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Stypoldione, a marine natural product that possesses an o-quinone functional group, has been shown to inhibit a variety of biological processes including cell division. We found that stypoldione binds covalently to sulfhydryl groups of thiol-containing compounds via addition of sulfur to the C-4' position of the quinone ring. We examined the ability of stypoldione to add to sulfhydryl groups of a number of thiol-containing substances, including glutathione, thiophenol, beta-mercaptoethanol, and the protein tubulin. We suggest that the biological actions of stypoldione may be caused by the addition of this compound to thiol groups of biological molecules.

The marine natural product manoalide (MLD) was shown to directly inactivate bee venom phospholipase A 2 (PLA 2 ). Inactivation was pH dependent (maximum inactivation occurred at pH 8.0), time dependent and concentration dependent. The IC 50 was estimated at 0.05 μM and virtually complete inactivation of the enzyme occurred at 4.0 μM. The time-dependent loss of PLA 2 activity suggested that inactivation does not follow typical Michaelis-Menten kinetics. Reversibility was studied directly by dilution and dialysis; both methods were ineffective in dissociating the MLD-PLA 2 complex. A kinetic plot of initial velocity ( v ) versus [PLA 2 ] supported our hypothesis that MLD apparently inactivates bee venom PLA 2 by an irreversible mechanism.

Understanding the fate of a single PCB isomer in a resident species may aid in assessing the risk to the marine community. Therefore, the elimination of 2,4,5,2',4',5'-hexachlorobiphenyl (HCBP) by the purple sea urchin, Strongylocentrotus purpuratus, following a single exposure, was investigated. The purple sea urchin was chosen because of its economic importance and ability to proliferate in certain polluted conditions. Single exposure may best mimic the effects of intermittent oceanic incineration or disposal, and 2,4,5,2',4',5'-HCBP was chosen due to its presence in common PCB mixtures and high chlorine content, thus strong lipophilicity.

The marine natural product manoalide (MLD), a potent inhibitor of phospholipases, completely inactivates bee venom phospholipase A2 (PLA2) by an irreversible mechanism. It has been proposed [K.B. Glaser and R.S. Jacobs, Biochem. Pharmac. 36, 2079 (1987)] that the reaction of MLD with PLA2 may involve the selective reactivity of MLD to a peptide sequence, possibly a Lys-X-X-Lys peptide. Localization of the MLD binding site on bee venom PLA2 demonstrated that upon MLD modification of bee venom PLA2 the only change in amino acid content was an apparent loss of Lys, corresponding to approximately three of the eleven Lys residues present. Selective chemical modification of Lys residues with [14C]maleic anhydride demonstrated that all eleven Lys residues on bee venom PLA2 were accessible to this reagent (11.6 mol maleyl group incorporated/mol of PLA2). Pretreatment of PLA 2 with MLD(

The effects of a structurally novel paralytic substance (lophotoxin) on quantal transmission parameters and the time course of synaptic potentials have been examined. This substance completely abolished potentials by reducing quantal size without affecting the release of quanta. Nerve conduction, membrane potential, and the passive electrical properties of the muscle end-plate remained unaffected. Lophotoxin appears to act directly on the acetylcholine receptor-channel complex, although perhaps not the cholinoreceptive site itself, as suggested by the unusual chemistry and onset kinetics of this toxin.

The marine natural product manoalide (MLD), a potent irreversible inhibitor of bee venom phospholipase A 2 (PLA 2 ), was shown to produce a chromophore ( λ max = 437 nm) during incubation with the enzyme. MLD also developed an identical chromophore when incubated with free lysine (Lys), cysteine (Cys) or tryptophan (Trp) but not with their N - α -amino-blocked analogs. These results suggest that the chromophore product was dependent on the presence of two nucleophilic groups which react by an ordered mechanism rather than by simple random collision. Lys polymers prevented MLD from inhibiting PLA 2 , whereas monomeric Lys did not. The optimal active polymer of Lys appeared to be a tetralysine (L 4 ) peptide, and a degree of selectivity was obtained when the Lys residues were in a 1,4-Lys arrangement. The rate of chromophore development with PLA 2 and the rate of inactivation of PLA 2 by MLD appear to be independent processes. Based on these data, it is possible that the irreversible inactivation of PLA 2 may involve an ordered reaction with a peptide sequence in PLA 2 containing a 1,4-Lys arrangement.

