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Multiple Beneficial Health Effects of Natural Alkylglycerols from Shark Liver Oil


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Alkylglycerols (alkyl-Gro) are ether lipids abundant in the liver of some elasmobranch fish species such as ratfishes and some sharks. Shark liver oil from Centrophorus squamosus (SLO), or alkyl-Gro mix from this source, have several in vivo biological activities including stimulation of hematopoiesis and immunological defences, sperm quality improvement, or anti-tumor and anti-metastasis activities. Several mechanisms are suggested for these multiple activities, resulting from incorporation of alkyl-Gro into membrane phospholipids, and lipid signaling interactions. Natural alkyl-Gro mix from SLO contains several alkyl-Gro, varying by chain length and unsaturation. Six prominent constituents of natural alkyl-Gro mix, namely 12:0, 14:0, 16:0, 18:0, 16:1 n-7, and 18:1 n-9 alkyl-Gro, were synthesized and tested for anti-tumor and anti-metastatic activities on a model of grafted tumor in mice (3LL cells). 16:1 and 18:1 alkyl-Gro showed strong activity in reducing lung metastasis number, while saturated alkyl- Gro had weaker (16:0) or no (12:0, 14:0, 18:0) effect. Multiple compounds and mechanisms are probably involved in the multiple activities of natural alkyl-Gro.
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Mar. Drugs 2010, 8, 2175-2184; doi:10.3390/md8072175
Marine Drugs
ISSN 1660-3397
Multiple Beneficial Health Effects of Natural Alkylglycerols
from Shark Liver Oil
Anne-Laure Deniau 1, Paul Mosset 2, Frédérique Pédrono 1, Romain Mitre 1, Damien Le Bot 1
and Alain B. Legrand 1,*
1 Laboratoire de Pharmacologie Moléculaire, Université de Rennes 1, France;
E-Mails: (A.-L.D.);
(F.P.); (R.M.); (D.L.B.)
2 Ecole Nationale Supérieure de Chimie de Rennes and Université Européenne de Bretagne, France;
* Author to whom correspondence should be addressed; E-Mail:;
Tel.: +33 (0) 2 23 23 48 75; Fax: +33 (0) 2 23 23 48 76.
Received: 7 June 2010; in revised form: 7 July 2010 / Accepted: 14 July 2010 /
Published: 19 July 2010
Abstract: Alkylglycerols (alkyl-Gro) are ether lipids abundant in the liver of some
elasmobranch fish species such as ratfishes and some sharks. Shark liver oil from
Centrophorus squamosus (SLO), or alkyl-Gro mix from this source, have several in vivo
biological activities including stimulation of hematopoiesis and immunological defences,
sperm quality improvement, or anti-tumor and anti-metastasis activities. Several
mechanisms are suggested for these multiple activities, resulting from incorporation of
alkyl-Gro into membrane phospholipids, and lipid signaling interactions. Natural
alkyl-Gro mix from SLO contains several alkyl-Gro, varying by chain length and
unsaturation. Six prominent constituents of natural alkyl-Gro mix, namely 12:0, 14:0, 16:0,
18:0, 16:1 n-7, and 18:1 n-9 alkyl-Gro, were synthesized and tested for anti-tumor and
anti-metastatic activities on a model of grafted tumor in mice (3LL cells). 16:1 and 18:1
alkyl-Gro showed strong activity in reducing lung metastasis number, while saturated alkyl-
Gro had weaker (16:0) or no (12:0, 14:0, 18:0) effect. Multiple compounds and
mechanisms are probably involved in the multiple activities of natural alkyl-Gro.
Keywords: alkylglycerols; shark liver oil; ether lipids; immunostimulation; anti-tumor
Mar. Drugs 2010, 8
1. Multiple Biological Activities of Alkylglycerols
Natural 1-O-alkylglycerols (alkyl-Gro) are bioactive ether lipids present in body cells and fluids.
They are precursors of ether phospholipids, which participate in structures and functions of membranes
in certain cells such as white blood cells or macrophages. Alkyl-Gro are also found in bone marrow
lipids and in milk [1].
Marine sources of alkyl-Gro such as the liver oil of certain shark species or rat fish (elasmobranch
fishes) contain high levels of these compounds as a mixture of few species varying by length and
unsaturation of the alkyl chain [2].
The usual composition of alkyl chains in alkyl-Gro from Greenland shark (Centrophorus
squamosus) liver oil (SLO) is as follow: 12:0, 1–2%. 14:0, 1–3%; 16:0, 9–13%; 16:1n-7, 11–13%;
18:0, 1–5%; 18:1n-9, 54–68%; 18:1n-7, 4–6%, and minor species (<1%).
Beneficial effects of SLO on health have been recognized in traditional medicine of northern
countries involved in fishing, such as Japan, Norway or Iceland. In these countries, the ancestral use of
SLO was empirical as strengthening or wound healing medication.
Experimental studies were performed during the last century, aiming to demonstrate whether
alkyl-Gro from SLO had biological properties and beneficial effects. Indeed, several studies did
observe interesting effects, such as hematopoiesis stimulation [3], lowering radiotherapy-induced
injuries [4], reducing tumor growth [5], or improving vaccination efficiency [6,7]. However, in most
cases, conclusions were mainly impaired by the poor definition of the mixtures used, in terms of purity
as well as chemical composition. Furthermore, none of these ancient publications studied or even
suggested mechanisms for alkyl-Gro multiple effects.
For several decades, the family of bioactive lipids has grown tremendously, and lipids are not
anymore seen only as fat and enemy of good health. All cells possess lipids and phospholipids, which
are essential components of membranes, and membrane lipids are also used as precursors for mediators
and messengers. Lipids and phospholipids have prominent roles in cell-to-cell communication and in
intracellular signals as well. Many lipid-derived bioactive molecules are agonists of specific membrane
receptors: besides prostanoids and leukotriens, recent discoveries of new lipid mediators include
docosanoids and many other eicosanoids such as isoprostanes, anandamide, 2-arachidonoylglycerol
and other natural lipids acting as cannabinoid receptor agonists. Phospholipidic mediators are as well
numerous, ubiquitous and of first rank interest; they include Platelet-activating Factor (PAF),
lyso-phosphatidic acid (Lyso-PA), lyso-phosphatidylcholine (Lyso-PC), and shingosine-1-P (SP-1P).
Several lipids act as intracellular second messengers (diacylglycerols, free fatty acids) or as regulators
of transcription factors (free fatty acids, Lyso-PA).
Thus, many of the signaling pathways involved in cellular functions and communications are
dependent on lipids. Where do cell membrane lipids come from? Interestingly, lipids are the single
biochemical class that allows variability in structure depending on the nutrition. Therefore, one may
modify, by nutritional supply, the lipid composition of cell membranes and as a result, the structures
and functions of membrane–derived bioactive lipids.
