Influence of cholesterol and prostaglandin E1 on the molecular organization of phospholipids in the erythrocyte membrane. A fluorescent polarization study with lipid-specific probes

Anthryl-labeled fluorescent probes closely mimicking phosphatidylcholine and sphingomyelin were applied to study the state of these phospholipids in the rabbit erythrocyte membrane. At normal cholesterol levels both probes exhibited higher fluorescence polarization values in the membranes than in phospholipid vesicles of similar lipid composition, indicating a decreased fluidity of the probe environment in erythrocyte ghosts. In ghosts prepared from normal erythrocytes no evidence of lateral separation of phosphatidylcholine and sphingomyelin was found. At higher cholesterol levels, however, these lipids appear to segregate. Probably the effect of cholesterol on the erythrocyte membrane lipids involves lipid-protein interactions. At physiological concentrations, prostaglandin E1 only weakly affects the state of phosphatidylcholine and sphingomyelin in erythrocyte membranes. Cholesterol enrichment amplifies the effect of prostaglandin E1. Although the prostaglandin E1-induced changes depended much upon whether the ghosts were enriched with cholesterol in vitro or in vivo, with both types of ghosts effects of prostaglandin E1 were seen at extremely low effector concentrations that may have presented a few molecules of prostaglandin per ghost. The structural and functional significance of these findings is discussed.     

A Novel Fluorescent Analog of the Dopamine Reuptake Inhibitor GBR12909

Russian Journal of Bioorganic Chemistry - Dopamine transporter is a transmembrane protein associated with regulation of dopaminergic signal transmission by dopamine reuptake from the synaptic cleft...     

O-Nitration of Prostaglandins: Synthesis of 15-O-Nitrates of 11-Deoxyprostaglandin E1 and Its Methyl Ester

O-Nitration of the allylic hydroxyl group in prostaglandins and the synthesis of 15-O-nitrates of 11-deoxyprostaglandin E₁ and its methyl ester are described for the first time.     

Arachidonoylcholine and N,N-dimethylaminoethyl arachidonate are new cholinergic compounds]

Choline and N,N-dimethylaminoethyl esters of arachidonic and some other fatty acids were synthesized. Experiments on the embryos and larvae of sea urchins, sensitive to cholinergic compounds, showed that arachidonoylcholine exhibited cholinomimetic activity similar to that of nicotine whereas N,N-dimethylaminoethyl arachidonate acted as an acetylcholine antagonist. The corresponding esters of docosahexaenoic acid displayed similar biological properties.     

O-Nitration of prostaglandins: synthesis of 15-O-nitrates of 11-deoxyprostaglandin E1 and its methyl ester

O-Nitration of the allylic hydroxyl group in prostaglandins and the synthesis of 15-O-nitrates of 11-deoxyprostaglandin E1 and its methyl ester are described for the first time.     

Cholinergic regulation of the sea urchin embryonic and larval development

Choline esters of polyenoic fatty acids block cleavage divisions of sea urchins and evoke the formation of one-cell multinuclear embryos. If the fatty acids AA-Ch or DHA-Ch are added at the mid or late blastula stage, many cells are extruded, forming extra-embryonic cell clusters near the animal pole of embryos or larvae. Both effects are prevented by dimethylaminoethyl esters of polyenoic fatty acids (AA-DMAE or DHA-DMAE) or their 5-hydroxytryptamides. Nicotinic acetylcholine receptor antagonists, imechine, d-tubocurarine or QX-222 provide partial protection against AA-Ch or DHA-Ch. The organophosphate pesticide, chlorpyrifos, or a combination of (-)-nicotine + phorbol 12-myristate 13-acetate, also evoke the mass extrusion of transformed embryonic cells at the animal pole of larvae. These effects are similarly antagonized by AA-DMAE, DHA-DMAE, or fatty acids 5-hydroxytryptamides. Taking together, these results suggest that AA-Ch and DHA-Ch act on sea urchin embryos and larvae as agonists of acetylcholine receptors, whereas AA-DMAE and DHA-DMAE act as antagonists. The ability of fatty acids 5-hydroxytryptamides to prevent the effects of AA-Ch or DHA-Ch may be due to restoration of the normal dynamic balance of cholinergic and serotonergic signaling during cleavage divisions and gastrulation.     

Rabbit plasma metabolomic analysis of Nitroproston®: a multi target natural prostaglandin based-drug

Introduction

Nitroproston® is a novel multi-target drug bearing natural prostaglandin E₂ (PGE₂) and nitric oxide (NO)-donating fragments for treatment of inflammatory and obstructive diseases (i.e., asthma and obstructive bronchitis).

Objectives

To investigate the effects of Nitroproston® administration on plasma metabolomics in vivo.

Methods

Experimental in vivo study randomly assigning the target drug (treatment group) or a saline solution without the drug (vehicle control group) to 12 rabbits (n?=?6 in each group). Untargeted (5880 initial features; 1869 negative–4011 positive ion peaks; UPLC–IT–TOF/MS) and 84 targeted moieties (Nitroproston® related metabolites, prostaglandins, steroids, purines, pyrimidines and amino acids; HPLC–QQQ–MS/MS) were measured from plasma at 0, 2, 4, 6, 8, 12, 18, 24, 32 and 60 min after administration.

Results

PGE₂, 13,14-dihydro-15-keto-PGE₂, PGB₂, 1,3-GDN and 15-keto-PGE₂ increased in the treatment group. Steroids (i.e., cortisone, progesterone), organic acids, 3-oxododecanoic acid, nicotinate d-ribonucleoside, thymidine, the amino acids serine and aspartate, and derivatives pyridinoline, aminoadipic acid and uric acid increased (p?<?0.05 AUCROC curve?>?0.75) after treatment. Purines (i.e., xanthine, guanine, guanosine), bile acids, acylcarnitines and the amino acids l-tryptophan and l-phenylalanine were decreased. Nitroproston® impacted steroidogenesis, purine metabolism and ammonia recycling pathways, among others.

Conclusion

Nitroproston®, a multi action novel drug based on natural prostaglandins, altered metabolites (i.e., guanine, adenine, cortisol, cortisone and aspartate) involved in purine metabolism, urea and ammonia biological cycles, steroidogenesis, among other pathways. Suggested mechanisms of action, metabolic pathway interconnections and useful information to further understand the metabolic effects of prostaglandin administration are presented.