Cyclic and linear vasopressin V1 and V1/V2 antagonists containing arginine in the 4-position

Substitution of arginine for glutamine in the 4-position of a vasopressin V1 antagonist has been reported to turn it into an agonist. We resynthesized this 4-arginine analog and synthesized additional cyclic and linear vasopressin antagonists containing a 4-arginine. The presence of a 4-arginine in the resynthesized and new analogs had relatively minor effects on their antivasopressin V1 and V2 antagonistic potencies.     

H2 receptor antagonists and human granulopoiesis

Summary The effect of 2 H₂ receptor antagonists (ranitidine and cimetidine) on the in vitro growth of human granulomonopoietic precursors (CFU-GM) was studied. Ranitidine, although having an anti H₂ receptor activity much greater than that of cimetidine, displays the same toxicity for CFU-GM.Acknowledgments. This work was supported by CNR, Rome, PFCCN and AIRC, Milan.     

Invertebrate neuropeptides resembling vasotocin and some analogues: Synthesis and pharmacological properties

Summary The solid phase synthesis of three invertebrate vasopressin-oxytocin homologs: AVP-like factor, F₁ ¹, ([Leu², Thr⁴] AVT)² isolated from subesophageal and thoracic ganglia ofLocusta migratoria ³, Arg-conopressin-S⁴. ([Ile², Arg⁴] AVT), Lys-conopressin-G⁴ ([Phe², Arg⁴] LVT), both isolated from the venom of fish-hunting marine snails of the genusConus and six of their analogues is reported. These analogues are: [Arg⁴] AVT, [Ile²] AVT, [Leu²] AVT, [Phe², Arg⁴] AVT, [Arg⁴] LVT and [Ile², Arg⁴] LVT. All peptides were tested for antidiuretic and vasopressor activities.     

Role of adenosine A1 and A2 receptors in the regulation of aldosterone production in rat adrenal glands

Summary To investigate the roles of adenosine A₁ and A₂ receptors in the regulation of aldosterone production, we examined the effects of adenosine and adenosine agonists (N⁶-cyclohexyl adenosine; selective adenosine A₁ receptor agonist and 5-N-ethylcarboxamine adenosine; selective adenosine A₂ receptor agonist) on aldosterone and cyclic AMP production in rat adrenal capsular cells. Neither adenosine nor 5-N-ethylcarboxamine adenosine caused significant effects on basal aldosterone or cyclic AMP production. Also, adenosine (10^–3M) showed no consistent effects on aldosterone and cyclic AMP production induced by ACTH. On the other hand, N⁶-cyclohexyl adenosine exhibited a significant inhibition of basal aldosterone and cyclic AMP production at doses of 10^–4 M and 10^–3 M; furthermore, 10^–3 M N⁶-cyclohexyl adenosine inhibited aldosterone and cyclic AMP production stimulated by ACTH. These results suggest that adenosine A₁ receptors are coupled to and inhibit adenylate cyclase and may be involved in the inhibition of aldosterone production.     

Increased formation of arginine deiminase byClostridium perfringens FD-1 growing in the presence of caffeine

Summary Caffeine slowed growth and markedly increased the formation of arginine deiminase in growingC. perfringens FD-1 when dextrin, but not maltose or maltotriose, served as the energy source. It is postulated that the ability of caffeine to induce arginine deiminase is related to an inhibition of polysaccharide utilization, resulting in a shift-down condition known to induce arginine deiminase and other enzymes in bacteria.     

Lack of effects of 5-HT3 antagonists on normal and morphine-attenuated sexual behaviours in female and male rats

Although 5-HT₁ and 5-HT₂ receptor activity is known to influence copulation, the effects of 5-HT₃ receptor-selective drugs on sexual activity have yet to be systematically studied. The following experiments investigated the effects of the 5-HT₃-selective antagonists MDL 72222, ondansetron and ICS 205-930 on female sexual behaviour; male rats were studied using ondansetron and granisetron. These compounds influenced neither male nor female copulatory behaviours, suggesting that 5-HT₃ receptors contribute little to the modulation of sexual activity. 5-HT₃ receptor antagonists block certain opioid-induced behaviours and opioids selectively inhibit sexual behaviours; therefore, the ability of ondansetron and ICS 205-930 to modify morphine-attenuated copulatory activity was also tested. While morphine inhibited copulation, 5-HT₃ antagonists failed to reverse the effects.     