SummaryThe effects of nicotinic acid on serum lipids have been studied in rats. Significant decreases in serum triglyceride and cholesterol were observed in fasted rats 4 hours after oral administration of nicotinic acid. Greater reductions in triglyceride occurred than in cholesterol. In addition, in another study, oral or parenteral administration of nicotinic acid significantly inhibited fat-induced chylomicronemia.

Luffolide (4) is a minor metabolite of the sponge Luffariella sp. from Palau. The structure of luffolide was determined by single crystal X-ray analysis. Luffolide is relatively unstable and undergoes a complex cyclization reaction to give the hexacyclic products 5 and 6. Luffolide (4) has some of the anti-inflammatory properties of manoalide (1): this may help to define the chemical reaction between manoalide (1) and phospholipase A2.

A new ochtodane from Chondrococcus hornemanii and the biotoxocity of other seaweed monoterpenes is reported.

SummaryLarge doses of testosterone blocked urinary electrolyte effects of desoxycorticosterone acetate (DCA) in adrenalectomized rats. The steroid reversed the Na/K response to DCA by simultaneously blocking Na retention and K loss. It did not affect Na/K in a manner opposing DCA action when given alone. These observations suggest competitive inhibition as the mechanism of effect for testosterone. Unlike progesterone, it was devoid of DCA-like effects on Na/K given alone, and it gave increasing DCA-blocking effect over a relatively wide range of doses.

SummaryThe mineralocorticoid effects of 9α-fluorodeoxycorticosterone acetate were investigated in adrenalectomized rats. A quantitative 4-point assay gave potency estimates of 12 and 14.3 for the steroid relative to DCA, as judged by reduction of urinary Na excretion and the ratio of Na K. respectively. Thus, addition of a 9α-fluoro radical can increase mineralocorticoid activity in a steroid lacking oxygen function at carbon 11. These and other published data suggest that 9α-halogenation plays a singularly important part in high DCA-like activity of various 9α-halo corticosteroids.

The irreversible neurotoxic action of beta-bungarotoxin (beta-BuTx) can be prevented by preincubation of the toxin with manoalide, a non-steroidal anti-inflammatory agent. Manoalide was also found to inactivate purified phospholipase A2 and thus prevent hydrolysis of phosphatidylcholine. PLA2 is a component found in several neurotoxic venoms and is also a rate limiting enzyme important in phospholipid metabolism and prostaglandin synthesis in man.

1 A double-blind trial with parallel treatment groups was conducted to compare the safety and efficacy of mianserin with amitriptyline. 2 This was a six week trial with weekly visits. Measurements at each visit included: 21 item Hamilton Depression (HAMD) Scale. Clinical Global Impression (CGI) Scale and Treatment Emergent Symptom Scale (TESS). 3 Mianserin and amitriptyline were comparable with respect to efficacy. 4 More adverse experiences were reported by amitriptyline patients. The predominant amitriptyline adverse experiences were of the anticholinergic type; the predominant mianserin adverse experience was drowsiness/fatigue. 5 The Efficacy Index (EI), a scale combining efficacy and adverse experiences, clearly demonstrated the superiority of mianserin over amitriptyline.

A new neuromuscular toxin, lophotoxin, has been isolated from several pacific gorgonians of the genus Lophogorgia. The structure of lophotoxin was deduced by combined spectrochemical methods, and belongs to the well-known cembrene class of diterpenoid molecules. Lophotoxin contains furanoaldehyde and alpha, beta-epoxy-gamma-lactone functional groups, in sharp contrast to the cationic ammonium functional groups of the established neurotoxins.

