Alkylglycerols Research Articles

Anti-Angiogenic and Cytotoxicity Effects of Selachyl Alcohol Analogues

The active ingredients in the shark liver oil (SLO) mixture were found to be a group of etherlinked glycerol known as alkylglycerols (AKGs). During the last century, initial clinical use of the SLO mixture was for treating leukemias and later preventing radiation sickness from cancer x-ray therapy. Selachyl alcohol is one of the most abundant AKGs in the SLO mixture and it displayed strong activity in reducing lung metastasis number on a model of grafted tumor in mice (Lewis lung carcinoma cells). In this study, selachyl alcohol analogue containing methoxyl (7), gem-difluorinated (8), azide (9) and hydroxyl (10) group at the 12 position in the alkyl chain were synthesized and compared regarding their cytotoxicity and anti-migratory effects on Human Umbilical Vein Endothelial Cell line. AKGs 7-10 were synthesized according to the literature procedure. The cytotoxicity of the studied AKGs was evaluated by the MTT test and Human Umbilical Vein Endothelial Cell line (HUVEC) was used as an in vitro model to evaluate their anti-migratory effects. The four AKGs have substantially the same toxicity threshold (≥ 12 μM), whereas they have an anti-migratory activity significantly different on endothelial cells. AKGs 9 and 10 significantly reduce the chemotactic migration induced by VEGF, but analogue (10) containing the hydroxyl group at the 12 position in the alkyl chain was the most potent anti-VEGF inhibitor. We presented here a series of four synthetic selachyl alcohol analogues, among which AKGs 9 and 10 showed the ability to inhibit endothelial cell migration. The relationship structures and anti-VEGF effects of these analogues were also evaluated and discussed. Unnatural synthesized AKGs could be explored as one new source of anticancer agents.

Development of a High-Performance Thin-Layer Chromatography Method for the Quantification of Alkyl Glycerolipids and Alkenyl Glycerolipids from Shark and Chimera Oils and Tissues

Ether lipids are composed of alkyl lipids with an ether bond at the sn-1 position of a glycerol backbone and alkenyl lipids, which possess a vinyl ether bond at the sn-1 position of the glycerol. These ether glycerolipids are present either as polar glycerophospholipids or neutral glycerolipids. Before studying the biological role of molecular species of ether glycerolipids, there is a need to separate and quantify total alkyl and alkenyl glycerolipids from biological samples in order to determine any variation depending on tissue or physiopathological conditions. Here, we detail the development of the first high-performance thin-layer chromatography method for the quantification of total alkyl and alkenyl glycerolipids thanks to the separation of their corresponding alkyl and alkenyl glycerols. This method starts with a reduction of all lipids after extraction, resulting in the reduction of neutral and polar ether glycerolipids into alkyl and alkenyl glycerols, followed by an appropriate purification and, finally, the linearly ascending development of alkyl and alkenyl glycerols on high-performance thin-layer chromatography plates, staining, carbonization and densitometric analysis. Calibration curves were obtained with commercial alkyl and alkenyl glycerol standards, enabling the quantification of alkyl and alkenyl glycerols in samples and thus directly obtaining the quantity of alkyl and alkenyl lipids present in the samples. Interestingly, we found a differential quantity of these lipids in shark liver oil compared to chimera. We quantified alkyl and alkenyl glycerolipids in periprostatic adipose tissues from human prostate cancer and showed the feasibility of this method in other biological matrices (muscle, tumor).

Oral Supplementation of an Alkylglycerol Mix Comprising Different Alkyl Chains Effectively Modulates Multiple Endogenous Plasmalogen Species in Mice.

Plasmalogens or alkenylphospholipids are a sub-class of glycerophospholipids with numerous biological functions and are thought to have protective effects against metabolic disease. Dietary supplementation with alkylglycerols (AKGs) has been shown to increase endogenous plasmalogen levels, however effective modulation of different molecular plasmalogen species has not yet been demonstrated. In this study, the effects of an orally-administered AKG mix (a mixture of chimyl, batyl and selachyl alcohol at a 1:1:1 ratio) on plasma and tissue lipids, including plasmalogens, was evaluated. Mice on a Western-type diet were treated with either an AKG mix or vehicle (lecithin) for 1, 2, 4, 8 and 12 weeks. Treatment with the AKG mix significantly increased the total plasmalogen content of plasma, liver and adipose tissue as a result of elevations in multiple plasmalogen species with different alkenyl chains. Alkylphospholipids, the endogenous precursors of plasmalogens, showed a rapid and significant increase in plasma, adipose tissue, liver and skeletal muscle. A significant accumulation of alkyl-diacylglycerol and lyso-ether phospholipids was also observed in plasma and tissues. Additionally, the dynamics of plasmalogen-level changes following AKG mix supplementation differed between tissues. These findings indicate that oral supplementation with an AKG mix is capable of upregulating and maintaining stable expression of multiple molecular plasmalogen species in circulation and tissues.

