Modulation of endothelial permeability by 1‐O‐alkylglycerols

Abstract

Regulation of endothelial barrier function often occurs through signalling involving phospholipase C activation which produces diacylglycerol (DAG), a lipidic second messenger activator of protein kinase C (PKC). Therefore, modification of lipidic composition of endothelial cell membranes might modify DAG production and, as a result, alter regulation of endothelial permeability. We investigated the in vitro effects of natural 1-O-alkylglycerols on porcine aortic endothelial cell permeability to dye-labelled albumin. [3H]-1-O-alkylglycerols (10 microm) were substantially incorporated into phosphatidylcholine (6.6%) and phosphatidylethanolamine (4.4%). Stimulation of endothelial cell monolayer with phorbol-myristate-acetate or with the calcium ionophore A23187 resulted in a raise in permeability to albumin. Pre-treatment with 1-O-alkylglycerols (10 microm, 24 h) had no effect on basal albumin permeability but totally inhibited the effect of phorbol-myristate-acetate, and brought the permeability of A23187-stimulated endothelial cell monolayers below control. After incubation of cells with [3H]-1-O-alkylglycerols (10 microm, 24 h), we detected the production of the analogue of DAG, and PKC inhibitor, [3H]-1-O-alkyl-2-acyl-glycerol, in resting cells. This production was increased by 58% under A23187 stimulation while phorbol-myristate-acetate had no effect. Our data demonstrate that natural 1-O-alkylglycerols modify endothelial permeability, and suggest that this effect could be mediated through alteration of lipidic signalling.

Nanoparticles of alkylglyceryl-dextran-graft-poly(lactic acid) for drug delivery to the brain: Preparation and in vitro investigation

“…While there was no evidence of targeting the nuclei, the nanoparticles appeared to have been localised in vesicles (possibly Golgi apparatus, as previously demonstrated for CS-OX4 nanoparticles). [21] The effect of PLA-DEX and PLA-DEX-OX4 nanoformulations on the integrity of confluent endothelial cell monolayers was investigated by monitoring changes in the transendothelial resistance (TEER) of either mouse bEnd3 or human hCMEC/D3 cell monolayers, both during incubation and following removal of nanoparticles. The mouse model reached $800 X resistance while the human model exhibited a resistance of $1500 X when the cell cultures achieved confluence (ca.…”

“…Considered non-toxic and non-immunogenic, dextran has been used historically as a safe plasma expander [18] and also to impart stabilisation in the blood-stream and ''stealth'' properties to injectable nanoparticles [19,20]. Among the materials investigated for enhancing drug penetration across the BBB, alkylglycerols have been shown to encourage a strong but transient increase in the transport of actives into the brain [21][22][23][24]. If co-administered into the right internal carotid artery, the same materials have been found to increase brain uptake of certain antineoplastic agents (such as cisplatin and methotrexate) or antibiotics (such as vancomycin and gentamycin) in C6 glioma bearing rats and animals with RG2 implanted tumours [25,26].…”

Chronic Supplementation With Shark Liver Oil for Reducing Tumor Growth and Cachexia in Walker 256 Tumor-Bearing Rats

“…Like n-3 PUFA, 1-O-alkylglycerols can insert in cell membrane and serve as a substrate for the formation of second messengers with ether linkage in the chemical structure, which are able to interfere in protein kinase C activity, involved in control of cell proliferation and differentiation (42,(57)(58)(59). Therefore it is necessary to consider that 1-O-alkylglycerol from SLO can contribute to tumor weight and cachexia reduction.…”

“…4) when compared to respective non-tumor-bearing groups (CSLO and C) and to preserve more body mass ( Table 1). The effect of SLO supplementation in tumor-bearing individuals has been reported especially in relation to its capacity in improving immune defenses (22,23,(27)(28)(29)(30)(42)(43)(44). However, we are not aware of other research groups, which studied the effect of SLO on cancer cachexia.…”

Ether lipids

“…Regarding the DAG analogues, 1-O-alkyl-2-acetyl-sn-glycerols as inhibitors of PKC raises the question about a probable anticancer effect of alkylglycerols, not only by direct PKC inhibition, but by their first incorporation into plasmanyl-phospholipids in cell membranes which release the DAG analogues by the action of phospholipase C. Such incorporation of alkylglycerols into plasmanyl-phospholipids, serving as precursors of the PKC inhibitors, 1-O-alkyl-2-acetyl-sn-glycerols has been demonstrated in porcine aortic endothelial cells (Marigny et al, 2002).…”