Arresting the mitotic oscillator and the control of cell proliferation: insights from a cascade model for cdc2 kinase activation

We consider a minimal cascade model previously proposed¹¹ for the mitotic oscillator driving the embryonic cell division cycle. The model is based on a bicyclic phosphorylation-dephosphorylation cascade involving cyclin and cdc2 kinase. By constructing stability diagrams showing domains of periodic behavior as a function of the maximum rates of the kinases and phosphatases involved in the two cycles of the cascade, we investigate the role of these converter enzymes in the oscillatory mechanism. Oscillations occur when the balance of kinase and phosphatase rates in each cycle is in a range bounded by two critical values. The results suggest ways to arrest the mitotic oscillator by altering the maximum rates of the converter enzymes. These results bear on the control of cell proliferation.     

Production of active and passive anaphylactic shock in the WBB6F1 mouse,a mast cell-deficient strain

Summary The role of mast cells in active and passive anaphylactic shock was examined using the WBB6F₁ mouse, a genetically mast cell-deficient strain. Lethal anaphylactic shock occurred at high incidence rates in mice actively sensitized to bovine serum albumin (BSA). The reaction was specific to BSA since the shock could not be elicited by human or guinea pig serum albumin in these animals. Lethal shock could be prevented by CV-3988 but not by cyproheptadine, which suggests that the shock is mediated by PAF but not by histamine and serotonin. Similarly, lethal shock was provoked by homologous antigens in mice which had been passively sensitized with allogeneic anti-benzylpenicilloyl (BPO) IgG₁ monoclonal antibody or with allogeneic or xenogeneic anti-BSA antiserum, but not in those sensitized with allogeneic anti-BPO IgE monoclonal antibody. These findings suggest that mast cells are not necessarily required for anaphylactic shock in the mouse.     

The action of the peptidoleukotriene LTD4 on intracellular calcium in rat mesangial cells

The dose-dependent effect of CGP 45715A on the LTD₄-induced Ca²⁺ response of glomerular mesangial cells has been studied. Our results demonstrate that the LTD₄-dependent increase in the cytosolic Ca²⁺ concentration primarily involves an InsP₃-mediated release of Ca²⁺ from intracellular storage sites and to a minor extent an enhanced influx of Ca²⁺ through receptor-operated Ca²⁺ channels located in the plasma membrane. The action of CGP 45715A on the Ca²⁺ response is an inhibitory one and is convincingly explained by a displacement of LTD₄ from its receptor site(s). The contractile effect of LTD₄ on pulmonary smooth muscle is proposed to be mainly caused by a receptor-mediated hydrolysis of phosphatidylinositol-4,5-bisphosphate.     

2-Amino-6-[(1'R,2'S)-1',2'-dihydroxypropyl]-3-methyl-pterin-4-one,a biologically active metabolite from the anthozoanAstroides calycularis Pallas

Summary 2-Amino-6-[(1'R,2'S)-1',2'-dihydroxypropyl]-3-methyl-pterin-4-one (1) has been isolated from the marine anthozoanAstroides calycularis; its structure was illustrated by spectral analyses including 2D-NMR and by partial synthesis.1 appears to possess cell-growth inhibiting activity.29 December 1986Work supported by C.N.R. (Progetto Finalizzato Chimica Fine e Secondaria) and by Ministero Pubblica Istruzione Italy. — Acknowledgments. Mass spectral data were provided by Servizio di Spettrometria di massa del C.N.R. e dell'Università di Napoli. The assistance of the staff is gratefully appreciated. Finally we would like to thank Prof. C. Pietropaolo for supplying chick embryo fibroblasts.     

