Effects of injury on the concentration ofα 1 andα 2 in the plasmas of male and female rats

Summary The effects of injury on the concentration of ₁-macroglobulin and ₂-macroglobulin in the plasmas of male and female rats has been investigated. At 5 days after injury to the male rats the ₁-macroglobulin concentration increased to 131% of its preinjury value. The ₂-macroglobulin concentration increased more rapidly to a maximum of 86 times its initial value. In the female rats ₂-macroglobulin increased only slightly and ₁-macroglobulin not at all.     

Isotrinervi-2β-ol. Structural isomers in the defense secretions of allopatric populations of the termiteTrinervitermes gratiosus

Summary The defense secretions of 3 allopatric populations of the nasute termiteTrinervitermes gratiosus were analyzed. One population afforded a new trinervitene, isotrinervi-2-ol, a missing link in the hypothetical biosynthesis of the trinervitenes. Populations could be readily distinguished on the basis of the chromatographic profiles of their major and minor soldier frontal gland secretions.These studies were initiated (1975–76) with partial financial support by the International Centre of Insect Physiology and Ecology, Nairobi, Kenya and NIH Postdoctoral Fellowship AI-05076. Support by the Department of Chemistry of the State University of New York at Stony Brook and the technical assistance of Mr J. Engstrom allowed completion of this investigation.     

Age-related differences in the urinary excretion of prostaglandin F2α catabolites in the rat

Summary Tritium-labelled PGF₂ was administered i.v. into rats of varying ages (2, 4, 6 weeks and adult). Urine was collected and assayed for radioactive products by thin-layer-chromatography. Results showed a distinctly different urinary profile between the 2-week-old and the adult rat. While the urinary pattern from the 2-week-old rat gave a single less polar product than PGF₂, the pattern from the adult rat gave products more polar than PGF₂. Urine from the 4- and 6-week-old rats gave a mixture of these types of products. These results indicate that some prostaglandin catabolic pathway (likely the -oxidative system) is activated in vivo within the 4–6-week postnatal period in the rat.Supported by a grant (MT-4181) to C.P.-A. from the Medical Research Council of Canada.This study is in partial fulfillment of the requirements for a Ph.D. degree in the Department of Pharmacology, University of Toronto.     

Molecular function of the novel α7β2 nicotinic receptor

The α7 nicotinic receptor is a promising drug target for neurological and inflammatory disorders. Although it is the homomeric member of the family, a novel α7β2 heteromeric receptor has been discovered. To decipher the functional contribution of the β2 subunit, we generated heteromeric receptors with fixed stoichiometry by two different approaches comprising concatenated and unlinked subunits. Receptors containing up to three β2 subunits are functional. As the number of β2 subunits increases in the pentameric arrangement, the durations of channel openings and activation episodes increase progressively probably due to decreased desensitization. The prolonged activation episodes conform the kinetic signature of α7β2 and may have an impact on neuronal excitability. For activation of α7β2 receptors, an α7/α7 binding-site interface is required, thus indicating that the three β2 subunits are located consecutively in the pentameric arrangement. α7-positive allosteric modulators (PAMs) are emerging as novel therapeutic drugs. The presence of β2 in the pentamer affects neither type II PAM potentiation nor activation by an allosteric agonist whereas it impairs type I PAM potentiation. This first single-channel study provides fundamental basis required to decipher the role and function of the novel α7β2 receptor and opens doors to develop selective therapeutic drugs.     

The role of mammalian target of rapamycin (mTOR) in the regulation of pancreatic β-cell mass: implications in the development of type-2 diabetes

Type-2 diabetes mellitus (T2DM) is a disorder that is characterized by high blood glucose concentration in the context of insulin resistance and/or relative insulin deficiency. It causes metabolic changes that lead to the damage and functional impairment of organs and tissues resulting in increased morbidity and mortality. It is this form of diabetes whose prevalence is increasing at an alarming rate due to the 'obesity epidemic', as obesity is a key risk factor in the development of insulin resistance. However, the majority of individuals who have insulin resistance do not develop diabetes due to a compensatory increase in insulin secretion in response to an increase in insulin demand. This adaptive response is sustained by an increase in both β-cell function and mass. Importantly, there is increasing evidence that the Serine/Threonine kinase mammalian target of rapamycin (mTOR) plays a key role in the regulation of β-cell mass and therefore likely plays a critical role in β-cell adaptation. Therefore, the primary focus of this review is to summarize our current understanding of the role of mTOR in stimulating pancreatic β-cell mass and thus, in the prevention of type-2 diabetes.     

