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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
www.mdpi.com/journal/marinedrugs
Review
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: anne-laure.deniau@chu-rennes.fr (A.-L.D.); frederique.pedrono@agrocampus-ouest.fr
(F.P.); romain.mitre@gmail.com (R.M.); damien.lebot@univ-rennes1.fr (D.L.B.)
2 Ecole Nationale Supérieure de Chimie de Rennes and Université Européenne de Bretagne, France;
E-Mail: paul.mosset@ensc-rennes.fr
* Author to whom correspondence should be addressed; E-Mail: alain.legrand@univ-rennes1.fr;
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
activities
OPEN ACCESS
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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
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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
activities.
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
confirmation.
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
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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
(S)-3-[(9Z)-9-hexadecen-1-yloxy]-1,2-propanediol.
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Figure 1. 1-O-alkyl-sn-glycerols obtained by chemical synthesis.
HO O
OH
(CH
2
)
11
CH
3
HO O
OH
(CH
2
)
13
CH
3
HO O
OH
(CH
2
)
15
CH
3
HO O
OH
(CH
2
)
17
CH
3
HO O
OH
HO O
OH
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].
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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
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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.
Acknowledgements
Région Bretagne, Ligue Nationale contre le Cancer, Société Polaris (Pleuven, 29).
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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. ...
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