Interaction between PGE2 and EGF receptor through MAPKs in mouse embryonic stem cell proliferation

Identifying the small molecules that permit precise regulation of embryonic stem (ES) cell proliferation should further support our understanding of the underlying molecular mechanisms of self renewal. In the present study, we showed that PGE₂ increased [³H]-thymidine incorporation in a time and dose dependent manner. In addition, PGE₂ increased the expression of cell cycle regulatory proteins, the percentage of cells in S phase and the total number of cells. PGE₂ obviously increased E-type prostaglandin (EP) receptor 1 mRNA expression level compare to 2, 3, 4 subtypes. EP1 antagonist also blocked PGE₂-induced cell cycle regulatory protein expression and thymidine incorporation. PGE₂ caused phosphorylation of protine kinase C, Src, epidermal growth factor (EGF) receptor, phosphatidylinositol 3-kinase (PI3K)/Akt phosphorylation, and p44/42 mitogen-activated protein kinase (MAPK), which were blocked by each inhibitors. In conclusion, PGE₂-stimulated proliferation is mediated by MAPK via EP1 receptor-dependent PKC and EGF receptor-dependent PI3K/Akt signaling pathways in mouse ES cells. Received 30 January 2009; received after revision 03 March 2009; accepted 10 March 2009     

Effects of photoperiod,temperature and testosterone-treatment on plasma T3 and T4 levels in the Djungarian hamster,Phodopus sungorus

Summary The effects of photoperiod, temperature and testosterone treatment on plasma T₃ and T₄ levels were investigated in the Djungarian hamster. Plasma T₃ level was affected by temperature (25°C<7°C) but not by photoperiod. Plasma T₄ level was affected by photoperiod (short day < long day) at 25°C. Administration of testosterone increased plasma T₄ level under short photoperiod at 25°C. Thus, higher plasma T₄ level under long photoperiod at 25°C might be induced by testosterone.     

Nature of the FeO2 bonding in myoglobin: An overview from physical to clinical biochemistry

Summary The iron(II)-dioxygen bond in myoglobin and hemoglobin is a subject of wide interest. Studieas range from examinations of physical-chemical properties dependent on electronic structure, to investigations of stability as a function of oxygen supply. Stability properties are of particular importance in vivo, since the oxygenated form is known to be oxidized easily to the ferric form, which cannot be oxygenated and is therefore physiologically inactive.Kinetic and thermodynamic studies of the stability of native oxymyoglobin have revealed a new feature in FeO₂ bonding. In vivo. the iron center is always subject to a nucleophilic attack of the water molecule or hydroxyl ion, which can enter the heme pocket from the surrounding solvent, and thereby irreversibly displace the bound dioxygen from MbO₂ in the form of O ₂ ^– so that the iron is converted to the ferric form. A free energy diagram for the potential reactions of FeO₂ visualizes myoglobin as a molecular structure that can provide in solution the delicate balance of kinetic and thermodynamic factors necessary to stabilize reversible oxygenation, as opposed to irreversible autoxidation to metmyoglobin.     

A novel interplay between membrane and nuclear melatonin receptors in human lymphocytes: significance in IL-2 production

Human lymphocyte melatonin, through membrane and nuclear receptors binding, acts as an activator in IL-2 production. Antagonism of membrane melatonin receptors using luzindole exacerbates the drop of the IL-2 production induced by PGE₂ in peripheral blood mononuclear and Jurkat cells. This paper studies the melatonin membrane and nuclear receptors interplay in PGE₂-diminished IL-2 production. The decrease in IL-2 production after PGE₂ and/or luzindole administration correlated with downregulation in the nuclear receptor RORα. We also highlighted a role of cAMP in the pathway, because forskolin mimicked the effects of luzindole and/or PGE₂ in the RORα expression. Finally, a significant RORα downregulation was observed in T cells permanently transfected with inducible MT₁ antisense. In conclusion, we show a novel connection between melatonin membrane receptor signalling and RORα expression, opening a new way to understand melatonin regulation in lymphocyte physiology. Received 23 September 2008; received after revision 19 November 2008; accepted 21 November 2008     

Tricyclic antidepressants antagonize prostaglandin (PG) E20induced contractions of the guinea pig ileum and hypomotility in the mouse

Summary The interactions of PGE₂ and 2 tricyclic antidepressants were tested both on the guinea pig ileum and motility in the mouse. PGE₂-induced contractions of the guinea pig ileum were irreversibly blocked by amitriptyline and desipramine. Chronic administration of amitriptyline and desipramine blocked PGE₂-induced hypomotility in the mouse.     