The main hypothesis for explaining multiple biological activities of alkyl-Gro was that they may be
incorporated into cell membrane phospholipids, and from there modify their physical properties such
as membrane fluidity and antioxidant status [8], or alter cell signaling through the phospholipase
Mar. Drugs 2010, 8
pathways. This concept has already been used in the multiple applications of n-3 fatty acid food
supplementation. Its extension to alkyl-Gro is clearly a help for understanding their multiple biological
2. Incorporation into Mediators and Second Messengers
Indeed, alkyl-Gro can be incorporated into the phospholipids of several cell types such as THP1
monocytes [9], endothelial cells [10] or blood platelets [11]. In endothelial cells, resulting
1-O-alkylglycerophospholipids participated in the production of 1-O-alkyl-2-acylglycerol [10], an
analog of diacylglycerol (DAG) with inhibiting effect on protein kinase C [12]. In transformed human
monocyte THP1 cells, alkyl-Gro were incorporated into 1-O-alkylglycerophosphatidylcholine, the
precursor of Platelet-activating Factor (PAF) [9], and incorporation of [3H] alkyl-Gro resulted in the
production of labeled PAF. Furthermore, alkyl-Gro incorporation resulted in amplifying and extending
the PAF production level after stimulation [9]. Increasing 1-O-alkyl-2-acyl-glycerophosphocholine in
membrane phospholipids could also increase the production of active PAF analogs by oxidation of
unsaturated fatty acid in the 2-position of glycerol [13,14].
3. Male Fertility
Spermatozoa produce PAF, and this mediator plays an important role in sperm physiology with
respect to capacitation, acrosome reaction and gamete fusion [15,16]. An attractive hypothesis was that
alkyl-Gro, which are PAF precursors, might have effects on sperm functions. Indeed, boar sperm
treated in vitro with a mixture of natural alkyl-Gro had increased percent motility and velocity
parameters. Furthermore, such treated sperm had better fertilization performances when used for
artificial inseminations [17], and this has found applications in breeding of several mammalian species.
In vivo studies in boars showed that oral intake of SLO (40 g/day, 28 days) improved sperm motility
and velocity, together with an increase in the levels of alkyl-Gro in sperm [18]. The possibility of
improving fertility by oral SLO supplementation is suggested by these data, however, needs
4. Immuno-Stimulation and Hematopoiesis
Since, on the one hand, ancient studies had shown that some alkyl-Gro stimulate hematopoiesis [3]
and antibody production [6], and, on the other hand, alkyl-Gro are found in body fluids including milk
[1], we hypothesized that oral treatment of pregnant animals could have beneficial effects on offspring
health. Indeed, oral treatment by SLO in pregnant sows resulted in the amplification of vaccination-
induced raise in specific immunoglobulins in serum of treated sows. This amplification of specific
antibodies was also observed in colostrum of treated sows, and as expected, in serum of piglets from
treated mothers. The piglets from treated sows had also higher leukocyte levels by raising populations
of polymorphonuclear cells, lymphocytes and monocytes [19]. This resulted in an overall improvement
in offspring health status and growth, however, besides alkyl-Gro activities, some of these beneficial
effects might also result from the presence of n-3 polyunsaturated fatty acids (PUFA) in SLO [19]. In
healthy humans, high doses of SLO (15 g/day) for four weeks induced changes in the cytokine profile
Mar. Drugs 2010, 8
and antioxidant status of serum together with an increase in total cholesterol and a decrease of its HDL
fraction. Again, since SLO contained also high proportions of squalene and PUFA, one cannot attribute
these different effects to alkyl-Gro only [20].
5. Anti-Tumor Activities
Using a model of solid tumor grafted in mice (Lewis lung carcinoma cells = LLC), we have
evaluated the anti-tumor effects of oral SLO and of natural alkyl-Gro purified from the same source.
We found that both treatments reduced significantly the growth of grafted tumors [21]. Furthermore,
both treatments also reduced the number of pulmonary metastases. These data demonstrated that
alkyl-Gro are active molecules accounting for anti-tumor activities of SLO. The mechanisms by which
alkyl-Gro exert these anti-tumor properties may be multiple. To evaluate anti-neoangiogenic activity,
we measured the density of an endothelial marker in solid tumors grafted in mice. After an alkyl-Gro
oral treatment as short as five days, we established that the density of von Willebrand factor in grafted
tumors was decreased by 26% as compared to control group [21]. Anti-neoangiogenic activities might
be one of the possible mechanisms for anti-tumor activities of alkyl-Gro [22]. Since basic Fibroblast
Growth Factor (bFGF), is a major angiogenesis stimulator [23], we studied the effect of natural mix of
alkyl-Gro on endothelial cell proliferation stimulated by bFGF and showed that alkyl-Gro reduced the
bFGF stimulating effect [24].
6. Chemical Synthesis of 1-O-Alkyl-sn-glycerols
Since most studies describing alkyl-Gro effects were obtained using a mix of several natural
compounds, it was of interest to explore the activity of each single compound. We synthesized six of
the major of natural alkyl-Gro mix, namely: (1) AKG 12:0 = 1-O-Dodecyl-sn-glycerol, (2) AKG
14:0 = 1-O-Tetradecyl-sn-glycerol, (3) AKG 16:0 = 1-O-Hexadecyl-sn-glycerol (chimyl alcohol),
(4) AKG 18:0 = 1-O-Octadecyl-sn-glycérol (batyl alcohol), (5) AKG 16:1 = 1-O-(Z)-9'-Hexadecenyl-
sn-glycerol, (6) AKG 18:1 = 1-O-(Z)-9'-Octadecenyl-sn-glycerol (selachyl alcohol) (Figure 1).
Saturated and monounsaturated (S)-1-O-alkylglycerols were synthesized in two and four steps,
respectively, from (R)-(-)-2,2-dimethyl-1,3-dioxolane-4-methanol. Alkylation of this latter compound
by 1-bromohexadecane and 1-bromooctadecane under basic conditions (KOH, n-Bu4NBr cat., DMSO,
60 °C) followed by acetonide cleavage under acid conditions (0.05 equivalent of p-toluenesulfonic acid
monohydrate in MeOH:H2O 10:1) afforded chimyl and batyl alcohols, which were purified by
recrystallization in petroleum ether and methanol, respectively. Selachyl alcohol and its lower
homolog, (S)-3-[(9Z)-9-hexadecen-1-yloxy]-1,2-propanediol, were respectively synthesized from oleic
and palmitoleic acids. These monounsaturated fatty acids were reduced by Red-Al to oleyl and
palmitoleyl alcohols. Their mesylation under classic conditions afforded the corresponding mesylates.