Natural and Enantiopure Alkylglycerols as Antibiofilms Against Clinical Bacterial Isolates and Quorum Sensing Inhibitors of Chromobacterium violaceum ATCC 12472

Resistance mechanisms occur in almost all clinical bacterial isolates and represent one of the most worrisome health problems worldwide. Bacteria can form biofilms and communicate through quorum sensing (QS), which allow them to develop resistance against conventional antibiotics. Thus, new therapeutic candidates are sought. We focus on alkylglycerols (AKGs) because of their recently discovered quorum sensing inhibition (QSI) ability and antibiofilm potential. Fifteen natural enantiopure AKGs were tested to determine their effect on the biofilm formation of other clinical bacterial isolates, two reference strains and their QSI was determined using Chromobacterium violaceum ATCC 12472. The highest biofilm inhibition rates (%) and minimum QS inhibitory concentration were determined by a microtiter plate assay and ciprofloxacin was used as the standard antibiotic. At subinhibitory concentrations, each AKG reduced biofilm formation in a concentration-dependent manner against seven bacterial isolates, with values up to 97.2%. Each AKG displayed QSI at different levels of ability without affecting the growth of C. violaceum. AKG (2S)-3-O-(cis-13’-docosenyl)-1,2-propanediol was the best QS inhibitor (20 μM), while (2S)-3-O-(cis-9’-hexadecenyl)-1,2-propanediol was the least effective (795 μM). The results showed for the first time the QSI activity of this natural AKG series and suggest that AKGs could be promising candidates for further studies on preventing antimicrobial resistance.

Enrichment of Alkylglycerols and Docosahexaenoic Acid via Enzymatic Ethanolysis of Shark Liver Oil and Short-path Distillation

ABSTRACT Enzymatic alcoholysis of squalene-free shark liver oil (SLO) for the enrichment of alkylglycerols (AKG) and docosahexaenoic acid (DHA) was investigated. The squalene-free SLO contained 75.11% triacylglycerols (TAG) and 18.69% diacylglycerol ethers (DAGE), and its DHA and total AKG contents were 7.52% and 6.17%, respectively. The catalytic discrimination against both DAGE and DHA was observed during the reaction, and the discrimination against DAGE was affected by lipase and reaction conditions. The ethanolysis reaction was carried out at 40°C for 24 h, where the reaction medium contained 20% ethanol and 3% Lipozyme® 435. The ethanolysis derivatives with 62.96% monoacylglycerol ethers, 30.93% monoacylglycerols, and 5.88% DAGE were obtained followed by short-path distillation, and its DHA and total AKG contents were improved to 23.17% and 33.98%, respectively. The study provides an approach for value-added utilization of SLO with low contents of AKG and n-3 polyunsaturated fatty acids.

Enzymatic Synthesis of Ether Lipids Rich in Docosahexaenoic Acid with Squalene as Reaction Medium

AbstractUsing squalene as reaction medium was tried for the enzymatic synthesis of ether lipids rich in docosahexaenoic acid (DHA) via transesterification of alkylglycerols (AKG) obtained from shark liver oil and DHA‐enriched ethyl esters (DHA‐EE) from Schizochytrium sp. The effects of reaction time, temperature, molar ratio (AKG /DHA‐EE), and enzyme dosage were investigated. DHA conversion of 74.47% was achieved for 48 hours of reaction at 60 °C using a molar ratio of 1:2 and an enzyme dosage of 30% based on AKG in the presence of squalene with Lipozyme® 435 (Novozymes, Tianjin, China) as the catalyst. With a high boiling point, squalene could act as a solvent without being vaporized from the reaction system under vacuum and improve the operational stability of immobilized lipase, which may be useful for enzymatic reactions under vacuum for lipid modification with byproducts of low boiling points.

