-azetidine-2-carboxylic acid (LACA) to analyse embryonic growth and determination and expression of the chondrogenic phenotype in vivo and in vitro.

The L-proline analog, L-azetidine-2-carboxylic acid, (LACA) was injected into embryonated eggs of the common fowl, Gallus domesticus at daily doses of 350 microgram/egg on one or several days betweeh 8 and 12 days of incubation. Treatment at nine-days of incubation preferentially retarded embryonic growth to the twelfth day but recovery of growth rate occurred by 15 days of incubation. Relationships between growth and LACA-inhibited aspects of collagenogenesis are discussed. The earliest aged embryos from which isolated stem cells from membrane bones will form secondary cartilage is ten days of incubation. Secondary chondrogenesis on the quadratojugal, a membrane bone of the skull, was inhibited by treatment of whole embryos with LACA at nine days of incubation but not by treatment at eight days. We concluded that an event involving collagen began at nine days of incubation, was blocked by LACA and was part of the process of chondrogenic determination of these stem cells. Addition of LACA to the medium in which already determined stem cells from the quadratojugal were cultured prevented expression of the chondrogenic phenotype. This proline analog is then a useful probe for events relating both to determination and to expression of the differentiated state, and allows conclusions to be drawn regarding the role of collagenogenesis in these events.

Animals↗
PubMed1985

Effects of L-azetidine-2-carboxylic acid on matrix secretion and Golgi structure in fibroblasts and osteoblasts of the mouse.

The effect of a proline analogue, L-azetidine-2-carboxylic acid (LACA), on collagenous matrix secretion by periodontal ligament fibroblasts and alveolar bone osteoblasts was studied by light and electron microscopic radioautography after injection of 3H-glycine; 3H-glycine labeled material accumulated in the cisternae of the rough endoplasmic reticulum and was not secreted for over 4 hours. The Golgi complex of both fibroblasts and osteoblasts showed a marked alteration of its composition after LACA administration. All Golgi saccules and collagen secretion granules disappeared within 2 hours. Flattened Golgi cisternae were still present and appeared to be unaffected by the administration of LACA. These observations indicate that Golgi saccules in collagen-secreting cells are the initial staging areas for the formation of collagen secretory granules and that there is a close correlation between form and function in the Golgi apparatus of collagen-secreting cells.

Alveolar Process↗
PubMed1985

Amino acid analogs while inducing heat shock proteins sensitize CHO cells to thermal damage.

Amino acid analogs have been shown to induce heat shock proteins (HSPs). We have examined the effect of these analogs on the thermal sensitivity of Chinese hamster fibroblasts (HA-1) and their stable heat-resistant variants. We found that exposure of HA-1 cells and their heat-resistant variants to canavanine or L-azetidine-2-carboxylic acid cause enhanced synthesis of the three major mammalian HSPs (molecular weight 70,000, 87,000, and 110,000 kd). Although the synthesis of HSPs was increased, the analogs did not induce thermotolerance, a transient ability to protect cells from thermal damage. On the contrary, the analog treatment increased the thermal sensitivity of HA-1 cells, but not of the heat-resistant strains, when these cells were exposed subsequently to elevated temperatures. Our tentative explanation for these findings is that the incorporation of amino acid analogs into HSPs or other cellular proteins sensitizes HA-1 cells to heat. The heat-resistant strains contain higher levels of constitutive HSPs. The additional functional HSPs in the heat-resistant variants may protect these cells from thermal stress. The presence of some newly synthesized analog-substituted, perhaps nonfunctional, HSPs need not affect this thermal protection.

Animals↗
PubMed1987

Effects of a new TRH analogue, YM-14673 on the central nervous system.

The effects of a new TRH analogue, YM-14673 (N alpha-[[S)-4-oxo-2-azetidinyl)carbonyl]-L-histidyl-L-prolinamide dihydrate) on the central nervous system were compared with those of TRH. YM-14673 was 10-40 times more potent than TRH in antagonizing pentobarbital-induced sleep and hypothermia, and ethanol-induced hypothermia in mice. YM-14673 accelerated recovery from disturbed consciousness induced by concussive head trauma in mice and normalized the behavior and spontaneous EEG disturbed by electrolytic lesion of the hypothalamus in cats with 25-100 times greater potency than that of TRH. In the tests on pentobarbital sleeping time and EEG disturbance, the cerebral activating activity of YM-14673 was 8-36 times longer-lasting than that of TRH. These results indicate that YM-14673 possesses potent arousal effects on the central nervous system. The mode of action of YM-14673 was also discussed.