Alkylation of (R)-(-)-2,2-dimethyl-1,3-dioxolane-4-methanol by these mesylates afforded the protected
targets as acetonides which under the same acid conditions as previously afforded selachyl alcohol and
Mar. Drugs 2010, 8
Figure 1. 1-O-alkyl-sn-glycerols obtained by chemical synthesis.
1-O-Dodecyl-sn-glycerol (12:0) 1-O-Tetradecyl-sn-glycerol (14:0)
1-O-Hexadecyl-sn-glycerol (16:0) 1-O-Octadécyl-sn-glycerol (18:0)
Chimyl alcohol Batyl alcohol
Selachyl alcohol
1-O-(Z)-9'-Hexadecenyl-sn-glycerol (16:1n-7)
1-O-(Z)-9'-Octadecenyl-sn-glycerol (18:1n-9)
7. Which 1-O-Alkylglycerols Have Anti-Tumor Activities?
The activities of alkyl-Gro natural mixture and of each of these compounds were compared using
the same in vivo model of solid tumor grafted in mice, using olive oil treatment as a control [24]. We
found that AKG 16:1 and 18:1 were the most potent compounds on tumor growth and lung
macrometastasis number, while other compounds (AKG 16:0 and 12:0) had weaker activities. We also
observed that AKG 18:0 did not reduce, but on the contrary, tended to increase tumor growth and
metastasis number [25].
We also observed important variations in spleen weights at the end of the experiment (day 20). In
non-grafted mice, natural mix of alkyl-Gro had no effect on spleen weights. Tumor graft induced a
strong increase in spleen weights of the control group. Alkyl-Gro treatments resulted in a reduction of
spleen weights in most groups, with stronger effects observed in AKG 16:1 and 18:1 groups, in which
spleen weights decreased to levels similar of those in non-grafted groups. Again, and by contrast with
the other compounds, spleen weight in AKG 18:0-treated group was significantly increased as
compared with olive oil-treated group [25].
8. Cytotoxicity and Effects of Alkylglycerols on Endothelial Cell Proliferation
On human umbilical vein endothelial cells (HUVEC), MTT test of cytotoxicity [26] revealed
absence of cytotoxic effects after 72 hours at concentrations lower than 20 µM for any synthetic
alkyl-Gro. At concentrations devoid of cytotoxic effects, synthetic 18:1 and 16:1 alkyl-Gro again had
the strongest effects on [3H]-thymidine incorporation into HUVEC, indicating that these two
unsaturated compounds might have the strongest inhibiting effect on neo-angiogenesis involved in
tumor development [25].
Mar. Drugs 2010, 8
9. Alkylglycerols and the Blood-Brain Barrier
Synthetic short chain alkyl-Gro such as 1-O-pentyl sn glycerol are interesting compounds, which
transiently open the blood brain barrier (BBB), allowing increased crossing of the BBB by therapeutic
molecules [27,28]. Parenteral 1-O-decyl-sn-glycerol may also increase carbamazepine crossing through
BBB [29]. Oxidation of the natural unsaturated alkyl-Gro on the double bound could lead to short-
chain alkyl-Gro with putative similar activities.
10. Concluding Remarks
Several biochemical and physiological mechanisms may be involved in the multiple effects of alkyl-
Gro. In spermatozoa, the stimulating and protecting effects of natural alkyl-Gro were partially reduced
in the presence of a PAF-receptor antagonist, indicating that interaction of alkyl-Gro with PAF
metabolism and/or activities [17]. In blood platelets, alkyl-Gro partially inhibited the
PAF-induced release of serotonin in vitro, suggesting that natural alkyl-Gro might act as a partial
agonist (agonist-antagonist) on the PAF receptor [11].
For a long time, it has been established that injection of batyl alcohol in rats and guinea pigs
increases the number of erythrocytes, leukocytes or platelets in blood [3,30]; by contrast selachyl
alcohol—the mono-unsaturated analog of batyl alcohol—is devoid of such activities [30,31], while this
compound showed strong anti-tumor activities.
Since alkyl-Gro are found in hematopoietic organs such as bone marrow, one may hypothesize that
they have an important role in hematopoiesis, and could behave as precursors of PAF, which has
stimulating functions in bone marrow cell lines [32,33]. Active PAF-analog production could also
result from oxidation and cleavage of poly-unsaturated fatty acids at the sn-2 position of the
1-O-alkylphospholipids [13,14].
In pigs, oral SLO increased both hematopoiesis and immunoglobulin production. These effects
could also be part of the mechanisms involved in anti-tumor effects of alkyl-Gro by raising immuno-
competent cell populations. Furthermore, alkyl-Gro have been shown to activate macrophages in vivo
[34], but only in the presence of non-adherent B an T cells in vitro, suggesting multi-factorial
cell-to-cell interactions [35]. Direct stimulating activity of alkyl-Gro on calcium signaling in human
Jurkat T lymphocytes has also been observed in vitro [36].
Among the synthetic compounds tested, the anti-tumor and anti-metastasis activities of natural
alkyl-Gro from SLO are mostly supported by the unsaturated compounds, which have 16 and 18
carbon alkyl chains. These activities are associated with a strong reduction of tumor-induced increase
in spleen weight. These two compounds represent mainly 70 to 80% of total alkyl-Gro from SLO,
explaining activity of natural mix of alkyl-Gro. However, the natural mix contains a minor compound,
AKG 18:0 which has remarkable opposite effects on spleen weight. Therefore the use of the two most
active compounds could be of interest for improving anti-tumor and anti-metastasis efficiency of alkyl-
Gro. The splenomegaly observed after 3LL cell graft reflects spleen invasion by immature myeloid
cells, predominantly neutrophil granulocytes, and is associated with a decrease in blood B and T
lymphocytes [37,38], both events impairing efficient immune responses to tumor cells. Amplification
of this response by the hematopoietic effect of batyl alcohol might explain spleen size rise induced by
Mar. Drugs 2010, 8
this compound together with its inactivity on tumor growth and metastasis. The mechanism of spleen
size reduction observed in grafted mice treated with AKG 18:1 and 16:1 is poorly understood; it could
however contribute to restore immune defenses against tumor cells. Activities of products resulting
from double bound oxidation could be part of the difference between unsaturated versus saturated
alkyl-Gro anti-tumor activities.
Mechanisms of anti-tumor effects could also be related to anti-angiogenic activities, since both
unsaturated alkyl-Gro reduced endothelial proliferation, which is involved in neo-angiogenesis.
