A new indolic antiauxin, α-(5,7-dichloroindole-3-)isobutyric acid: its chemical synthesis and biological activity

Summary A new potent antiauxin, -(5,7-dichloroindole-3-)isobutyric acid has been synthesized and shown to inhibit auxin-mediated elongation ofAvena coleoptiles and to stimulate root growth of rice seedlings. Its activity is stronger than -(p-chlorophenoxy)isobutyric acid and is comparable to that of 2,3,5-triiodobenzoic acid, which are typical antiauxins.     

In vivo effects of immunostimulating lipopeptides on mouse liver microsomal cytochromes P-450 and on paracetamol-induced toxicity

Summary Immunomodulating lipopeptides lauroyl-L-Ala--D-Glu-LL-A2pmNH2-Gly (RP 44.102) and lauroyl-L-Ala--D-Glu-LL-A2pmNH2 (RP 56.142) were found to protect mice against the hepatotoxicity of paracetamol, which is due to cytochrome P-450 dependent formation of toxic metabolites and radicals. In fact they decreased the amount of hepatic microsomal cytochrome P-450, and the level of CCl₄-induced lipid peroxidation. In contrast lauroyl-L-Ala--D-Glu-DD-A2pmNH2 (RP 53.204), which only differs by the configuration of the two chiral carbons of A2pm (diaminopimelic acid) and is not an immunomodulating agent, failed to protect against poisoning by paracetamol and had no effect on the level of hepatic cytochrome P-450 or the microsomal CCl₄-induced lipid peroxidation. This provides a clear connection between the immunostimulating properties of a compound and its effects on xenobiotic biotransformations.     

Evolutionary and ecological implications of cardenolide sequestration in the monarch butterfly

Summary Monarch butterflies sequester cardenolides from their larval host plants in the milkweed genusAsclepias for use in defense against predation. Of 108Asclepias species in North America, monarchs are known to feed as larvae on 27. Research on 11 of these has shown that monarchs sequester cardenolides most effectively, to an asymptote of approximately 350 g/0.1 g dry butterfly, from plants with intermediate cardenolide contents rather than from those with very high or very low cardenolide contents. SinceAsclepias host plant species are distributed widely in space and time across the continent, monarchs exploit them by migration between breeding and overwintering areas. After overwintering in central Mexico, spring migrants east of the Rocky Mountains exploit three predominantAsclepias species in the southern USA that have moderately high cardenolide contents. Monarchs sequester cardenolides very effectively from these species. First generation butterflies are thus well protected against predators and continue the migration north. Across the northern USA and southern Canada most summer breeding occurs on a fourthAsclepias species and in autumn most of these monarchs migrate back to Mexican overwintering sites. The ecological implications of this cycle of cardenolide sequestration for the evolution of monarch migration are discussed.     

Lack of effect of dihydroergotamine on endothelial and smooth muscle cell proliferation and endothelial cell prostanoid production

Summary The most important effect of dihydroergotamine is venoconstriction, but certain metabolic effects and changes in vessel prostanoid activity have also been suggested. In this study endothelial cell production of 6-keto PGF₁ and TxB₂ was quantitated in vitro. No evidence of altered prostanoid production was noted after incubation with dihydroergotamine (exposure ranging from 5×10^–3 to 5×10^–7 g/l). Similarly, no effect of dihydroergotamine on the growth rates of endothelial cells or smooth muscle cells in vitro was documented.     

Zinc antagonizes the effect of botulinum type A toxin at the mouse neuromuscular junction

Summary Zn²⁺ (10–100 M) elevated the frequency of miniature end-plate potentials (MEPPs) in the mouse diaphragm. The effect did not depend on external Ca²⁺. Botulinum type A toxin (BTX_A, 50 ng/ml) abolished MEPPs almost completely within 30 min. Zn²⁺ (100 M) restored MEPPs and increased their frequency after they had been abolished by BTX_A in Ca²⁺-free solutions. The antagonistic effect of Zn²⁺ in the Ca²⁺-free solution was reduced by exposing the diaphragm to the toxin in the Ca²⁺-free solutions containing high K⁺. Thus, the action of BTX_A is probably enhanced by depolarization of the motor nerve terminals.     