Animals↗
PubMed1988

Effects of a new TRH analogue, YM-14673 on a passive avoidance test as a possible criterion of improvement in cognitive disturbance in rodents.

Effects of a new TRH analogue, YM-14673 (N alpha-[[(S)-4-oxo-2-azetidinyl]carbonyl]-L-histidyl-L-prolinamide dihydrate) on cognitive disturbance of passive avoidance response were studied in rodents in comparison with those of TRH and CDP-choline. The latency for entering from the illuminated into the dark compartments was shortened in anoxia and scopolamine-treated rats, cycloheximide-treated mice and cerebral ischemic gerbils. The shortened latency in these models was prolonged by administration of both YM-14673 and TRH in doses without effect on spontaneous movement. YM-14673 was about 10 times more potent than TRH in ameliorating the cognitive disturbance, whereas CDP-choline showed no influence on the learning ability. These results suggest that YM-14673 and TRH possess facilitatory effects on cerebral function and that YM-14673 was distinct from CDP-choline in pharmacological profile.

Amnesia↗
PubMed1988

Antagonizing effects of YM-14673, a new TRH derivative, on behavioral and electroencephalographic changes in reserpinized animals.

Effects of YM-14673 (N alpha-[[S)-4-oxo-2-azetidinyl)-carbonyl]-L-histidyl-L-prolinamide dihydrate), a new TRH derivative, on reserpine-induced behavioural and electroencephalographic changes were observed in comparison with those of TRH. YM-14673 antagonized reserpine-induced hypothermia and decrease in convulsion threshold in mice. The number of PGO waves recorded from the lateral geniculate body was decreased by administration of YM-14673 in reserpinized cats. The anti-reserpine activity of intravenous YM-14673 was about 8-20 times more potent than that of TRH. In inhibiting reserpine-induced hypothermia, the oral ED2 degrees C relative to IV ED2 degrees C as an indirect indication of absorption rate of the drugs was 15 for both YM-14673 and TRH. These results suggest that YM-14673 possesses more potent facilitatory effects on the central monoamine systems than TRH.

Animals↗
PubMed1977

Carcinogenicity of nitrosoazetidine and tetradeuteronitrosoazetidine in Sprague-Dawley Rats.

Nitrosoazetidine was fed to rats in drinking water at three different concentrations. At 2 mmol (10 mmol total dose) all of the rats died with hepatocellular carcinomas by the 62nd week. This was a greater response than to an equivalent dose of nitrosopyrrolidine. At 0.67 mmol, 6 of 21 rats developed liver tumors, and at 0.17 millimolar 2 of 30 animals had liver tumors. The comparable responses to feeding of nitrosoazetidine-2,2,4,4-d4 were 3 of 21 rats with liver tumors at 0.69 millimolar and 3 of 30 rats with liver tumors at 0.17 mmol. These results show only a small deuterium isotope effect in liver carcinogenesis with nitrosoazetidine.

Animals↗
PubMed1977

Variant Chinese hamster cells resistant to the proline analog L-azetidine 2-carboxylic acid.

Variants resistant to the toxic effects of the proline analog L-azetidine 2-carboxylic acid (AZCA) have been isolated from the Chinese hamster tissue culture line G3 by a three-step selection procedure using increasing concentrations of AZCA. Cells surviving each of the three selective steps have been examined for AZCA resistance and for proline uptake, biosynthesis, and degradation. The largest increment in AZCA resistance is acquired in the third step and is due to overproduction of proline as a result of increased activity of the enzyme system responsible for the conversion of glutamic acid to glutamic gamma-semialdehyde. It is not accompanied by an increase in the rate of formation of proline from ornithine or in the rate of proline uptake or degradation.

Azetidinecarboxylic Acid↗
PubMed1986

Effects of antifibrotic substances on pancreatic fibrosis following acute necrotizing pancreatitis.

