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Roles of Brain Lipids in Glial Activation
Abstract
Lipids were believed to be the major components of the brain structure. However, recent accumulated findings show that they can also play various roles in the brain, inducing cellular signaling, protecting neuronal cell death, preventing glial activation and even maintaining division of neural stem cells. In the present review, we first summarize physiological roles of brain lipids, then focus on ether-type glycerophospholipids, plasmalogens (Pls) showing recent evidences of how Pls can modulate the cellular signaling in the brain to maintain its integrity and to protect from the glial activation. Finally, we discuss the differential effects of other brain lipids in the glial activation.
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Peripheral nerve injury (PNI) triggers cellular and molecular changes in the spinal cord. However, little is known about how the polyunsaturated fatty acid-containing phosphatidylcholines (PUFA-PCs) are regulated in the spinal cord after PNI and the association of PUFA-PCs with the non-neuronal cells within in the central nervous system (CNS). In this study, we found that arachidonic acid-containing phosphatidylcholine (AA-PC), [PC(16:0/20:4)+K]+, was significantly increased in the ipsilateral ventral and dorsal horns of the spinal cord after sciatic nerve transection, and the increased expression of [PC(16:0/20:4)+K]+ spatiotemporally resembled the increase of reactive microglia and the astrocytes. From the lipidomics point of view, we conclude that [PC(16:0/20:4)+K]+ could be the main phospholipid in the spinal cord influenced by PNI, and the regulation of specific phospholipid molecule in the CNS after PNI is associated with the reactive microglia and astrocytes.
The special glycerophospholipids plasmalogens (Pls) are enriched in the brain and reported to prevent neuronal cell death by enhancing phosphorylation of Akt and ERK signaling in neuronal cells. Though the activation of Akt and ERK was found to be necessary for the neuronal cells survival, it was not known how Pls enhanced cellular signaling. To answer this question, we searched for neuronal specific orphan GPCR (G-protein coupled receptor) proteins, since these proteins were believed to play a role in cellular signal transduction through the lipid rafts, where both Pls and some GPCRs were found to be enriched. In the present study, pan GPCR inhibitor significantly reduced Pls-induced ERK signaling in neuronal cells, suggesting that Pls could activate GPCRs to induce signaling. We then checked mRNA expression of 19 orphan GPCRs and 10 of them were found to be highly expressed in neuronal cells. The knockdown of these 10 neuronal specific GPCRs by short hairpin (sh)-RNA lentiviral particles revealed that the Pls-mediated phosphorylation of ERK was inhibited in GPR1, GPR19, GPR21, GPR27 and GPR61 knockdown cells. We further found that the overexpression of these GPCRs enhanced Pls-mediated phosphorylation of ERK and Akt in cells. Most interestingly, the GPCRs-mediated cellular signaling was reduced significantly when the endogenous Pls were reduced. Our cumulative data, for the first time, suggest a possible mechanism for Pls-induced cellular signaling in the nervous system.
Because human breast milk is a rich source of phospholipids and gangliosides and breastfed infants have improved learning compared with formula-fed infants, the importance of dietary phospholipids and gangliosides for brain development is of interest.
We sought to determine the effects of phospholipids and gangliosides on brain and cognitive development.
Male and female piglets from multiple litters were artificially reared and fed formula containing 0% (control), 0.8%, or 2.5% Lacprodan PL-20 (PL-20; Arla Foods Ingredients), a phospholipid/ganglioside supplement, from postnatal day (PD) 2 to PD28. Beginning on PD14, performance in a spatial T-maze task was assessed. At PD28, brain MRI data were acquired and piglets were killed to obtain hippocampal tissue for metabolic profiling.
