Antitumor effect of a new retinoic acid analog

Zusammenfassung Retinsäure hat einen prophylaktischen und therapeutischen Effekt auf chemisch induzierte benigne und maligne epitheliale Tumoren. Die Wirkungen werden durch das Auftreten der sogenannten Hypervitaminose A-Symptome limitiert. Es werden die biologischen Eigenschaften eines aromatischen Retinsäure-Analogen (Figur) beschrieben, bei dem das Verhältnis zwischen den Dosen, die eine Tumorhemmung bewirken, und denen, die eine Hypervitaminose A erzeugen, 10mal günstiger ist als bei Retinsäure. Papillomregression und Hypervitaminose A sind nicht eng miteinander gekoppelt. Eine Dissoziation dieser biologischen Eigenschaften führt zu Substanzen mit besserem therapeutischem Quotient.     

Effects of retinoic acid on embryonic development of mice in culture

The effects of all-trans-retinoic acid (RA) (tretinoin) on the craniofacial development of mouse embryos were examined using whole embryo culture. In day 8 embryos cultured for 48 h, embryonic growth was inhibited concentration-dependently by all-trans-RA treatment. Most of the treated embryos exhibited hypoplasia of the primary palatal processes and a reduction in the development of the first visceral arches. In day 10 embryos cultured for 48 h, although embryonic growth was not inhibited at any concentrations of all-trans-RA, median cleft lip (93%), hypoplasia of the primary palatal processes (37%) and limb reduction deformities (48%) occurred commonly. Furthermore, RA treatment greatly reduced the size of the secondary palatal processes. The incorporation of 3H-thymidine in the treated maxillary processes was decreased to 65% of the control value at 1.0 x 10(-7) M all-trans-RA. These findings indicate that all-trans-RA is teratogenic in mouse whole embryo culture.     

Effects of retinoic acid on embryonic development of mice in culture

Summary The effects of all-trans-retinoic acid (RA) (tretinoin) on the craniofacial development of mouse embryos were examined using whole embryo culture. In day 8 embryos cultured for 48 h, embryonic growth was inhibited concentration-dependently by all-trans-RA treatment. Most of the treated embryos exhibited hypoplasia of the primary palatal processes and a reduction in the development of the first viscreral arches. In day 10 embryos cultured for 48 h, although embryonic growth was not inhibited at any concentrations of all-trans-RA, median cleft lip (93%), hypoplasia of the primary palatal processes (37%) and limb reduction deformities (48%) occurred commonly. Furthermore, RA treatment greatly reduced the size of the secondary palatal processes. The incorporation of³H-thymidine in the treated maxillary processes was decreased to 65% of the control value at 1.0×10^–7 M alltrans-RA. These findings indicate that all-trans-RA is teratogenic in mouse whole embryo culture.     

Demonstration of retinoic acid isomers in human urine under physiological conditions

Untransformed retinoic acid has never been demonstrated in human excreta under normal physiological conditions. We have developed a two-step liquid chromatographic system for the demonstration of subnanogram amounts of this compound in human urine without administration of any precursor.     

Possible stimulatory effect of retinoic acid on pulmonary macrophages

Summary Retinoic acid was administered to hamsters suffering from N-nitroso-N-methylurethane-induced fibrosing alveolitis. A significant increase in macrophage numbers was seen in the lungs of retinoid-treated animals as compared to the unsupplemented group.     

Demonstration of retinoic acid isomers in human urine under physiological conditions

Summary Untransformed retinoic acid has never been demonstrated in human excreta under normal physiological conditions. We have developed a two-step liquid chromatographic system for the demonstration of subnanogram amounts of this compound in human urine without administration of any precursor.The work was supported by a grant of the N.F.S.R. to W.L.     

Possible stimulatory effect of retinoic acid on pulmonary macrophages.

Retinoic acid was administered to hamsters suffering from N-nitroso-N-methylurethane-induced fibrosing alveolitis. A significant increase in macrophage numbers was seen in the lungs of retinoid-treated animals as compared to the unsupplemented group.     

Effect of retinoic acid on liver transglutaminase activity and carbon tetrachloride-induced liver damage in mice

Transglutaminase (TGase) activity in the cytosol fraction of the mouse liver increased following intraperitoneal injection of retinoic acid. Retinoic acid inhibited the carbon tetrachloride-induced increase in serum alanine transaminase activity. These findings suggest that TGase is involved in the effect of retinoic acid on carbon tetrachloride-induced liver damage.     

Further studies on the effects of corticosterone on adrenocortical cells of hypophysectomized ACTH-treated rats

Riassunto Con metodi morfometrici è stato studiato l'effetto di dosi parafisiologiche di corticosterone sulle cellule corticosurrenaliche (zona fascicolata) di ratti ipofisectomizzati trattati con dosi di mantenimento di ACTH. I dati ottenuti indicano che tali dosi di ormone inibiscono direttamente la funzionalità delle cellule corticosurrenaliche. Questi risultati suggeriscono che la componente periferica dei meccanismi a feed-back che intervengono nella regolazione della funzione corticosurrenalica, giochi un ruolo fisiologico significativo.     