Tolerability and Safety of a Nutritional Supplement with Potential as Adjuvant in Colorectal Cancer Therapy: A Randomized Trial in Healthy Volunteers.

Bioactive supplements display relevant therapeutic properties when properly applied according to validated molecular effects. Our previous research efforts established the basis to develop a dietary supplement based on a Rosmarinus officinalis supercritical extract. This was enriched in phenolic diterpenes (RE) with proven properties against signaling pathways involved in colon tumorigenesis, and shark liver oil rich in alkylglycerols (AKG) as a bioactive lipid vehicle to improve RE bioavailability and synergize with the potential therapeutic action of the extract. Herein, we have investigated the tolerability and safety of the supplement and the biological and molecular effects from an immuno-nutritional perspective. Sixty healthy volunteers participated in a six week, double-blind, randomized parallel pilot study with two study arms: RE-AKG capsules (CR) and control capsules (CC). Mean age (±SD) of volunteers was 28.32 (±11.39) and 27.5 (±9.04) for the control and the study groups, respectively. Safety of the CR product consumption was confirmed by analyzing liver profile, vital constants, and oxidation markers (LDLox in blood and isoprostanes and thromboxanes in urine). The following were monitored: (1) the phenotyping of plasmatic leukocytes and the ex vivo response of lipopolysaccharide (LPS)-stimulated peripheral blood mononuclear cells (PBMCs); (2) expression of genes associated with immune-modulation, inflammation, oxidative stress, lipid metabolism, and tumorigenesis; and (3) the correlation of selected genetic variants (SNPs) with the differential responses among individuals. The lack of adverse effects on liver profile and oxidation markers, together with adequate tolerability and safe immunological adaptations, provide high-quality information for the potential use of CR as co-adjuvant of therapeutic strategies against colorectal cancer.

Critical lipids link breastfeeding to healthy adipose tissue in infancy and adulthood.

The study of beige adipose tissue (BeAT) has recently gained popularity because of its potential as a therapeutic target for the treatment of obesity and other metabolic disorders. While BeAT regulation is well understood in adults, the critical signals regulating BeAT during infant development need to be better defined. The bioactive components in breast milk have been primarily studied in the context of immunity. In this issue of the JCI, Yu and Dilbaz et al. identify how a class of breast milk-specific lipid mediators referred to as alkylglycerols (AKGs) maintain BeAT in infants and prevent the transdifferentiation of BeAT into lipid-storing white adipose tissue (WAT).

Inhibition of quorum sensing by compounds from two eunicea species and synthetic saturated alkylglycerols

Background: the emergence of bacterial resistance has led to a search for new natural products as alternatives starting points to prevent and control diseases caused by microorganisms. Among the potential candidates were bioactive compounds from octocorals of the genus Eunicea due to their chemical structures and their wide range of biological activities. Objective: the purpose of this study was to evaluate the quorum sensing inhibition (QSI) and antibacterial activity of compounds previously isolated from two Eunicea species and synthesized alkylglycerols (AKG). Methods: the QSI of three nonpolar compounds and a mixture of AKGs from Eunicea were evaluated by a microtiter plate assay using Chromobacterium violaceum (ATCC 31532). Four naturally occurring, saturated, and enantiomerically pure AKGs, all of which were derived from the chiral precursor (R)-solketal, were synthesized from alkyl chains of 12, 14, 16 and 18 carbons, and their structures were spectroscopically verified by NMR, ESI-MS and optical rotation data. Their QSI by the disc diffusion assay and minimum inhibitory concentrations (MIC) against 14 clinical bacterial isolates in microtiter plates were determined. Results: cembradiene 1, the AKG mixture and AKG (2S)-3-O-dodecyl-1,2-propanediol 4 inhibit QS at the same concentration as kojic acid (10 µg/well or 20 µg/disc, respectively). In this study, the bioactive compounds 1, stearyl oleate 2, acylglycerol 3 and AKGs 4 and (2S)-3-O-tetradecyl-1,2-propanediol 5 showed in vitro IQS activity for the first time. Additionally, 4 and 5 displayed in vitro antibacterial activity against Listeria innocua and Staphylococcus aureus (MIC = 32 µg/mL for both 4 and 5), Enterococcus faecalis (128 µg/mL and 64 µg/mL respectively), Micrococcus luteus (128 µg/mL for both) and Brevibacillus brevis (Bacillus brevis) (512 µg/mL and 64 µg/mL respectively). Conclusion: results suggest that natural compounds 1, 2, 3, 4 and 5 showed QSI, also 4 and 5 have antibacterial activity and they are an interesting alternative to continue researching their effect against pathogenic microorganisms.