Rôle of the nucleus in the maintenance of the protein level in the algaAcetabularia mediterranea

Riassunto Sono state studiate le variazioni del rapporto tra l'N proteico e non proteico in segmenti rigeneranti, nucleati ed anucleati, diAcetabul. medit. I risultati ottenuti hanno dimostrato che il predetto rapporto aumenta in entrambi i segmenti il primo giorno dopo l'operazione. Nei giorni seguenti esso diminuisce in entrambi i segmenti, ma più sensibilmente in quelli anucleati, nei quali va al di sotto del valore medio delle alghe normali già dopo il 3°–4° giorno.     

Poinsinet's Edition of the Naturalis historia (1771–1782) and the Revival of Pliny in the Sciences of the Enlightenment

This paper analyses the revival of Pliny's Naturalis historia within the scientific culture of the late eighteenth and early nineteenth centuries, focusing on a French effort to produce an edition with annotations by scientists and scholars. Between the Renaissance and the early eighteenth century, the Naturalis historia had declined in scientific importance. Increasingly, it was relegated to the humanities, as we demonstrate with a review of editions. For a variety of reasons, however, scientific interest in the Naturalis historia grew in the second half of the eighteenth century. Epitomizing this interest was a plan for a scientifically annotated, Latin-French edition of the Naturalis historia. Initially coordinated by the French governmental minister Malesherbes in the 1750s, the edition was imperfectly realized by Poinsinet a few decades later. It was intended to rival two of the period's other distinguished multi-volume books of knowledge, Diderot and D'Alembert's Encyclopédie and Buffon's Histoire naturelle, to which we compare it. Besides narrating the scientific revival of the Historia naturalis during this period, we examine its causes and the factors contributing to its end in the first half of the nineteenth century.     

Influence of the structure of theN-terminal extremity ofα-MSH on the melanophore stimulating activity of this hormone

Zusammenfassung Drei strukturelle Analoge des-MSH wurden synthetisiert und auf ihre Melanophoren-stimulierende Wirksamkeit untersucht. Für das Auftreten einer ausgeprägten biologischen Aktivität scheint die Anwesenheit einerN-Acetyl-Gruppe an dem Aminoende der Peptidkette wichtiger zu sein als das Vorhandensein der zwei ersten amino-endständigen Aminosäurereste der-MSH-Kette.     

Influence of cyproterone acetate on the activity ofβ-glucuronidase in the hypothalamus and cerebral cortex of the male mouse

Summary Daily s.c. injections of cyproterone acetate greatly decrease the protein content and-glucuronidase activity in the mouse hypothalamus. These effects are reversible and the recovery capacity of the animal seems to be inversely related to the duration of antiandrogenic treatment.Financial aid was given by CNR (finalized project Biologia della Riproduzione) and Ministry of Education. Thanks are also due to Prof. G. Chieffi for suggestions and to Mr R. Auriemma for maintenance of experimental animals.     

Effects of PGE2 and PGF2α on the simulation by noradrenaline and oxytocin of human cervical muscle activity at term

Summary Cervical specimens were obtained by needle biopsy in connection with caesarean section at term pregnancy. The preparations were superfused in an organ chamber and contractions were registered isometrically. Prostaglandin (PG) E₂ and F₂ inhibited spontaneous contractions. The stimulatory action of noradrenaline was not influenced by PGF₂ but was reduced by PGE₂ whereas both PGs abolished the excitatory effect of oxytocin.     

Role of the ubiquitin–proteasome system in the regulation of P2Y13 receptor expression: impact on hepatic HDL uptake