From carrot to clinic: an overview of the retinoic acid signaling pathway

Vitamin A is essential for the formation and maintenance of many body tissues. It is also important for embryonic growth and development and can act as a teratogen at critical periods of development. Retinoic acid (RA) is the biologically active form of vitamin A and its signaling is mediated by the RA and retinoid X receptors. In addition to its role as an important molecule during development, RA has also been implicated in clinical applications, both as a potential anti-tumor agent as well as for the treatment of skin diseases. This review presents an overview of how dietary retinoids are converted to RA, hence presenting the major players in RA metabolism and signaling, and highlights examples of treatment applications of retinoids. Moreover, we discuss the origin and diversification of the retinoid pathway, which are important factors for understanding the evolution of ligand-specificity among retinoid receptors.     

Sialic acid in human cancer

Zusammenfassung Die Sialinsäure welche im menschlichen Krebsgewebe vorhanden ist, wurde isoliert, charakterisiert und gemessen. Im krebsartigen und normalen Gewebe wurde nur N-Acetyineuraminsäure gefunden. Die Sialinsäure im Pankreas-Adenokarzinom war ums 4fache grösser als in normalen Kontrollgeweben.     

Effects of retinoic acid on ascites cells of the TA3 mouse mammary carcinoma

Retinoic acid caused a decrease in adhesiveness but no growth change in the allotransplantable TA3-Ha cell and no change in adhesiveness or growth in the strain specific TA3-St cell. The retinoic acid binding protein was detected in the TA3-Ha, but not the TA3-St, cell.     

Effects of retinoic acid on ascites cells of the TA3 mouse mammary carcinoma

Summary Retinoic acid caused a decrease in adhesiveness but no growth change in the allotransplantable TA3-Ha cell and no change in adhesiveness or growth in the strain specific TA3-St cell. The retinoic acid binding protein was detected in the TA3-Ha, but not the TA3-St, cell.This study was supported in pat by Public Health Service Grants CA-08418 and CA-18600 from the National Cancer Institute, National Institutes of Health. This is publication 955 of the Robert W. Lovett Group for the Study of Diseases Causing Deformities. We gratefully acknowledge the contributions of Drs Luigi M. De Luca and Anton M. Jetten of the Laboratory of Cellular Carcinogenesis and Tumor Promotion, National Cancer Institute, National Institutes of Health, Bethesda, MD, without whose help this study would not have been possible.     

Effect of retinoic acid on liver transglutaminase activity and carbon tetrachloride-induced liver damage in mice.

Transglutaminase (TGase) activity in the cytosol fraction of the mouse liver increased following intraperitoneal injection of retinoic acid. Retinoic acid inhibited the carbon tetrachloride-induced increase in serum alanine transaminase activity. These findings suggest that TGase is involved in the effect of retinoic acid on carbon tetrachloride-induced liver damage.     

Effects of retinoic acid on the fibrinolytic activity of HL 60 human promyelocytic leukemia cells

Summary Fibrinolytic activity of HL 60 human leukemic cells was found to increase in parallel with myeloid differentiation following retinoic acid but not dimethylsulfoxide treatment. However, both retinoic acid and dimethylsulfoxide produced an increase in acid phosphatase and a decrease in muramidase.     

Acyl-CoA thioesterase 9 (ACOT9) in mouse may provide a novel link between fatty acid and amino acid metabolism in mitochondria

Acyl-CoA thioesterase (ACOT) activities are found in prokaryotes and in several compartments of eukaryotes where they hydrolyze a wide range of acyl-CoA substrates and thereby regulate intracellular acyl-CoA/CoA/fatty acid levels. ACOT9 is a mitochondrial ACOT with homologous genes found from bacteria to humans and in this study we have carried out an in-depth kinetic characterization of ACOT9 to determine its possible physiological function. ACOT9 showed unusual kinetic properties with activity peaks for short-, medium-, and saturated long-chain acyl-CoAs with highest V _max with propionyl-CoA and (iso) butyryl-CoA while K _cat/K _m was highest with saturated long-chain acyl-CoAs. Further characterization of the short-chain acyl-CoA activity revealed that ACOT9 also hydrolyzes a number of short-chain acyl-CoAs and short-chain methyl-branched CoA esters that suggest a role for ACOT9 in regulation also of amino acid metabolism. In spite of markedly different K _ms, ACOT9 can hydrolyze both short- and long-chain acyl-CoAs simultaneously, indicating that ACOT9 may provide a novel regulatory link between fatty acid and amino acid metabolism in mitochondria. Based on similar acyl-CoA chain-length specificities of recombinant ACOT9 and ACOT activity in mouse brown adipose tissue and kidney mitochondria, we conclude that ACOT9 is the major mitochondrial ACOT hydrolyzing saturated C₂-C₂₀-CoA in these tissues. Finally, ACOT9 activity is strongly regulated by NADH and CoA, suggesting that mitochondrial metabolic state regulates the function of ACOT9.     

Shock effects on plants: Tannic acid and chlorogenic acid in yam roots

Résumé Les tanins de l'acide chlorogénique s'accumulent immédiatement après que les racines d'ignames ont été soumises à des chocs de 10 à 44 (0.6–2.66 kg/cm²), consistant en une pulsation de la pression comparable à une rafale d'air dans un tube. L'accumulation des tanins est inversement proportionelle à la pression. Mais, l'acide chlorogénique s'accumule progressivement avec élèvation du niveau du choc.