Temperature-Dependent Alkyl Glycerol Ether Lipid Composition of Mesophilic and Thermophilic Sulfate-Reducing Bacteria

The occurrence of non-isoprenoid alkyl glycerol ether lipids in Bacteria and natural environments is increasingly being reported and the specificity and diagenetic stability of these lipids make them powerful biomarkers for biogeochemical and environmental studies. Yet the environmental controls on the biosynthesis of these peculiar membrane lipids remain poorly documented. Here, the lipid content of two mesophilic (Desulfatibacillum aliphaticivorans and Desulfatibacillum alkenivorans) and one thermophilic (Thermodesulfobacterium commune) sulfate-reducing bacteria—whose membranes are mostly composed of ether lipids—was investigated as a function of growth temperature (20–40°C and 54–84°C, respectively). For all strains, the cellular lipid content was lower at sub- or supra-optimal growth temperature, but the relative proportions of dialkyl glycerols, monoalkyl glycerols and fatty acids remained remarkably stable whatever the growth temperature. Rather than changing the proportions of the different lipid classes, the three strains responded to temperature changes by modifying the average structural composition of the alkyl and acyl chains constitutive of their membrane lipids. Major adaptive mechanisms concerned modifications of the level of branching and of the proportions of the different methyl branched lipids. Specifically, an increase in temperature induced mesophilic strains to produce less dimethyl branched dialkyl glycerols and 10-methyl branched lipids relative to linear structures, and the thermophilic strain to decrease the proportion of anteiso relative to iso methyl branched compounds. These modifications were in agreement with a regulation of the membrane fluidity. In one mesophilic and the thermophilic strains, a modification of the growth temperature further induced changes in the relative proportions of sn-2 vs sn-1 monoalkyl glycerols, suggesting an unprecedented mechanism of homeoviscous adaptation in Bacteria. Strong linear correlations observed between different ratios of alkyl glycerols and temperature allow to hypothesize the use of these specific lipids as indicators of temperature changes in the environment.

Effect of alkylglycerol‐rich oil and rosemary extract on oxidative stability and antioxidant properties of a cooked meat product

Taking into account the bioactive and healthy properties of alkylglycerols (AKG) and the antioxidant rosemary extract (RE), the production of a cooked meat product with partial replacement of animal fat by AKG‐rich oil and inclusion of RE was performed. Six batches were manufactured: Control, control + RE (0.045%RE); low‐AKG (0.75%AKG‐oil), low‐AKG + RE (0.75%AKG‐oil + 0.045%RE); high‐AKG (4.3%AKG‐oil) and high‐AKG + RE (4.3%AKG‐oil + 0.045%RE). Fatty acid and lipid profile, changes on lipid oxidation (TBARS), antioxidant ability (TEAC), and carnosic acid were determined during refrigerated storage (0, 30, 60 days). A relevant replacement of animal fat by AKG‐rich oil was obtained (around 20% for the high‐AKG samples), together with healthier indexes of the fatty acid profile. A slight trend to worse lipid oxidation due to addition of AKG‐rich oil was measured, but being only significantly higher for the high‐AKG treatment in absence of RE. A significant better stability was measured due to inclusion of RE for all the treatments. Therefore, the oxidation of both low‐AKG + RE and high‐AKG + RE treatments were significantly comparable to the control batch. After storage, TBARS values increased for all the batches. Samples containing RE showed better TEAC values after the storage. In agreement, the amount of carnosic acid kept constant during the self‐life of the products.Practical applications: Cooked meat products combining the bioactive ingredients AKG‐rich oil and RE might be produced, without compromising the oxidative stability and with potential healthier and functional interest due to AKG enrichment, healthier fatty acid indexes, and antioxidant activity. Furthermore, the amount of one of the main bioactive compounds of RE, carnosic acid, would be preserved during the storage of the meat products, regardless of the addition of labile oils such as AKG‐rich oil.Taking into account the bioactive and healthy properties of alkylglycerols (AKG) and the antioxidant rosemary extract (RE), the production of a cooked meat product with partial replacement of animal fat by AKG‐rich oil and inclusion of RE was performed. Meat products combining both bioactive ingredients might be produced, without compromising the oxidative stability and with potential healthier and functional interest.

