Polyunsaturated fatty acids (PUFA) constitute an influential group of molecules that promote health by an as yet unknown mechanism. They are structurally distinguished from less unsaturated fatty ...acids by the presence of a repeating
CH–CH
2–CH
unit that produces an extremely flexible chain rapidly reorienting through conformational states. The most highly unsaturated case in point is docosahexaenoic acid (DHA) with 6 double bonds. This review will summarize how the high disorder of DHA affects the properties of the membrane phospholipids into which the PUFA incorporates, focusing upon the profound impact on the interaction with cholesterol. Results obtained with model membranes using an array of biophysical techniques will be presented. They demonstrate DHA and the sterol possesses a mutual aversion that drives the lateral segregation of DHA-containing phospholipids into highly disordered domains away from cholesterol. These domains are compositionally and organizationally the opposite of lipid rafts, the ordered domain enriched in predominantly saturated sphingolipids “glued” together by cholesterol that is believed to serve as the platform for signaling proteins. We hypothesize that DHA-rich domains also form in the plasma membrane and are responsible, in part, for the diverse range of health benefits associated with DHA.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Docosahexaenoic acid (DHA) is the longest, most unsaturated, and hence, most oxidizable fatty acid commonly found in nature. The mechanisms behind DHA's many biological functions remain a subject of ...much debate. Here we review one important, but often unstudied, aspect of DHA function, namely, the potential role of its many oxidation products. We divide this review into camps, enzymatic and non-enzymatic oxidations, and report their effects primarily on induction of apoptosis in cancer cells. We conclude that the study of the effects of lipid peroxidation products on biochemical function will be a difficult but highly rewarding area for future studies.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
We have previously suggested that the
ω-3 polyunsaturated fatty acid, docosahexaenoic acid (DHA) may in part function by enhancing membrane lipid phase separation into lipid rafts. Here we further ...tested for differences in the molecular interactions of an oleic (OA) versus DHA-containing phospholipid with sphingomyelin (SM) and cholesterol (CHOL) utilizing
2H NMR spectroscopy, differential scanning calorimetry, atomic force microscopy, and detergent extractions in model bilayer membranes.
2H NMR and DSC (differential scanning calorimetry) established the phase behavior of the OA-containing 1-
2H
31palmitoyl-2-oleoyl-
sn-glycero-3-phosphoethanolamine (16:0-18:1PE-d
31)/SM (1:1) and the DHA-containing 1-
2H
31palmitoyl-2-docosahexaenoyl-
sn-glycero-3-phosphoethanolamine (16:0-22:6PE-d
31)/SM (1:1) in the absence and presence of equimolar CHOL. CHOL was observed to affect the OA-containing phosphatidylethanolamine (PE) more than the DHA-containing PE, as exemplified by >2× greater increase in order measured for the perdeuterated palmitic chain in 16:0-18:1PE-d
31/SM (1:1) compared to 16:0-22:6PE-d
31/SM (1:1) bilayers in the liquid crystalline phase. Atomic force microscopy (AFM) experiments showed less lateral phase separation between 16:0-18:1PE-rich and SM/CHOL-rich raft domains in 16:0-18:1PE/SM/CHOL (1:1:1) bilayers than was observed when 16:0-22:6PE replaced 16:0-18:1PE. Differences in the molecular interaction of 16:0-18:1PE and 16:0-22:6PE with SM/CHOL were also found using biochemical detergent extractions. In the presence of equimolar SM/CHOL, 16:0-18:1PE showed decreased solubilization in comparison to 16:0-22:6PE, indicating greater phase separation with the DHA-PE. Detergent experiments were also conducted with cardiomyocytes fed radiolabeled OA or DHA. Although both OA and DHA were found to be largely detergent solubilized, the amount of OA that was found to be associated with raft-rich detergent-resistant membranes exceeded DHA by almost a factor of 2. We conclude that the OA-PE phase separates from rafts far less than DHA-PE, which may have implications for cellular signaling.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Encounter: story, self, metaphor, person Stillwell, William
Person-centered & experiential psychotherapies,
10/2/2019, 2019-10-02, Volume:
18, Issue:
4
Journal Article
Peer reviewed
Individuals are invited to the kind of Encounter Groups referenced in this article with language such as this: 'We sit together in a circle, using the opportunity to talk and otherwise communicate. ...Our aim is to understand and experience our personal relatedness to happenings that concern us. Our conversations are essentially sincere but not without humor. People actually listen, and we hear ourselves as who we more deeply and subtly are. We come to know our lives better and meet other people in a more significant and heartfelt way.' The author's most extensive experience has been with nonprofessionals and people from the helping professions. For the most part, these groups of a few hours to a week, are organized around participants' individually personal intentions. In these facilitated or non-facilitated Person-Centered groups all participants make interactive negotiated entry with others into a process that has the potential for their experiencing a dis-solving-and-coming-to-be of their selves. Their participation may lead to counter-intentional outcomes.