Several biochemical mechanisms could be involved in the multiple activities of alkyl-Gro. Their
role in increasing PAF precursor and amplifying PAF production [9] could explain effects related to
PAF activities. These activities include inflammation and sperm functions, but also immune-
regulations [39,40]. Another interesting track is the interaction of 1-O-alkyl-2-acylglycerol with protein
kinase C. This compound, which is produced following cell stimulation after alkyl-Gro incorporation
in membrane phospholipids [10], is an analog of DAG which inhibits PKC [12];
1-O-alkyl-2-acylglycerol binds to, but do not activates PKC-ε and competes with DAG [41]; this could
result in cell growth arrest as observed in endothelial cells [21]. Although the relation between
unsaturation and anti-tumor activities of alkyl-Gro remains poorly understood, it appears that each
molecule may have specific mechanism of action and particular activities.
Patents: WO 2006/024742, USA 11/453/309, FR n°0953443.
Région Bretagne, Ligue Nationale contre le Cancer, Société Polaris (Pleuven, 29).
1. Hallgren, B.; Larsson, S.O. The glyceryl ethers in man and cow. J. Lipid Res. 1962, 3, 39–43.
2. Bordier, C.G.; Sellier, N.; Foucault, A.P.; Le Goffic, F. Purification and characterization of deep
sea shark Centrophorus squamosus liver oil 1-O-alkylglycerol ether lipids. Lipids 1996, 31,
3. Linman, J.W.; Long, M.J.; Korst, D.R.; Bethell, F.H. Studies on the stimulation of hemopoiesis by
batyl alcohol. J. Lab. Clin. Med. 1959, 54, 335–343.
4. Brohult, A.; Brohult, J.; Brohult, S.; Joelsson, I. Effect of alkoxyglycerols on the frequency of
injuries following radiation therapy for carcinoma of the uterine cervix. Acta Obst. Gynecol.
Scand. 1977, 56, 441–448.
5. Brohult, A.; Brohult, J.; Brohult, S. Regression of tumour growth after administration of
alkoxyglycerols. Acta Obstet. Gynecol. Scand. 1978, 57, 79–83.
6. Ngwenya, B.Z.; Foster, D.M. Enhancement of antibody production by lysophosphatidylcholine
and alkylglycerol. Proc. Soc. Exp. Biol. Med. 1991, 196, 69–75.
7. Brohult, A.; Brohult, J.; Brohult, S. Effect of irradiation and alkoxyglycerol treatment on the
formation of antibodies after salmonella vaccination. Experientia 1972, 28, 954–955.
8. Debouzy, J.-C.; Crouzier, D.; Lefebvre, B.; Dabouis, V. Study of alkylglycerol containing shark
liver oil: a physic chemical support for biological effects. Drug Target Insights 2008, 3, 125–135.
Mar. Drugs 2010, 8
9. Hichami, A.; Duroudier, V.; Leblais, V.; Vernhet, L.; Le Goffic, F.; Ninio, E.; Legrand, A.
Modulation of platelet-activating-factor production by incorporation of naturally occurring 1-O-
alkylglycerols in phospholipids of human leukemic monocyte-like cells THP-1. Eur. J. Biochem.
1997, 250, 242–248.
10. Marigny, K.; Pédrono, F.; Martin-Chouly, C.; Youmine, H.; Saïag, B.; Legrand, A.B. Modulation
of endothelial permeability by 1-O-alkylglycerols. Acta Physiol. Scand. 2002, 176, 263–268.
11. Pédrono, F.; Cheminade, C.; Legrand, A.B. Natural 1-O-alkylglycerols reduce platelet-activating
factor-induced release of [3H]-serotonin in rabbit platelets. Prostag. Leukot. Ess. Fatty Acids
2004, 71, 19–23.
12. Heymans, F.; Da Silva, C.; Marrec, N.; Godfroid, J.-J.; Castagna, M. Alkyl analogs of
diacylglycerols as activators of protein kinase C. FEBS Lett. 1987, 218, 35–40.
13. Kamido, H.; Eguchi, H.; Ikeda, H.; Imaizumi, T.; Yamana, K.; Hartvigsen, K.; Ravandi, A.;
Kuksis, A. Core aldehydes of alkyl glycerophosphocholines in atheroma induce platelet
aggregation and inhibit endothelium-dependent arterial relaxation. J. Lipid Res. 2002, 43,
14. Hartvigsen, K.; Ravandi, A.; Harkewicz, R.; Kamido, H.; Bukhave, K.; Holmer, G.; Kuksis, A. A-
O-alkyl-2--oxo)acyl-sn-glycerols from shark liver oil and human milk fat are potential
precursors of PAF mimics and GHB. Lipids 2006, 41, 679–693.
15. Kraus, C.S.; Gervasi, G.; Fori, G.; Baldi E. Effect of platelet-activating factor on motility and
acrosome reaction on human spermatozoa. Hum. Reprod. 1994, 9, 471–476.
16. Fukuda, A.; Roudebush, W.E.; Thatcher, S.S. Platelet-activating factor enhances the acrosome
reaction, fertilization in vitro by subzonal sperm injection and resulting embryonic development in
the rabbit. Hum. Reprod. 1994, 9, 94–99.
17. Cheminade, C.; Gautier, V.; Hichami, A.; Allaume, P.; Le Lannou, D.; Legrand A.B. 1-O-
alkylglycerols improve boar sperm motility and fertility. Biol. Reprod. 2002, 66, 421–428.
18. Mitre, R.; Cheminade, C.; Allaume, P.; Legrand, P.; Legrand, A.B. Oral intake of shark liver oil
modifies lipid composition and improves motility and velocity of boar sperm. Theriogenology
2004, 62, 1557–1566.
19. Mitre, R.; Etienne, M.; Martinais, S.; Salmon, H.; Allaume, P.; Legrand, P.; Legrand, A.B.
Humoral defence improvement and haematopoiesis stimulation in sows and offspring by oral
supply of shark liver oil to mothers during gestation and lactation. Br. J. Nutr. 2005, 94,
20. Lewkowicz, P.; Banasik, M.; Glowacka, E.; Lewkowicz, N; Tchorzewski, H. Effect of high doses
of shark liver oil supplementation on T cell polarization and peripheral blood polymorphonuclear
cell function. Pol. Merk. Lek. 2005, 18, 686–692.
21. Pedrono, F.; Martin, B.; Leduc, C.; Le Lan, J.; Saïag, B.; Legrand, P.; Moulinoux, J.P.; Legrand,
A.B. Natural alkylglycerols restrain growth and metastasis of grafted tumour in mice. Nutr.
Cancer 2004, 48, 64–69.
22. Skopinska-Rózewska, E.; Krotkiewski, M.; Sommer, E.; Rogala, E.; Filewska, M.; Bialas-
Chromiec, B.; Pastewka, K.; Skurzak, H. Inhibitory effect of shark liver oil on cutaneous
Mar. Drugs 2010, 8
angiogenesis induced in Balb/c mice by syngeneic sarcoma L-1, human urinary bladder and
human kidney tumour cells. Oncol. Rep. 1999, 6, 1341–1343.