Stypoldione, a marine natural product that possesses an o-quinone functional group, has been shown to inhibit a variety of biological processes including cell division. We found that stypoldione binds covalently to sulfhydryl groups of thiol-containing compounds via addition of sulfur to the C-4' position of the quinone ring. We examined the ability of stypoldione to add to sulfhydryl groups of a number of thiol-containing substances, including glutathione, thiophenol, beta-mercaptoethanol, and the protein tubulin. We suggest that the biological actions of stypoldione may be caused by the addition of this compound to thiol groups of biological molecules.

Lophotoxin, a compound isolated from corals of the genus Lophogorgia, produced paralysis and death when injected s.c. in mice ( ld 50 = 8.9 mg/kg ). In the isolated rat phrenic nerve-hemidiaphragm preparation, lophotoxin irreversibly abolished nerve-stimulated contraction but did not affect the contraction produced by direct stimulation of the muscle. In the frog rectus abdominis preparation, ACh-induced contractures were blocked by lophotoxin, but KCl-induced contractures were not affected. Though these findings do not exclude the possibility of a presynaptic action of lophotoxin on axons and/or nerve terminals, they do indicate that the toxin produces an irreversible postsynaptic blockade at the neuromuscular junction.

Stypoldione (Fig. 1), an ortho-quinone monoalcohol with a molecular weight of 426, is derived from the brown seaweed Stypopodium zonale. It was found as part of a study by Gerwick & Fenical (1981) in which mechanisms of chemical defense against foraging in the marine environment were being elucidated. Living samples of the alga had been observed to be toxic to fish in aquaria, and algal extracts were then investigated using icthyotoxicity as an indication of biological activity. Stypoldione was not the most potent of the compounds extracted from S. zonale, but due to its chemical stability, was chosen as representative of the compounds isolated.

The standard method for quantification and presentation of an experimental variable in real time is the use of visual display on the ordinate of an oscilloscope screen or chart recorder. This paper describes a relatively simple electronic circuit, using commercially available and inexpensive integrated circuits (IC), which generates an audible tone, the pitch of which varies in proportion to a running variable of interest. This device, which we call an "Audioscope," can accept as input the monitor output from any instrument that expresses an experimental parameter as a dc voltage. The Audioscope is particularly useful in implanting microelectrodes intracellularly. It may also function to mediate the first step in data recording on magnetic tape, and/or data analysis and reduction by electronic circuitary. We estimate that this device can be built, with two-channel capability, for less than $50, and in less than 10 hr by an experienced electronics technician.

The marine natural product lophotoxin has produced a non-reversible antagonism of parasympathetic and sympathetic functions that are known to be mediated by C6 sub-type nicotinic receptors. Transmission through anuran paravertebral ganglia was eliminated in 20-40 min by 10-30-min treatments with 16-32 microM lophotoxin, in a time course resembling the onset of block of C10 sub-type nicotinic receptors at the neuromuscular junction and in cultured BC3H-1 cells. The action persisted through 16 h of washout. Nerve conduction was unaffected. Somewhat longer treatments (80 min) of in vitro ileal sections resulted in loss of sensitivity to nicotine, but not to acetylcholine, for at least 5 h. These data indicate that lophotoxin can serve as a more universal nicotinic receptor probe than the alpha-neurotoxins, which may bind to both C6 and C10 sub-types, but block only the C10.

The results of research conducted in ground-based flight simulators must be interpreted with care in view of the potential effects of differences between the simulated and actual flight environments. A study comparing various flight-director displays in a moving-base simulator was replicated without motion. Significantly different results occurred as a function of the presence or absence of motion. Implications of these results raise doubt concerning the validity of findings from simulator experiments in which whole-body acceleration cues might be a factor.