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The ever-increasing amount of trans fatty acids in the human diet has been linked to a variety of afflictions, most notably coronary heart disease and arteriosclerosis. The mechanism of why the ...replacement of cis fatty acids with their trans counterparts can be detrimental to the health of an individual remains a mystery. Here, we compare the differences in membrane physical properties including molecular dynamics, lateral lipid packing, thermotropic phase behavior, “fluidity”, lateral mobility, and permeability between model membranes (lipid monolayers and bilayers) composed of cis- and trans-containing phosphatidylcholines (PCs). The PCs tested have a total of zero, one, two, or four cis (oleic or linoleic) or trans (elaidic or linoelaidic) double bonds. These experiments all confirm the basic hypothesis that trans fatty acids produce membrane properties more similar to those of saturated chains than to those of acyl chains containing cis double bonds; i.e., cis double bonds induce much larger membrane perturbations than trans double bonds.
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IJS, KILJ, NUK, PNG, UL, UM
Epidemiological evidence strongly links fish oil, which is rich in docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), with low incidences of several types of cancer. The inhibitory effects ...of omega-3 polyunsaturated fatty acids on cancer development and progression are supported by studies with cultured cells and animal models. Propofol (2,6-diisopropylphenol) is the most extensively used general anesthetic-sedative agent employed today and is nontoxic to humans at high levels (50 microg/ml). Clinically relevant concentrations of propofol (3 to 8 microg/ml; 20 to 50 microM) have also been reported to have anticancer activities. The present study describes the synthesis, purification, characterization and evaluation of two novel anticancer conjugates, propofol-docosahexaenoate (propofol-DHA) and propofol-eicosapentaenoate (propofol-EPA).
The conjugates linking an omega-3 fatty acid, either DHA or EPA, with propofol were synthesized and tested for their effects on migration, adhesion and apoptosis on MDA-MB-231 breast cancer cells.
At low concentrations (25 microM), DHA, EPA or propofol alone or in combination had minimal effect on cell adhesion to vitronectin, cell migration against serum and the induction of apoptosis (only 5 to 15% of the cells became apoptotic). In contrast, the propofol-DHA or propofol-EPA conjugates significantly inhibited cell adhesion (15 to 30%) and migration (about 50%) and induced apoptosis (about 40%) in breast cancer cells.
These results suggest that the novel propofol-DHA and propofol-EPA conjugates reported here may be useful for the treatment of breast cancer.
The molecular organization of cholesterol in phospholipid bilayers composed of 1,2-diarachidonylphosphatidylcholine (20:4–20:4PC), 1-stearoyl-2-arachidonylphosphatidylcholine (18:0–20:4PC), and ...20:4–20:4PC/18:0–20:4PC (1/1
mol) was investigated by solid-state
2H NMR and by low- and wide-angle x-ray diffraction (XRD). On the basis of distinct quadrupolar powder patterns arising from 3
α-
2H
1cholesterol intercalated into the membrane and phase separated as solid, solubility
χ
chol
NMR
=
17
±
2
mol% and tilt angle
α
0
=
25
±
1° in 20:4–20:4PC were determined. The corresponding values in 18:0–20:4PC were
χ
chol
NMR
≥
50
mol% and
α
0
=
16
±
1°. Cholesterol solubility determined by XRD was
χ
chol
XRD
=
15
±
2
mol% and
χ
chol
XRD
=
49
±
1
mol% for 20:4–20:4PC and 18:0–20:4PC, respectively. XRD experiments show that the solid sterol is monohydrate crystals presumably residing outside the bilayer. The
2H NMR spectrum for equimolar 3
α-
2H
1cholesterol added to mixed 20:4–20:4PC/18:0–20:4PC (1/1
mol) membranes is consistent with segregation of cholesterol into 20:4–20:4PC and 18:0–20:4PC microdomains of <160
Å in size that preserve the molecular organization of sterol in the individual phospholipid constituents. Our results demonstrate unambiguously that cholesterol has low affinity to polyunsaturated fatty acids and support hypotheses of lateral phase separation of membrane constituents into sterol-poor/polyunsaturated fatty acid-rich and sterol-rich/saturated fatty acid-rich microdomains.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