23. Presta, M.; Dell’Era, P.; Mitola, S.; Moroni, E.; Ronca, R.; Rusnati, M. Fibroblast growth
factor/Fibroblast growth factor receptor system in angiogenesis. Cytokine Growth Factor Rev.
2005, 16, 159–178.
24. Pédrono, F.; Saïag, B.; Moulinoux, J.-P.; Legrand, A.B. 1-O-alkylglycerols reduce the stimulating
effects of bFGF on endothelial cell proliferation in vitro. Cancer Lett. 2007, 251, 317–322.
25. Deniau, A.-L.; Mosset, P.; Le Bot, D.; Legrand, A.B. Which alkylglycerols from shark liver oil
have anti-tumour activities? Biochimie 2010, doi:10.1016/j.biochi.2009.12.010.
26. Mosmann, T. Rapid colorimetric assay for cellular growth and survival: application to
proliferation and cytotoxicity assays. J. Immunol. Meth. 1983, 65, 55–63.
27. Erdlenbruch, B.; Jendrossek, V.; Eibl, H.; Lakomek, M. Transient and controllable opening of the
blood-brain barrier to cytostatic and antibiotic agents by alkylglycerols in rats. Exp. Brain Res.
2000, 135, 417–422.
28. Erdlenbruch, B.; Jendrossek, V.; Kugler, W.; Eibl, H.; Lakomek, M. Increased delivery of
erucylphosphocholine to C6 gliomas by chemical opening of the blood-brain barrier using
intracarotid alkylglycerols in rats. Cancer Chemother. Pharmacol. 2002, 50, 299–304.
29. Madhusudhan, B.; Rambhau, D.; Apte, S.S.; Gopinath, D. 1-O-alkylglycerol stabilized
carbamazepine intraveinous o/w nanoemulsions for drug targeting in mice. J. Drug Targeting
2007, 15, 154–161.
30. Osmond, D.G.; Roylance, P.J.; Webb, A.J.; Yoffey, J.M. The action of batyl alcohol and selachyl
alcohol on the bone marrow of guinea pig. Acta Haemat. 1963, 29, 180–186.
31. Linman, J.W. Hematopoietic effects of glyceryl ethers. III. Inactivity of selachyl alcohol. Proc.
Soc. Exp. Biol. Med. 1960, 104, 703–706.
32. Denizot, Y.; Guglielmi, L.; Donnard, M.; Trimoreau, F. Platelet-activating factor and normal and
leukaemic haematopoiesis. Leuk. Lymphoma. 2003, 44, 775–782.
33. Dupuis, F.; Levasseur, S.; Jean-Louis, F.; Dulery, C.; Praloran, V.; Denizot, Y.; Michel, L.
Production, metabolism and effect of platelet-activating factor on the growth of the human K562
cell line. Bichim. Biophys. Acta 1997, 1359, 241–249.
34. Yamamoto, N.; Ngwenya, B.Z.; Sery, T.W.; Pieringer, R.A. Activation of macrophages by ether
analogues of lysophospholipids. Cancer Immunol. Immunother. 1987, 25, 185–192.
35. Yamamoto, N.; St Claire, D.A., Jr.; Homma, S.; Ngwenya, B.Z. Activation of mouse macrophages
by alkylglycerols, inflammation products of cancerous tissues. Cancer Res. 1988, 48, 6044–6049.
36. Pédrono, F.; Khan, N.A.; Legrand, A.B. Regulation of calcium signalling by 1-O-alkylglycerols in
human Jurkat T cells. Life Sci. 2004, 74, 2793–2801.
37. Lee, J.-K.; Back, T.C.; Komschlies, K.L.; Ruscetti, F.W.; Young, H.A.; Wiltrout, R.H.
Hematopoietic switch from lymphoid to granulocytic development in 3LL tumor-bearing mice. In
Vivo 2001, 15, 255–264.
38. Shin-Ya, M.; Mazda, O.; Tsuchihara, C.; Hirai, H.; Imanishi, J.; Takeuchi, M. Interleukin-2
abolishes myeloid cell accumulation induced by Lewis lung carcinoma. J. Interferon Cytokine
Res. 2003, 23, 631–638.
Mar. Drugs 2010, 8
39. Al-Darmaki, S.; Knightshead, K.; Ishihara, Y.; Best, A.; Schenkein, H.A.; Tew, J.G.; Barbour,
S.E. Delineation of the role of platelet-activating factor in the immunoglobulin G2 antibody
response. Clin. Diagn. Lab. Immunol. 2004, 4, 720–728.
40. Matsumura, Y.; Byrne, S.N.; Nghiem, D.X.; Miyahara, Y.; Ullrich, S.E. A role for inflammatory
mediators in the induction of immunoregulatory B cells. J. Immunol. 2006, 177, 4810–4817.
41. Houck, K.L.; Fox, T.E.; Sandirasegarane, L.; Kester, M. Ether-linked diglycerides inhibit vascular
smooth muscle cell growth via decreased MAPK and PI3K/Akt signalling. Am. J. Physiol. 2008,
295, 1657–1668.
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... L'intérêt thérapeutique des AKG est étroitement lié à l'utilisation de l'huile de foie de requin dans la médecine traditionnelle scandinave mais aussi japonaise [Deniau et al., 2010]. Concentrée en AKG, l'huile de foie de requin était utilisée pour soigner les plaies, traiter les problèmes respiratoires et digestifs ainsi que les lymphadénopathies * [Iannitti et Palmieri, 2010]. ...
... Dès 1996, les AKG de l'huile de foie de requin, notamment SH5 et SH6, étaient déjà connus pour leurs activités bactériostatique, fongistatique, anti-inflammatoire et hématopoïétique [Bordier et al., 1996]. En 2010, l'efficacité thérapeutique des AKG, incluant SH5 et SH6, dans le cancer, la radiothérapie et la stimulation de l'immunité a été documentée [Deniau et al., 2010;Iannitti et Palmieri, 2010]. Une étude réalisée en 2014 par Qian et ses collaborateurs a montré que SH5 et SH6 avaient un effet immunomodulateur en stimulant la prolifération ainsi que la maturation de lymphocytes murins in vitro [Qian et al., 2014]. ...