This study was designed to search for a way to inhibit pancreatic fibrosis following acute pancreatitis. Experimental necrotizing pancreatitis was induced by a freezing procedure in the pancreas of male Wistar rats. After the freezing procedure, the rats were divided into 3 groups: nothing addition was done to the control group, while the other 2 groups received daily intraperitoneal administration of antifibrotic substances (colchicine or L-azetidine-2-carboxylic acid (AZC)) for 6 weeks. Pancreatic enzymes in the serum were not markedly influenced by administration of antifibrotic substances, and there were no differences in the ratios of dry to wet weights of the pancreas between groups with and without these drugs. After freezing, the hydroxyproline levels in the pancreas of the control group increased from 1 to 4 weeks and then decreased during the 5th and 6th weeks. All groups receiving colchicine or AZC exhibited a significant decrease in the hydroxyproline levels at 2 to 4 weeks compared with the control group (P less than 0.01). Histological examination also showed the inhibition of pancreatic fibrosis, agreeing with changes in the hydroxyproline levels in groups receiving colchicine or AZC. These results suggest that administration of antifibrotic substances, colchicine and AZC, have the possibility of inhibiting pancreatic fibrosis following acute pancreatitis.

Animals↗
PubMed1987

Translational repression by chemical inducers of the stress response occurs by different pathways.

The mechanism by which chemical inducers of the stress response inhibit protein synthesis was examined. All the chemicals tested principally inhibit the initiation phase of translation. Covalent modification of the initiation factor proteins does not constitute a common mechanism. Eukaryotic initiation factor (eIF)-2 alpha phosphorylation is moderately to strongly induced by Na arsenite and diamide, but only slightly to imperceptibly affected by iodoacetamide, azetidine carboxylic acid, and canavanine. eIF-4B dephosphorylation does not occur in any case. The only consistent change detected is the hyperphosphorylation of the 28,000 Da heat stress protein. These results indicate that these diverse chemicals, all of which enhance the transcription of the stress mRNAs, do not inhibit translation by a common, recognized mechanism; it is likely that several distinct pathways leading to inhibition exist.

Arsenic↗
PubMed1976

Incorporation of L-azetidine-2-carboxylic acid into hemoglobin S in sickle erythrocytes in vitro.

L-Azetidine-2-carboxylic acid, the naturally occurring lower homologue of L-proline, is incorporated into hemoglobin S (sickle hemoglobin) in vitro. Sickle erythrocytes from patients with sickle cell anemia incubated with L-[3H] azetidine-2-carboxylate synthesized radiolabeled hemoglobin which when isolated from cell lysates, co-chromatographed with hemoglobin S on DEAE-cellulose columns. The alpha/beta ratio of azetidine carboxylate incorporation into the globin chains of sickle hemoglobin was 0.94, which is consistent with the presence of four proline residues in each polypeptide chain. Incorporation of azetidine carboxylate into hot trichloroacetic acid-insoluble material in sickle erythrocytes indicated that the homologue was present in the polypeptide backbone of the globin chains of sickle hemoglobin. Amino acid analysis of the hot trichloroacetic acid-insoluble material from sickle erythrocytes which had been incubated with radiolabeled azetidine carboxylate indicated that 75% of the radioactivity could be accounted for as intact homologue while 20% of the radioactivity co-chromatographed with alanine. These results suggest that azetidine carboxylate is incorporated unaltered into hemoglobin S in addition to being metabolized to alanine in sickle erythrocytes prior to incorporation into protein. The kinetics of thermal precipitation of hemoglobin S (oxygen ligand) into which radioactive azetidine carboxylate or radioactive proline had been incorporated in vitro is identical. This observation, together with the behavior of hemoglobin S and the globin chains from hemoglobin S containing azetidine carboxylate during ion-exchange chromatography, indicates that homologue replacement of prolyl residues does not significantly alter the overall charge or stability of the hemoglobin S tetramer. Azetidine carboxylate did not inhibit uptake of radiolabeled proline by sickle erythrocytes suggesting that the homologue does not adversely affect amino acid transport in these cells.

Amino Acids↗