Alkylglycerol Derivatives, a New Class of Skin Penetration Modulators.

The absorption modulating activity of two alkylglycerol derivatives (batyl and chimyl alcohol) on skin barrier properties was evaluated. Biophysical tests such as transepidermal water loss (TEWL) and attenuated total reflectance–Fourier transform infrared (ATR-FTIR) spectroscopy, as well as in vitro skin permeation studies, were performed in order to determine the effect of these compounds as chemical absorption modulators. Four drugs were used as models: three NSAIDS (diclofenac, naproxen, and piroxicam) and glycyrrhizic acid. The results showed that treatment of the skin with alkylglycerols caused (i) a reduction on the amount of drug permeated; (ii) a reduction in TEWL; and (iii) changes in the ATR-FTIR peaks of stratum corneum lipids, indicative of a more ordered structure. All of these findings confirm that alkyl glycerols have an absorption retarding effect on the drugs tested. Such effects are expected to give rise to important applications in the pharmaceutical and cosmetic sectors, in cases where it is desirable for the drug to remain in the superficial layers of the skin to achieve a local effect.

Alkylglycerols reduce serum complement and plasma vascular endothelial growth factor in obese individuals.

Alkylglycerols (AKGs), isolated or present in shark liver oil have anti-inflammatory properties. Complement 3 (C3) and 4 (C4) participate in lipid metabolism and in obesity, contributing to the metabolic syndrome and to the low-grade inflammation associated with obesity. In a randomized, controlled, crossover study, 26 non-diabetes obese individuals were assigned two preparations with low (LAC, 10mg AKGs) and high (HAC, 20mg AKGs) AKG content. Intervention periods were of 3weeks preceded by 2-week washout periods in which shark liver oil was avoided. Cholesterol, C3, C4, and vascular endothelial growth factor (VEGF) decreased in a linear trend (P<0.01) from baseline (control) to LAC and HAC. Values after HAC were significantly lower (P<0.05) versus both baseline and after LAC. No adverse effects were observed or reported. Data from this pilot study open a promising field for the study of the beneficial effects of AKGs on cardiovascular risk factors in obese individuals.

Jurassic surgery and immunity enhancement by alkyglycerols of shark liver oil.

BackgroundShark liver oil (SLO) contains both alkylglycerols (AKG) and squalene and is an ancient remedy among the fishermen on the west coast of Norway and Sweden. Literature reports showed that alkyglycerols enhance Fc–receptor mediated phagocytosis, increase humoral immune response and delay hypersensitivity reactions.MethodsOn this background we performed an open spontaneous study on 40 very old aged surgical patients preoperatively treated with alkyglycerols (500 mg twice a day for 4 weeks), in order to reduce the risks of operation, counteracting the postoperative inflammatory and anergic conditions thus achieving quick and plain recovery. To better understand the possible therapeutic impact of alkyglycerols we compared on a case/control basis treated versus untreated patients submitted contemporarily to the identical operation and exposed to the same environmental and seasonal risks.ResultsThe onset of complications was reduced in the alkyglycerols treated group and the compliance to the natural treatment was excellent without any serious adverse effect. WBC count and IgG significant increase (respectively p <0.05 and p <0.001) might explain some sort of protection against infectious agents and wound repair adverse events. Also lymphocytes concentration significantly increased in the AKG treated group (p <0.001) whereas a slight decrease was observed in the control group. Conversely neutrophils significantly decreased in the AKG treated group (p <0.001) meaning that patients have no more infections and have re-established their physiologic state. However a significant increase was observed in the control group (p <0.05). CRP significantly decreased in the group receiving AKG (p <0.05), thus evidencing a slight antiinflammtory effect of the product. Also ESR decreased from a baseline in the group receiving AKG.ConclusionsIn conclusion we suggest the opportunity to introduce this nutraceutical product in dosages of 500 mg twice a day to very old people before surgical treatment for an effective modulation of leukocytes and soluble immune reactivity according with the shark liver oil consumption trend in the northern Europe countries folk medicine. For this reason it might be advisable a wider study on a substantially bigger patients cohort focused on the complication rate prevention or control.

Alkylglycerols modulate the proliferation and differentiation of non-specific agonist and specific antigen-stimulated splenic lymphocytes.