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Le vieillissement du corps humain crée un terrain propice au développement de certaines pathologies. Afin de ralentir ou retarder l’apparition des effets physiologiques normaux ou pathologiques liés à l’âge, différentes stratégies de recherche peuvent être développées. Aussi, dans le cadre de cette thèse, plusieurs éponges marines, collectées à Mayotte, ont été évaluées pour leur capacité à produire des métabolites aux propriétés anti-âge. L’évaluation des activités biologiques a été menée sur les cibles suivantes : élastase et tyrosinase (vieillissement cutané), CDK7 et protéasome (cancers), Fyn kinase (maladie d’Alzheimer), catalase (stress oxydant) et sirtuine 1 (différentes fonctions biologiques). Les éponges Lendenfeldia sp. et Scopalina hapalia, en raison de leurs activités biologiques, ont été sélectionnées pour des études chimiques. L'extraction, l'isolement et l'identification de leurs métabolites ont été entrepris par différentes techniques chromatographiques (CLMP, CLHP…) et spectroscopiques (SMHR, RMN 1D et 2D). Vingt métabolites appartenant aux classes chimiques des alkylglycérols, des buténolides, des dicétopipérazines, des épidioxystérols, des phospholipides ainsi que des polybromodiphényléthers ont été isolés de ces deux éponges. Il est à noter que quatre métabolites de structures nouvelles ont été isolés de S. hapalia dont la composition chimique n’avait été jusqu’à ce jour que très peu étudiée. Par ailleurs, peu d’études portant sur la caractérisation et le potentiel de production de métabolites d’intérêts de la communauté microbienne associée à S. hapalia ont été retrouvées dans la littérature. Dans cette thèse, la communauté bactérienne de cette éponge a été caractérisée, par une approche de métagénomique ciblée. Cette étude a mis en lumière une communauté majoritairement dominée par les Protéobactéries suivis par les Cyanobactéries, les Bacteroidetes, les Planctomycètes ainsi que les Actinobactéries. L’étude de la diversité microbienne cultivable a permis l’isolement de microorganismes appartenant aux genres Bacillus, Micromonospora, Salinispora, Rhodococcus, Aspergillus, Chaetomium et Nigrospora. Enfin, trente microorganismes ont été caractérisés pour leur capacité à produire des molécules bioactives en mettant en œuvre les techniques de culture classique couplées à une récupération in situ des molécules produites par les microorganismes. L’évaluation des activités anti-âge des extraits produits a été réalisée par un criblage sur les sept cibles biologique étudiées. Quinze souches différentes ont été identifiées comme prometteuses pour la recherche de métabolites aux différentes propriétés anti-âge.
... AKG have previously been reported to play an imperative role in the modulation of immunity through the enhancement of macrophage activation and increasing the plasma levels of immunoglobulin in rodents. In vitro studies have suggested that AKG play the role of antimicrobial agents and exhibit various biological activities and great therapeutic potential [120]. ...
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The beneficial effects of fish-derived lipid bioactives have come to prominence over the last few decades, especially for their utilization in fish oils, supplements, and nutraceuticals. Omega-3 (n-3) polyunsaturated fatty acids (PUFA), lipid vitamins, carotenoids, and polar lipid bioactives from fish have shown to possess a vast range of beneficial effects against a multitude of chronic disorders and especially against inflammation-and cardiovascular disorders (CVD). The observed cardio-protective effects and health benefits are believed to be attributed to the synergy of these fish-derived lipid bioactives. Within the present article the recent findings in the literature on the lipid content of the mainly consumed fish species, their bio-functionality, and cardio-protective benefits is thoroughly reviewed. Moreover, the recovery and valorization of such lipid bioactives from fish by-products and fishing by-catch, in order to reduce waste, while developing useful products containing cardio-protective lipids from the leftover materials of fisheries and aquaculture industries, are also of industrial and environmental interest. Emphasis is also given to the effects of heat treatments during fish processing on the structures and bio-functionality of these marine lipid bioactives, based on the paradigm of different cooking methodologies and thermal processing, while the compounds produced during such treatment(s) with detrimental changes in the fish lipid profile, which can reduce its cardio-protective efficacy, are also reviewed. Novel green extraction technologies and low temperature processing and cooking of fish and fishery by-products are needed to reduce these undesirable effects in a sustainable and environmentally friendly way.
... Oral supplement of SLO and natural purified alkyl-Gro shows the anti-tumour effects. The development of grafted tumour can be reduced and compaction of the number of pulmonary metastases can be done by the supplement of these two components (Pedrono et al. 2004;Deniau et al. 2010). ...
... With this insight, a next logical step would be to modulate ether lipid species with a view toward preventing or attenuating AD onset and progression, or to influence surrogate AD risk markers (Aβ, phosphorylated tau, or cognition) in the early stages of disease. Modulation of ether lipid species in humans has been demonstrated in several studies, 31,37 where the biologically active precursor, alkylglycerols, that can be synthesized 50 or derived from natural sources in various marine animals 27,51 has been used to bypass the rate-limiting peroxisomal step to upregulate plasmalogen synthesis. Because the vinyl-ether bond of plasmalogen species is highly susceptible to acid hydrolysis, ingestion of these species may not be the optimal approach to raise plasmalogen levels. ...
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The apolipoprotein E gene (APOE) genotype is the first and strongest genetic risk factor for late‐onset Alzheimer’s disease and has emerged as a novel therapeutic target for AD. The encoded protein (Apolipoprotein E, APOE) is well‐known to be involved in lipoprotein transport and metabolism, but its effect on lipid metabolic pathways and the potential mediating effect of these on disease risk have not been fully defined. We performed lipidomic analysis on three independent cohorts (AIBL, n = 693; ADNI, n=207; BHS, n=4,384) and defined the association between APOE polymorphisms (ε4 and ε2) and plasma lipid species. To identify associations independent of lipoprotein metabolism, the analyses was performed with adjustment for clinical lipids (total cholesterol, HDL‐C and triglycerides). Causal mediation analysis was performed to estimate the proportion of risk in the outcome model explained by a direct effect of APOE genotype on prevalent AD — the average direct effect (ADE) — and the proportion that was mediated by lipid species or lipidomic risk models — the average causal mediation effect (ACME). We identified multiple associations of species from lipid classes such as ceramide, hexosylceramide, sphingomyelin, plasmalogens, alkyldiacylglycerol and cholesteryl esters with APOE polymorphisms (ε4 and ε2) that were independent of clinical lipoprotein measurements. There were 104 and 237 lipid species associated with APOE ε4 and ε2 respectively which were largely discordant. Of these 116 were also associated with Alzheimer’s disease. Individual lipid species (notably the alkyldiacylglycerol subspecies) or lipidomic risk models of APOE genotypes mediated up to 10% and 30% of APOE ε4 and ε2 treatment effect on AD risks respectively. We demonstrate a strong relationship between APOE polymorphisms and peripheral lipid species. Lipids species mediate a proportion of the effects of APOE genotypes in risk of AD, particularly resilience with e2. Our results highlight the involvement of lipids in how APOE e2 mediates its resilience to AD and solidify their involvement with the disease pathway.