Diet affected maze performance, with piglets that were fed 0.8% and 2.5% PL-20 making fewer errors than control piglets (80% vs. 75% correct on average; P < 0.05) and taking less time to make a choice (3 vs. 5 s/trial; P < 0.01). Mean brain weight was 5% higher for piglets fed 0.8% and 2.5% PL-20 (P < 0.05) than control piglets, and voxel-based morphometry revealed multiple brain areas with greater volumes and more gray and white matter in piglets fed 0.8% and 2.5% PL-20 than in control piglets. Metabolic profiling of hippocampal tissue revealed that multiple phosphatidylcholine-related metabolites were altered by diet.
In summary, dietary phospholipids and gangliosides improved spatial learning and affected brain growth and composition in neonatal piglets.
© 2014 American Society for Nutrition.
Cholesterol has been shown to promote cell proliferation/migration in many cells; however the mechanism(s) have not yet been fully identified. Here we demonstrate that cholesterol increases Ca(2+) entry via the TRPM7 channel, which promoted proliferation of prostate cells by inducing activation of the AKT and/or the ERK pathway. Additionally, cholesterol mediated Ca(2+) entry induced calpain activity that showed a decrease in E-cadherin expression, which together could lead to migration of prostate cancer cells. Overexpression of TRPM7 significantly facilitated cholesterol dependent Ca(2+) entry, cell proliferation and tumor growth. Whereas, TRPM7 silencing or inhibition of cholesterol synthesis by statin showed a significant decrease in cholesterol-mediated activation of TRPM7, cell proliferation, and migration of prostate cancer cells. Consistent with these results, statin intake was inversely correlated with prostate cancer patients and increase in TRPM7 expression was observed in samples obtained from prostate cancer patients. Altogether, we provide evidence that cholesterol-mediated activation of TRPM7 is important for prostate cancer and have identified that TRPM7 could be essential for initiation and/or progression of prostate cancer.
Neuronal cells are susceptible to many stresses, which will cause the apoptosis and neurodegenerative diseases. The precise molecular mechanism behind the neuronal protection against these apoptotic stimuli is necessary for drug discovery. In the present study, we have found that plasmalogens (Pls), which are glycerophospholipids containing vinyl ether linkage at sn-1 position, can protect the neuronal cell death upon serum deprivation. Interestingly, caspse-9, but not caspase-8 and caspase-12, was cleaved upon the serum starvation in Neuro-2A cells. Pls treatments effectively reduced the activation of caspase-9. Furthermore, cellular signaling experiments showed that Pls enhanced phosphorylation of the phosphoinositide 3-kinase (PI3K)-dependent serine/threonine-specific protein kinase AKT and extracellular-signal-regulated kinases ERK1/2. PI3K/AKT inhibitor LY294002 and MAPK/ERK kinase (MEK) inhibitor U0126 treatments study clearly indicated that Pls-mediated cell survival was dependent on the activation of these kinases. In addition, Pls also inhibited primary mouse hippocampal neuronal cell death induced by nutrient deprivation, which was associated with the inhibition of caspase-9 and caspase-3 cleavages. It was reported that Pls content decreased in the brain of the Alzheimer's patients, which indicated that the reduction of Pls content could endanger neurons. The present findings, taken together, suggest that Pls have an anti-apoptotic action in the brain. Further studies on precise mechanisms of Pls-mediated protection against cell death may lead us to establish a novel therapeutic approach to cure neurodegenerative disorders.
Diacylglycerol kinases (DGKs) are a diverse family of enzymes that catalyze the conversion of diacylglycerol (DAG), a crucial second messenger of receptor-mediated signaling, to phosphatidic acid (PA). Both DAG and PA are bioactive molecules that regulate a wide set of intracellular signaling proteins involved in innate and adaptive immunity. Clear evidence points to a critical role for DGKs in modulating T cell activation, function, and development. More recently, studies have elucidated factors that control DGK function, suggesting an added complexity to how DGKs act during signaling. This review summarizes the available knowledge of the function and regulation of DGK isoforms in signal transduction with a particular focus on T lymphocytes.