The protective effect of high density lipoproteins (HDL) against atherosclerosis is mainly attributed to their capacity to transport excess cholesterol from peripheral tissues back to the liver for further elimination into the bile, a process called reverse cholesterol transport (RCT). Recently, the importance of the P2Y₁₃ receptor (P2Y₁₃-R) was highlighted in HDL metabolism since HDL uptake by the liver was decreased in P2Y₁₃-R deficient mice, which translated into impaired RCT. Here, we investigated for the first time the molecular mechanisms regulating cell surface expression of P2Y₁₃-R. When transiently expressed, P2Y₁₃-R was mainly detected in the endoplasmic reticulum (ER) and strongly subjected to proteasome degradation while its homologous P2Y₁₂ receptor (P2Y₁₂-R) was efficiently targeted to the plasma membrane. We observed an inverse correlation between cell surface expression and ubiquitination level of P2Y₁₃-R in the ER, suggesting a close link between ubiquitination of P2Y₁₃-R and its efficient targeting to the plasma membrane. The C-terminus tail exchange between P2Y₁₃-R and P2Y₁₂-R strongly restored plasma membrane expression of P2Y₁₃-R, suggesting the involvement of the intra-cytoplasmic tail of P2Y₁₃-R in expression defect. Accordingly, proteasomal inhibition increased plasma membrane expression of functionally active P2Y₁₃-R in hepatocytes, and consequently stimulated P2Y₁₃-R-mediated HDL endocytosis. Importantly, proteasomal inhibition strongly potentiated HDL hepatic uptake (>200 %) in wild-type but not in P2Y₁₃-R-deficient mice, thus reinforcing the role of P2Y₁₃-R expression in regulating HDL metabolism. Therefore, specific inhibition of the ubiquitin–proteasome system might be a novel powerful HDL therapy to enhance P2Y₁₃-R expression and consequently promote the overall RCT.     

Heavy water intake in tissues. II. H2O−D2O exchange in the myelinated nerve of the frog

Summary The kinetic parameters of D₂O intake in the frog sciatic nerve are obtained by means of infrared spectroscopy. 3 aqueous compartments: a non-exchangeable one (29%) and 2 compartments of quasi-free exchangeable water: 50% intracellular and 21% extracellular, are revealed.The first communication in this series is V. Vasilescu, D.-G. Mrgineanu and Eva Katona, Naturwiss.62, 187 (1975).For such derivations reference is made to the above mentioned mathematical model or to related works on compartmental analysis, reviewed by A. Rescigno and J. S. Beck, in: Foundations of Mathematical Biology, vol. II. Ed. R. Rosen, Academic Press, New York 1972.     

The influence of N-methyl-N-β-chloroethyl hydrazines on the mitotic index of Ehrlich ascites tumor cells and the leukopoiesis of the mouse

Summary The cytostatic activity of N-methyl-N--chloroethylbenzaldehyd hydrazone, (B1) is at least equal to that of procarbazine when its effect is tested with the Ehrlich ascites tumor cells of the mouse and the Yoshida sarcoma of the rat. B1 causes a slighter decrease of mitotic cells and no shift from prophase to metaphase. These results suggest that the cytostatic effect of B1 is due to interference with cell metabolism or an effect at the cell membrane and not to an effect on cell proliferation. This assumption is supported by a considerable depression, of lymphocytes and a minor effect on granulopoiesis, which is especially sensitive towards proliferation toxins. All these findings suggest a different mechanism of action of B1 and procarbazine.     

Antiproliferative effect of β-elemene in chemoresistant ovarian carcinoma cells is mediated through arrest of the cell cycle at the G2-M phase

Elemene is a natural antitumor plant drug. However, the effect of elemene on cell growth in ovarian cancer is unknown. In this study, we show that -elemene inhibited the proliferation of cisplatin-resistant human ovarian cancer cells and their parental cells, but had only a marginal effect in human ovary cells, indicating differential inhibitory effects on cell growth between ovarian cancer cells and normal ovary cells. We also demonstrated for the first time that -elemene markedly enhanced cisplatin-induced growth inhibition in resistant cells compared to sensitive cells. In addition, cell cycle analysis revealed a synergistic effect of -elemene and cisplatin on the induction of cell cycle G2-M arrest in our resistant ovarian carcinoma cells. Furthermore, we showed that treatment of these cells with both drugs downregulated cyclin B1 and Cdc2 expression, but elevated the levels of p53, p21waf1/cip1, p27kip1 and Gadd45. Finally, the combination of -elemene and cisplatin was found to increase the phosphorylation of Cdc2 and Cdc25C, which leads to a reduction in Cdc2-cyclin B1 activity. These novel findings suggest that -elemene sensitizes chemoresistant ovarian carcinoma cells to cisplatin-induced growth suppression partly through modulating the cell cycle G2 checkpoint and inducing cell cycle G2-M arrest, which lead to blockade of cell cycle progression.Received 19 January 2005; accepted 5 February 2005