... With this insight, a next logical step would be to modulate ether lipid species with a view toward preventing or attenuating AD onset and progression, or to influence surrogate AD risk markers (Aβ, phosphorylated tau, or cognition) in the early stages of disease. Modulation of ether lipid species in humans has been demonstrated in several studies, 31,37 where the biologically active precursor, alkylglycerols, that can be synthesized 50 or derived from natural sources in various marine animals 27,51 has been used to bypass the rate-limiting peroxisomal step to upregulate plasmalogen synthesis. Because the vinyl-ether bond of plasmalogen species is highly susceptible to acid hydrolysis, ingestion of these species may not be the optimal approach to raise plasmalogen levels. ...
Full-text available
Introduction: The apolipoprotein E (APOE) genotype is the strongest genetic risk factor for late-onset Alzheimer’s disease. However, its effect on lipid metabolic pathways, and their mediating effect on disease risk, is poorly understood. Methods: We performed lipidomic analysis on three independent cohorts (the Aus�tralian Imaging, Biomarkers and Lifestyle [AIBL] flagship study, n = 1087; the Alzheimer’s Disease Neuroimaging Initiative [ADNI] 1 study, n = 819; and the Bussel�ton Health Study [BHS], n = 4384), and we defined associations between APOE ε2 and ε4 and 569 plasma/serum lipid species. Mediation analysis defined the proportion of the treatment effect of the APOE genotype mediated by plasma/serum lipid species. Results: A total of 237 and 104 lipid species were associated with APOE ε2 and ε4, respectively. Of these 68 (ε2) and 24 (ε4) were associated with prevalent Alzheimer’s disease. Individual lipid species or lipidomic models of APOE genotypes mediated up to 30% and 10% of APOE ε2 and ε4 treatment effect, respectively. Discussion: Plasma lipid species mediate the treatment effect of APOE genotypes on Alzheimer’s disease and as such represent a potential therapeutic target.
Under the conditions of the feed of 400 moles of alcohol+100 moles of glycerol, 313 K‐573 K and 0.1 MPa, based on Gibbs free energy global minimization, an improved genetic algorithm was used for the thermodynamic equilibrium analysis on the synthesis processes of alkyl glyceryl ethers respectively from methanol+glycerol, ethanol+glycerol, isobutanol+glycerol and tert‐butanol+glycerol. The columnar stacking charts and 3D contour graphs were used to compare the effects of temperature, pressure and the feed ratio to the equilibrium conversion, product selectivity, and equilibrium composition. The basic laws of the synthesis processes of alkyl glycerol ethers in homogeneous and heterogeneous states were investigated in a wide temperature range. Through comparison, it was found that the isopropanol+glycerol system is easier to convert into alkyl glycerol ethers, followed by the ethanol +glycerol system. The methanol+glycerol system and tert‐butanol +glycerol system are greatly affected by pressure and temperature, and their conversions and selectivities are relatively low. This article is protected by copyright. All rights reserved.
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Fatty acid (FA) balance is strictly related to human health. The composition of fatty acids in lipid membranes seems to be influenced by diet. Shark liver oil (SLO) supplementation has been widely used recently in the prevention and treatment of human diseases. We analyzed the impact of short-term SLO supplementation on certain biochemical parameters and erythrocyte FA composition in a group of young healthy women. Our results showed that 6 weeks of SLO supplementation led to a significant decrease in C-reactive protein levels in sera and intracellular cholesterol levels in peripheral blood mononuclear cells. SLO supplementation caused a significant increase in the content of the polyunsaturated omega-3 FAs: docosahexaenoic acid, docosapentaenoic acid and α-linolenic acid. In the group of omega-6 FAs, we observed a significant elevation of arachidonic and dihomo-gamma-linoleic acid content. Due to these alterations, the omega-3 index increased significantly from 3.6% (before) to 4.2% (after supplementation). We also observed the impact of SLO supplementation on the membrane fluidity index. The ratio between saturated and unsaturated FAs decreased significantly from 13.1 to 9.9. In conclusion, our results show that even short-term SLO supplementation can improve human erythrocyte fatty acid composition and other parameters that may have health-promoting consequences.
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Lipid metabolism is tightly linked to adiposity. Comprehensive lipidomic profiling offers new insights into the dysregulation of lipid metabolism in relation to weight gain. Here, we investigated the relationship of the human plasma lipidome and changes in waist circumference (WC) and body mass index (BMI). Adults (2653 men and 3196 women), 25–95 years old who attended the baseline survey of the Australian Diabetes, Obesity and Lifestyle Study (AusDiab) and the 5-year follow-up were enrolled. A targeted lipidomic approach was used to quantify 706 distinct molecular lipid species in the plasma samples. Multiple linear regression models were used to examine the relationship between the baseline lipidomic profile and changes in WC and BMI. Metabolic scores for change in WC were generated using a ridge regression model. Alkyl-diacylglycerol such as TG(O-50:2) [NL-18:1] displayed the strongest association with change in WC (β-coefficient = 0.125 cm increment per SD increment in baseline lipid level, p = 2.78 × 10-11. Many lipid species containing linoleate (18:2) fatty acids were negatively associated with both WC and BMI gain. Compared to traditional models, multivariate models containing lipid species identify individuals at a greater risk of gaining WC: top quintile relative to bottom quintile (odds ratio, 95% CI = 5.4, 3.8–6.6 for women and 2.3, 1.7–3.0 for men). Our findings define metabolic profiles that characterize individuals at risk of weight gain or WC increase and provide important insight into the biological role of lipids in obesity.
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The glyceryl ethers were studied in lipids from human bone marrow, spleen, and milk; from yellow bone marrow and milk of cow; and from the yolk of hens' eggs. The highest concentrations were found in human red bone marrow and in human milk. No glyceryl ethers could be demonstrated in red cells or egg yolk. Besides the main components (chimyl, batyl, and selachyl alcohols), several new glyceryl ethers were found. The glyceryl ethers in man and cow were generally much more saturated than those in the liver oils of elasmobranch fish, although a fairly high degree of unsaturation was found in the glyceryl ethers of human milk.
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Shark liver oil (SLO), is used in natural medicine as immunity stimulant, cardiovascular protector and anti ageing reagent. These properties were related with the high amounts of alkylglycerols (22%) obtained from Greenland shark liver. After a control of the mean SLO composition by NMR and MS, surface and membrane interactions and antioxidant properties were investigated using NMR, ESR and ST measurements and the in vitro consequences on erythrocytes and cells were studied. An estimation of the composition of this extract was performed. Moreover, SLO was found not haemolytic (A concentration inducing 50% haemolysis, HC50 could not be reached) and superficial tension measurements revealed slight tension active properties. The 31P and 2H –NMR and ESR studies of phospholipid dispersions (dimyristoyl phosphatidyl cholin, DMPC) in the presence of SLO showed a significant increase in membrane fluidity at low temperature (below phase transition temperature) predominantly observed at the surface level. The anti oxidant activity was also confirmed, similar as that observed for vitamin E.
