The Marine Natural Product 3,5‐dibromo‐2‐(2,4‐dibromo‐phenoxy)phenol, Inhibits Contractile Activity in the Guinea‐pig Ileum

Abstract

1. The tetrabrominated diphenyl ether 3,5-dibromo-2-(2,4-dibromophenoxy)phenol (BPE), a natural marine product isolated from a sponge, was tested for pharmacological activity in guinea-pig ileum. 2. BPE (2 mumol/L) decreased basal force and the frequency of spontaneous contractions of the ileum. It also significantly decreased contractions of the ileum induced by 5 mmol/L barium and to electrical stimulation at parameters which stimulated intrinsic nerves. 3. The slopes of concentration-response curves to acetylcholine (ACh), histamine and 5-hydroxytryptamine (5-HT) were significantly reduced by BPE at concentrations of 2 mumol/L or greater. 4. BPE (2 mumol/L) did not affect calcium-induced contractions of longitudinal muscle fibres from guinea-pig ileum which were stripped of their cellular membrane. It (6 mumol/L) also had no effect on ATP levels in longitudinal muscle fibres. 5. BPE (2 mumol/L) reduced both phasic and tonic components of contractions induced by raising the extracellular concentration of K+ to 15, 30, 45 or 60 mmol/L (in the presence of atropine, propranolol, phentolamine and desensitization to 5-HT to inhibit the effects of nerve transmitter release). 6. BPE (2 mumol/L) reduced carbachol-induced contractions of ileum pre-incubated in 1 mumol/L felodipine, a blocker of L-type voltage-operated calcium channels (VOCC). 7. BPE dose dependently (0.6-6 mumol/L) reduced contractions induced by Ca2+ in both K+ depolarized ileum and in tissue exposed to carbachol (10 mumol/L) in the presence of felodipine (0.1 mumol/L). 8. These results suggest that BPE affects intracellular messenger systems controlling cytosolic calcium and/or blocks entry of calcium into the cell through both VOCC and receptor-operated channels (ROC).

Low endemism, continued deep-shallow interchanges, and evidence for cosmopolitan distributions in free-living marine nematodes (order Enoplida)

“…Morphological evidence previously indicated that most deep-sea genera are ubiquitous and benthic community assemblages are similar worldwide [18], although a number of novel deep-sea genera had been identified [19-21]. Within our dataset, deep-sea specimens comprised a taxonomically diverse group of genera representing every major phylogenetic lineage in the Enoplida (Figure 1).…”

“…This genus does not appear to have any recent shallow-water relatives in molecular phylogenies and appears to have split off early from other genera within the Enchelidiidae (Clade IIa, Figure 1); more extensive sampling is needed to further elucidate generic relationships within this family. Similarly, the genus Cricohalalaimus (Clade IIIc, Figure 1) has only been described from deep-sea sediments [19]-- molecular evidence indicates that this taxon represents a divergent lineage that is most closely related to genera Thalassoalaimus and Litinium (SSU and LSU support values >98%), even though the distinct morphology of Cricohalalaimus does not intuitively suggest a relationship with either group.…”

Purification of a New Dimeric Protein fromCliona vastificaSponge, which Specifically Blocks a Non-L-Type Calcium Channel in Mouse Duodenal Myocytes

“…Many other peptides with biological activity have been isolated from sponges, but as far as we know, no calcium channel effectors have been described until now. A previous report has shown that sponge extracts are able to block carbachol-induced contractions in intestinal smooth muscle, which are insensitive to dihydropyridines (21). These observations suggest that these organisms could synthesize calcium channel effectors.…”

Certain ortho-hydroxylated brominated ethers are promiscuous kinase inhibitors that impair neuronal signaling and neurodevelopmental processes

“…2) disruptions of calcium homeostasis/signaling as shown in one of the earliest mechanistic studies of PBDEs (26) and more recently demonstrated in several cell types including human neuronal precursors (27,28); 3) toxicity produced by mitochondrial disruptions including uncoupling of oxidative phosphorylation (29) and subsequent elevated production of reactive oxygen species (ROS) which can lead to DNA damage and apoptosis; 4) dysregulation of epigenetic mechanisms including DNA methylation, chromatin dynamics, and non-coding RNAs--an emerging point of investigation that we have recently reviewed (30). It is possible that one or more of these molecular mechanisms contribute to exposure-related behavioral abnormalities; however, the extent of their involvement, if any, remains unclear.…”