Submarine hot springs and the origin of life

The discovery of hydrothermal vents at oceanic ridge crests and the appreciation of their importance in the element balance of the oceans is one of the main recent advances in marine geochemistry. It is likely that vents were present in the oceans of the primitive Earth because the process of hydrothermal circulation probably began early in the Earth's history. Here we examine the popular hypothesis that life arose in these vents. This proposal, however, is based on a number of misunderstandings concerning the organic chemistry involved. An example is the suggestion that organic compounds were destroyed on the surface of the early Earth by the impact of asteroids and comets, but at the same time assuming that organic syntheses can occur in hydrothermal vents. The high temperatures in the vents would not allow synthesis of organic compounds, but would decompose them, unless the exposure time at vent temperatures was short. Even if the essential organic molecules were available in the hot hydrothermal waters, the subsequent steps of polymerization and the conversion of these polymers into the first organisms would not occur as the vent waters were quenched to the colder temperatures of the primitive oceans.     

Effect of protein kinase C activation and depletion on insulin stimulation of glycogen synthesis in cultured hepatoma cells

Summary Insulin stimulation of glycogen synthesis was nearly abolished in hepatoma cells shortly treated with 4 ß-phorbol 12 \-myristate, 13 -acetate (protein kinase C activation) but remained unmodified in cells chronically treated with the phorbol ester (protein kinase C depletion). Thus, although exogenous activation of protein kinase C results in an inhibition of insulin action, protein kinase C depletion has no influence on this process. The results suggest that, in hepatoma cells, no endogenous activation of protein kinase C may occur in response to the signal triggered by insulin.     

The dead-end elimination theorem and its use in protein side-chain positioning

The prediction of a protein's tertiary structure is still a considerable problem because the huge amount of possible conformational space1 makes it computationally difficult. With regard to side-chain modelling, a solution has been attempted by the grouping of side-chain conformations into representative sets of rotamers2??. Nonetheless, an exhaustive combinatorial search is still limited to carefully indentified packing units?? containing a limited number of residues. For larger systems other strategies had to be developed, such as the Monte Carlo Procedure?? and the genetic algorithm and clustering approach?. Here we present a theorem, referred to as the 'dead-end elimination' theorem, which imposes a suitable condition to identify rotamers that cannot be members of the global minimum energy conformation. Application of this theorem effectively controls the computational explosion of the rotamer combinatorial problem, thereby allowing the determination of the global minimum energy conformation of a large collection of side chains.     

Comparative aspects of structure and action of molluscan neuropeptides

A number of neuropeptides were isolated from the ganglia and muscles of molluscs, and their actions were examined. Diverse neuropeptides, in addition to several classical neurotransmitters, were suggested to be involved in the regulation of the anterior byssus retractor muscle ofMytilus. A wide structural variety of members of theMytilus inhibitory peptide family was observed in each of the generaMytilus, Achatina andHelix. Gly-Trp-NH₂, the C-terminal dipeptide fragment of the neuropeptide AGPWamide, showed a more potent action than the parent peptide in all of the muscles examined. Peptides related to some molluscan neuropeptides were found to be distributed interphyletically. Some neuropeptides containing ad-amino acid residue were found inAchatina andMytilus. These aspects of molluscan neuropeptides are thought not to be exceptional.     

Changes in erythrocyte membrane lipid composition affect the transient decrease in membrane order which accompanies insulin receptor down-regulation

We have recently demonstrated, using electron paramagnetic resonance (EPR) spectroscopy, that insulin receptor internalization in response to insulin incubation (down-regulation) in human erythrocytes is accompanied by a transient decrease in membrane order, as measured by the 2T order parameter. Since membrane lipids play such an important role in receptor internalization, we investigated the possible effects that an alteration of the normally-occurring lipid profile might have on down-regulation and the concomitant transient decrease in membrane order. Consequently, human erythrocytes enriched with cholesterol and erythrocytes from cirrhotic patients were examined, because both of these groups of cells have a higher cholesterol/phospholipid molar ratio (CH/PL) than controls. The 5-nitroxystearate spin label, which inserts into the lipid bilayer of cell membranes, was used to monitor changes in 2T for a 3-h period at 37°C. We report here that both cholesterol-enriched and cirrhotic erythrocytes do not down-regulate, as demonstrated by binding assays, and that they do not show the typical transient decrease in membrane order observed in controls. The results seem to indicate that a more ordered membrane inhibits internalization of the insulin receptor in erythrocytes, and that an increase in membrane disorder is necessary for insulin receptor down-regulation.