Alkylglycerols (AKGs) are ether-linked glycerols derived from shark liver oil and found in small amounts in human milk. Previous studies showed that oral AKGs administration significantly increased the immune response in mice. The aim of the present study was to investigate the in vitro immunomodulatory effect of AKGs on stimulating splenic lymphocyte responses. C57BL/6 mice were immunized with hepatitis B surface antigen (HBsAg). Splenic B cells were purified and stimulated with anti-BCR and anti-CD38. Meanwhile, splenic CD4+ T cells were purified and stimulated with anti-CD3 and anti-CD28. For antigen specific stimulation, the purified CD4+ T cells were cocultured with HBsAg -pulsed dendritic cells. The stimulated lymphocytes were treated with different concentrations of AKGs. The cell proliferation was assessed by [3H]-thymidine incorporation assay. The maturation of B cells was assessed by examining the germline (GL) transcription of IgG (γ1) mRNA expression, and the surface expressions of CD80/CD86 markers were examined by flow cytometry analysis. Th1/Th2 polarity was assessed by T-BET (Th1)/GATA-3 (Th2) flow cytometry assay and by characteristic cytokines ELISA assay (TNF-α and IFN-γ for Th1; IL-4 and IL-10 for Th2). It was found that AKGs significantly increased the BCR/CD38 -stimulated B cell proliferation. The T cell proliferation in response to CD3/CD28 or specific antigen stimulation was also increased by AKGs. The transcriptional level of IgG (γ1) and the expressions of CD80/CD86 molecules were markedly increased by AKGs in BCR/CD38 -stimulated B cells. Meanwhile, the results showed that AKGs increased the expression of T-BET transcriptional factor and the production of Th1 cytokines (TNF-α and IFN-γ) upon CD3/CD28 stimulation; whereas, levels of Th2 cytokines (IL-4 and IL-10) were decreased by AKGs. Our study demonstrated that AKGs can modulate immune responses by boosting the proliferation and maturation of murine lymphocytes in vitro.

Antitumor and anti-cachectic effects of shark liver oil and fish oil: comparison between independent or associative chronic supplementation in Walker 256 tumor-bearing rats

BackgroundShark liver oil (SLOil) and fish oil (FOil), which are respectively rich in alkylglycerols (AKGs) and n-3 polyunsaturated fatty acids (PUFAs), are able to reduce the growth of some tumors and the burden of cachexia. It is known that FOil is able to reduce proliferation rate and increase apoptotic cells and lipid peroxidation of tumor cells efficiently. However, there are few reports revealing the influence of SLOil on these parameters. In the current study, effects of FOil chronic supplementation on tumor growth and cachexia were taken as reference to compare the results obtained with SLOil supplementation. Also, we evaluated if the association of SLOil and FOil was able to promote additive effects.MethodsWeanling male Wistar rats were divided into 4 groups: fed regular chow (C), supplemented (1 g/kg body weight) with SLOil (CSLO), FOil (CFO) and both (CSLO + FO). After 8 weeks half of each group was inoculated with Walker 256 cells originating new groups (W, WSLO, WFO and WSLO + FO). Biochemical parameters of cachexia, tumor weight, hydroperoxide content, proliferation rate and percentage of apoptotic tumor cells were analysed. Fatty acids and AKG composition of tumor and oils were obtained by high performance liquid chromatography and gas chromatography – mass spectrometry, respectively. Statistical analysis was performed by unpaired t-test and one-way ANOVA followed by a post hoc Tukey test.ResultsFourteen days after inoculation, SLOil was able to restore cachexia parameters to control levels, similarly to FOil. WSLO rats presented significantly lower tumor weight (40%), greater tumor cell apoptosis (~3-fold), decreased tumor cell proliferation (35%), and higher tumor content of lipid hydroperoxides (40%) than observed in W rats, but FOil showed more potent effects. Supplementation with SLOil + FOil did not promote additive effects. Additionally, chromatographic results suggested a potential incorporation competition between the n-3 fatty acids and the AKGs in the tumor cells’ membranes.ConclusionsSLOil is another marine source of lipids with similar FOil anti-cachectic capacity. Furthermore, despite being less potent than FOil, SLOil presented significant in vivo antitumor effects. These results suggest that the chronic supplementation with SLOil may be adjuvant of the anti-cancer therapy.