A central tenet of the lipid raft model is the existence of non-raft domains. In support of this view, we have established in model membranes that a phosphatidylethanolamine (PE)-containing ...docosahexaenoic acid (DHA) forms organizationally distinct non-raft domains in the presence of sphingomyelin (SM) and cholesterol (Chol). We have shown that formation of DHA-rich domains is driven by unfavorable molecular interactions between the rigid Chol molecule and the highly flexible DHA acyl chain. However, the molecular interactions between SM and the DHA-containing PE, which could also contribute to the formation of DHA-rich non-raft domains, have not been sufficiently investigated. To address this issue, we use differential scanning calorimetry (DSC) to study the phase behavior of mixtures of SM with either 1-palmitoyl-2-docosahexaenoyl-
sn-glycero-3-phosphoethanolamine (16:0-22:6PE) or 1-palmitoyl-2-oleoyl-
sn-glycero-3-phosphoethanolamine (16:0-18:1PE), an oleic acid (OA)-containing control, over a wide range of concentrations. Deconvolution of binary DSC scans shows that both 16:0-22:6PE and 16:0-18:1PE phase separate from SM. Analysis of transition temperatures and partial phase diagrams, constructed from the DSC scans for the first time, shows that 16:0-22:6PE displays greater non-ideal mixing with SM compared to 16:0-18:1PE. Our findings support a model in which DHA- and OA-containing PEs differentially phase separate from SM over a wide range of molar ratios to initiate the formation of non-raft domains, which is greatly enhanced by DHA, but not OA, in the presence of cholesterol.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Epidemiological evidence has established that ingestion of long-chain polyunsaturated omega-3 fatty acids (omega-3 PUFAs), abundant in fish oils, have profound effects on many human disorders and ...diseases, including cardiovascular disease and cancer. Here we briefly review the dietary recommendations and the food sources that are naturally enriched by these fatty acids. There are also a number of products including eggs, bread, and cereals available to supplement omega-3 fatty acid dietary intake. Some of these supplements are proposed to aid different pathological conditions. While the beneficial effects of omega-3 fatty acids can no longer be doubted, their molecular mechanism of action remains elusive. Without question, the action of omega-3 fatty acids is complex and involves a number of integrated signaling pathways. This review focuses on one of the possible cellular mechanisms by which the omega-3 PUFAs, docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), may function. Studies with cancer cells suggest that DHA induces cell cycle arrest and apoptosis by activating protein phosphatases, leading to dephosphorylation of retinoblastoma protein (pRB). Protein phosphatases are also involved with the protein Bcl2, which regulates the release of cytochrome c from mitochondria, and eventually, activation of the apoptotic enzyme caspase 3.
The molecular organization of cholesterol in 1,2-didocosahexaenoylphosphatidylcholine (22:6-22:6PC) and 1-stearoyl-2-docosahexaenoylphosphatidylcholine (18:0-22:6PC) bilayers was investigated. Using ...low- and wide-angle X-ray diffraction (XRD), we determined that the solubility of the sterol at 20 °C was 11 ± 3 mol % in 22:6-22:6PC vs 55 ± 3 mol % in 18:0-22:6PC bilayers. Solubility in the dipolyunsaturated membrane rose to 17 ± 3 mol % at 40 °C, while in the saturated−polyunsaturated membrane there was no change within experimental uncertainty. We compared the molecular orientation of 3α-2H1cholesterol incorporated into 22:6-22:6PC bilayers to its solubility limit and into 18:0-22:6PC bilayers to a comparable concentration (10 mol %) in solid-state 2H NMR experiments. The sterol possessed a tilt angle α0 = 24° ± 1° in 22:6-22:6PC that was independent of temperature over a range from 20 to 40 °C. In contrast, the value was α0 = 21° ± 1° in 18:0-22:6 bilayers at 20 °C and increased to α0 = 24° ± 1° at 40 °C. We attribute the low solubility of cholesterol in 22:6-22:6PC membranes to steric incompatibility between the rigid steroid moiety and the highly disordered docosahexaenoic acid (DHA) chain, which has the potential to promote lateral heterogeneity within DHA-rich membranes. Considering 22:6-22:6PC to be the most unsaturated phospholipid found in vivo, this model membrane study provides a point of reference for elucidating the role of sterol−lipid interactions in controlling local compositional organization. Our results form the basis for a model that is consistent with cholesterol's ability to modulate the activity of certain neural transmembrane proteins.
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