Natural killer-like activity in human cultured lymphoid cells propagated in the presence of interleukin-2: acquired resistance to prostaglandin E2- or dexamethasone-mediated suppression

Summary The cytotoxic activity of human peripheral blood lymphocytes against the natural killer-sensitive target K562 was suppressed both by prostaglandin E₂ and dexamethasone. On the other hand, cultured lymphoid cells propagated in the presence of interleukin-2 showed strong cytotoxic reactivity against K562 targets, and were resistant to prostaglandin E₂- or dexamethasone-mediated suppression.     

Multiple roles of the DSCR1 (Adapt78 or RCAN1) gene and its protein product Calcipressin 1 (or RCAN1) in disease

The DSCR1 (Adapt78) gene¹ is transiently induced by stresses to temporarily protect cells against further potentially lethal challenges. However, chronic expression of the DSCR1 (Adapt78) gene has now been implicated in several pathological conditions including Alzheimer’s disease, Down syndrome and cardiac hypertrophy. Calcipressin 1 has been shown to function through direct binding and inhibition of the serine threonine protein phosphatase Calcineurin. Pharmacological inhibition of calcineurin, by the immunosuppressive drugs cyclosporin A and FK506, affects a wide variety of diseases. It is, therefore, likely that this endogenous calcineurin inhibitor, calcipressin 1, may also play a role in a variety of human diseases. ¹Please note that the mammalian DSCR1 gene is also called Adapt78 or RCAN1, and its protein products have been named Calcipressin1, MCIP1 and RCAN1. A proposal to adopt a single gene name of RCAN1 and a protein name RCAN1 (for Regulator of Calcineurin) has been endorsed by the HUGO Gene Nomenclature Committee, but final approval must await agreement from a majority of researchers in the field. Received 2 March 2005; received after revision 27 May 2005; accepted 19 July 2005     

Breaking biological symmetry in membrane proteins: The asymmetrical orientation of PsaC on the pseudo-C2 symmetric Photosystem I core

The elucidation of assembly pathways of multi-subunit membrane proteins is of growing interest in structural biology. In this study, we provide an analysis of the assembly of the asymmetrically oriented PsaC subunit on the pseudo C₂-symmetric Photosystem I core. Based on a comparison of the differences in the NMR solution structure of unbound PsaC with that of the X-ray crystal structure of bound PsaC, and on a detailed analysis of the PsaC binding site surrounding the F_X iron-sulfur cluster, two models can be envisioned for what are likely the last steps in the assembly of Photosystem I. Here, we dissect both models and attempt to address heretofore unrecognized issues by proposing a mechanism that includes a thermodynamic perspective. Experimental strategies to verify the models are proposed. In closing, the evolutionary aspects of the assembly process will be considered, with special reference to the structural arrangement of the PsaC binding surface. Received 22 October 2008; received after revision 17 November 2008; accepted 05 December 2008     

Effects of exchange transfusion with perfluorochemical emulsions on hepatic oxygen supply and blood flow in the rat

Summary Exchange-transfusion to hematocrit 20 with isotonic perfluorochemical (PFC) emulsions containing 3% hydroxyethylstarch (HES) in rats breathing 100% oxygen produced significant reductions of hepatic PO₂ and blood flow in comparison to rats hemodiluted with isotonic 3% or 6% HES solution. The results indicate that PFC and/or emulsifiers were associated with adverse effects on liver blood supply.This work was supported by a grant from the Kentucky Affiliate of the American Heart Association.     

VIP and histamine H2 receptor activity in human fetal gastric glands

Summary Vasoactive intestinal peptide (VIP, EC₅₀=6.4×10^–10 M) and histamine (EC₅₀=3×10^–6 M) activated the cyclic AMP generating system in gastric glands isolated from two human fetuses at 23 weeks gestation. Histamine antagonism by the H₂ receptor blockers cimetidine (Ki=0.35×10^–6 M) and ranitidine (ki=0.51×10^–7 M) clearly characterized the histaminic activation as being of the H₂ type. It is suggested that these two vasoactive hormones may operate as neurocrine/paracrine regulators of the differentiation and/or function of the human gastric mucosa in utero.