Acute effects of short‐chain alkylglycerols on blood‐brain barrier properties of cultured brain endothelial cells

The blood-brain barrier (BBB) restricts drug penetration to the brain preventing effective treatment of patients suffering from brain tumours. Intra-arterial injection of short-chain alkylglycerols (AGs) opens the BBB and increases delivery of molecules to rodent brain parenchyma in vivo. The mechanism underlying AG-mediated modification of BBB permeability is still unknown. Here, we have tested the effects of AGs on barrier properties of cultured brain microvascular endothelial cells. The effects of two AGs, 1-O-pentylglycerol and 2-O-hexyldiglycerol were examined using an in vitro BBB model consisting of primary cultures of rat brain endothelial cells, co-cultured with rat cerebral glial cells. Integrity of the paracellular, tight junction-based, permeation route was analysed by functional assays, immunostaining for junctional proteins, freeze-fracture electron microscopy, and analysis of claudin-claudin trans-interactions. AG treatment (5 min) reversibly reduced transendothelial electrical resistance and increased BBB permeability for fluorescein accompanied by changes in cell morphology and immunostaining for claudin-5 and β-catenin. These short-term changes were not accompanied by alterations of inter-endothelial tight junction strand complexity or the trans-interaction of claudin-5. AG-mediated increase in brain endothelial paracellular permeability was short, reversible and did not affect tight junction strand complexity. Redistribution of junctional proteins and alterations in the cell shape indicate the involvement of the cytoskeleton in the action of AGs. These data confirm the results from in vivo studies in rodents characterizing AGs as adjuvants that transiently open the BBB.

Activités antitumorale et antimétastasique des alkylglycérols naturels : relation structure-activité

Oral alkylglycerols (AKG) from shark liver oil (SLO) have multiple biological activities including immuno-stimulation and anti-tumour properties. In several cell types they are incorporated into phospholipids and therefore they may produce modified messengers and mediators following cellular activation of the phospholipase pathway. Structure of naturally occurring AKG vary depending on length and unsaturation of the alkyl chain. We synthesized six of the major natural constituants of AKG from SLO and tested their anti-tumour and anti-metastasis activities on a model of solid tumour grafted in mice. We found that unsaturated compounds were the most active for reducing tumour volume, lung metastasis number, and splenomegaly. Saturated compounds had weaker, no, or deleterious activities on this model. These data suggest that the selective use of unsaturated natural AKG would improve anti-tumour activities as compared to natural mix of AKG.

The adjuvant potential of synthetic alkylglycerols

Alkylglycerols (AGs) have shown immune stimulant and adjuvant activity in many studies, but natural sources are not so accessible and their extraction from them is very complicated. Therefore, a group of chemists at IFAL have synthesized AG analogs. The aim of this work was to evaluate the adjuvant potential of different synthetic AGs. A mix of ovoalbumin (Ova) and AGs increase anti-Ova IgG antibodies production in sera of immunized mice. The predominant subclass was IgG1 although higher levels of IgG2a were observed as the carbon chain length of AGs increased. AGs also induced the production of IL-12 and nitric oxide (NO) in the U937 human histiocyte and J774 mouse macrophage cell lines, respectively. These results indicate that synthetic AGs are effective adjuvants for the standardized antigen, Ova.

Blood-Brain Barrier Disruption Following the Internal Carotid Arterial Perfusion of Alkyl Glycerols

Non ionic, amphipathic molecules form vesicles and this property correlates with the disruption of membranes. In the present studies, high mM concentrations of aliphatic alcohols, 1- O -hexyldiglycerol (HDG) and 1- O -heptyltriglycerol (HTG), are shown to cause enhanced drug transport into brain via disruption of the blood-brain barrier (BBB) in vivo, as determined with an internal carotid artery perfusion method. The intravenous administration of comparable concentrations of HDG or HTG caused no increase in BBB transport of drug. The enhanced transport of drug showed a dependency on molecular weight as 45 mM HTG increased the transport of sucrose, 360 Da, but did not increase the transport of arginine vasopressin (AVP), 1084 Da, although AVP transport across the BBB was increased by 80 mM HDG or HTG. Quasielastic light scattering measurements provided evidence for the formation of vesicular structures in aqueous solutions containing high mM concentrations of the HDG or HTG. In summary, these studies demonstrate BBB disruption following the internal carotid arterial infusion of high mM concentrations of membrane active alkyl glycerols.