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. [ 3
1-O-Alkylglycerols (alkyl-Gro), naturally occurring compounds abundant in shark liver oil, protect patients from radiotherapy side-effects. However, the protection mechanism is not well understood. It might be mediated by alkyl-Gro incorporation into pools of platelet-activating factor (PAF) precursor and subsequent modification of PAF biosynthesis. Using a 3H-labelled or unlabelled natural alkyl-Gro mixture, in which prominent alkyl chains were C18:1(9) (54–65%), C16:1(7) (5–15.5%), and C16:0 (5–10%), we investigated the incorporation of alkyl-Gro into phospholipids of human leukemic monocyte-like THP-1 cells. Incubation of cells for 24 h with [3H]alkyl-Gro (10 μM) resulted in their incorporation into 1-O-alkyl-2-acyl-sn-glycero-3-phosphocholine (1097 ± 25.1 pmol/2×106 cells) and into 1-alkyl-2-acyl-sn-glycero-3-phosphoethanolamine (640.4 + 12.5 pmol/2×106 cells) with a total yield of 6.5%. Such incorporation induced production of 1-O-[3H]alkyl-2-acetyl-sn-glycero-3-phosphocholine ([3H]PAF), which was increased after stimulation by the calcium ionophore A23187. HPLC analysis of the [3H]PAF molecular species indicated that the three major [3H]alkyl-Gro were used for [3H]PAF synthesis in ratios similar to that of the mixture. Total production of biologically active PAF, as measured by the platelet-aggregation bioassay, was also increased by alkyl-Gro incorporation in resting (+20%) and in A23187-stimulated (+59%) THP-1 cells. HPLC analysis of the [3H]PAF produced in the presence of [3H]acetate, confirmed that levels of PAF, but not of its 1-acyl analog, were increased by alkyl-Gro incorporation in resting and stimulated cells. However, the rise in [3H]acetyl-PAF, which resulted mainly from C16:0 PAF, was reduced by about 50% in the presence of the PAF-receptor antagonist SR 27417, providing evidence that stimulation of total PAF synthesis was caused by the increase in the precursor pool and autocrine amplification of PAF-induced PAF production. Thus, the supplementation of THP-1 cells in culture with naturally occurring alkyl-Gro led to the incorporation of alkyl-Gro into ether-containing phospholipids, which were subsequently used for PAF synthesis. Furthermore, alkyl-Gro incorporation resulted in a significant rise in PAF production by THP-1 cells under resting and stimulated conditions. These results may be of importance for modulating PAF production in several pathophysiological conditions, such as peroxysome deficiencies, that are associated with a lack of ether lipid synthesis.
A regression of tumour growth is observed when alkoxyglycerols are administered prior to radiation treatment of patients suffering from cancer of the uterine cervix. This regression has been demonstrated by a change in the quotient between the incidence of early and advanced stages.
Alkylglycerols (alkyl-Gro) are ether lipids abundant in shark liver oil (SLO), and oral SLO or alkyl-Gro mix from this source have several in vivo biological activities including stimulation of haematopoiesis an immunological defences, or anti-tumour and anti-metastasis activities in vivo. Composition of natural alkyl-Gro mix contains several alkyl-Gro varying by chain length and unsaturation, and individual anti-tumour activity of each molecule present in natural mix remained unknown. We synthesized six prominent constituents of natural alkyl-Gro mix, namely 12:0, 14:0 16:0, 18:0, 16:1 n-7, and 18:1 n-9 alkyl-Gro. Using an in vivo model of grafted tumour in mice (3LL cells), we studied and compared the oral anti-tumour and anti-metastasis activities of each of these 6 alkyl-Gro. 16:1 and 18:1 alkyl-Gro showed strong activity in reducing lung metastasis number, while saturated alkyl-Gro had weaker (16:0) or no (12:0, 14:0, 18:0) effect. Spleen weights at day 20 after graft were also measured and showed tremendous variations depending on the treatment. Tumour graft resulted in a raise in spleen weight in control group, this raise was nearly abolished in 16:1 and 18:1 alkyl-Gro-treated mice, and was reduced in 14:0 and 16:0 alkyl-Gro-treated mice. Conversely, 18:0 alkyl-Gro-treated mice showed spleen weigh raise as compared with untreated grafted mice. These new data demonstrate a prominent role of unsaturation in the anti-tumour activities of alkyl-Gro.
Diglycerides (DGs) are phospholipid-derived second messengers that regulate PKC-dependent signaling pathways. Distinct species of DGs are generated from inflammatory cytokines and growth factors. Growth factors increase diacyl- but not ether-linked DG species, whereas inflammatory cytokines predominately generate alkyl, acyl- and alkenyl, acyl-linked DG species in rat mesenchymal cells. These DG species have been shown to differentially regulate protein kinase C (PKC) isotypes. Ester-linked diacylglycerols activate PKC-epsilon and cellular proliferation in contrast to ether-linked DGs, which lead to growth arrest through the inactivation of PKC-epsilon. It is now hypothesized that ether-linked DGs inhibit mitogenesis through the inactivation of ERK and/or Akt signaling cascades. We demonstrate that cell-permeable ether-linked DGs reduce vascular smooth muscle cell growth by inhibiting platelet-derived growth factor-stimulated ERK in a PKC-epsilon-dependent manner. This inhibition is specific to the ERK pathway, since ether-linked DGs do not affect growth factor-induced activation of other family members of the MAPKs, including p38 MAPK and c-Jun NH(2)-terminal kinases. We also demonstrate that ether-linked DGs reduce prosurvival phosphatidylinositol 3-kinase (PI3K)/Akt signaling, independent of PKC-epsilon, by diminishing an interaction between the subunits of PI3K and not by affecting protein phosphatase 2A or lipid (phosphatase and tensin homologue deleted in chromosome 10) phosphatases. Taken together, our studies identify ether-linked DGs as potential adjuvant therapies to limit vascular smooth muscle migration and mitogenesis in atherosclerotic and restenotic models.
The incidence of injuries following intracavitary and external radiation therapy is markedly decreased in all stages of the disease by the administration of alkoxyglycerols. Complex injuries (due to radiation injury and tumour growth in combination) were reduced to about 1/3 in a group receiving alkoxyglycerols prophylactically, i.e. before, during and after radiation treatment, when compared with a control group. Using non-prophylactic administration of alkoxyglycerols, i.e. during and after radiation treatment, no effect was observed on complex injuries, while--as for the prophylactic group--the injuries due to radiation only, were significantly decreased. The use of so called "increased amount" of radium in the intracavitary irradiator was followed by an unexpectedly high incidence of radiation injuries, which was considerably reduced, however, by alkoxyglycerols, especially when administered prophylactically.