The reorganization of metabolic pathways in cancer facilitates the flux of carbon and reducing equivalents into anabolic pathways at the expense of oxidative phosphorylation. This provides rapidly dividing cells with the necessary precursors for membrane, protein and nucleic acid synthesis. A fundamental metabolic perturbation in cancer is the enhanced synthesis of fatty acids by channeling glucose and/or glutamine into cytosolic acetyl-CoA and upregulation of key biosynthetic genes. This lipogenic phenotype also extends to the production of complex lipids involved in membrane synthesis and lipid-based signaling. Cancer cells display sensitivity to ablation of fatty acid synthesis possibly as a result of diminished capacity to synthesize complex lipids involved in signaling or growth pathways. Evidence has accrued that phosphatidylcholine, the major phospholipid component of eukaryotic membranes, as well as choline metabolites derived from its synthesis and catabolism, contribute to both proliferative growth and programmed cell death. This review will detail our current understanding of how coordinated changes in substrate availability, gene expression and enzyme activity lead to altered phosphatidylcholine synthesis in cancer, and how these changes contribute directly or indirectly to malignant growth. Conversely, apoptosis targets key steps in phosphatidylcholine synthesis and degradation that are linked to disruption of cell cycle regulation, reinforcing the central role that phosphatidylcholine and its metabolites in determining cell fate.
Sialic acids are a family of nine-carbon acidic monosaccharides that occur naturally at the end of sugar chains attached to the surfaces of cells and soluble proteins. In the human body, the highest concentration of sialic acid (as N-acetylneuraminic acid) occurs in the brain where it participates as an integral part of ganglioside structure in synaptogenesis and neural transmission. Human milk also contains a high concentration of sialic acid attached to the terminal end of free oligosaccharides, but its metabolic fate and biological role are currently unknown. An important question is whether the sialic acid in human milk is a conditional nutrient and confers developmental advantages on breast-fed infants compared to those fed infant formula. In this review, we critically discuss the current state of knowledge of the biology and role of sialic acid in human milk and nervous tissue, and the link between sialic acid, breastfeeding and learning behaviour.
Neuroinflammation involves the activation of glial cells in neurodegenerative diseases such as Alzheimer's disease (AD). Plasmalogens (Pls) are glycerophospholipids constituting cellular membranes and play significant roles in membrane fluidity and cellular processes such as vesicular fusion and signal transduction.
In this study the preventive effects of Pls on systemic lipopolysaccharide (LPS)-induced neuroinflammation were investigated using immunohistochemistry, real-time PCR methods and analysis of brain glycerophospholipid levels in adult mice.
Intraperitoneal (i.p.) injections of LPS (250 μg/kg) for seven days resulted in increases in the number of Iba-1-positive microglia and glial fibrillary acidic protein (GFAP)-positive astrocytes in the prefrontal cortex (PFC) and hippocampus accompanied by the enhanced expression of IL-1β and TNF-α mRNAs. In addition, β-amyloid (Aβ3-16)-positive neurons appeared in the PFC and hippocampus of LPS-injected animals. The co-administration of Pls (i.p., 20 mg/kg) after daily LPS injections significantly attenuated both the activation of glial cells and the accumulation of Aβ proteins. Finally, the amount of Pls in the PFC and hippocampus decreased following the LPS injections and this reduction was suppressed by co-treatment with Pls.
These findings suggest that Pls have anti-neuroinflammatory and anti-amyloidogenic effects, thereby indicating the preventive or therapeutic application of Pls against AD.
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The present study was undertaken to examine the effect of cerebrosides derived from the sea cucumber Acaudina molpadioides and the starfish Asterias amurensis on the anti-tumor activity in vitro and in vivo. The results indicated that both Acaudina molpadioides cerebrosides (AMC) and Asterias amurensis cerebrosides (AAC) exhibited an inhibitory effect on cell proliferation through induction of apoptosis in S180 cells. Moreover, administration of AMC and AAC (50 mg/kg BW) on S180 tumor bearing mice reduced the tumor weight by 45.24 % and 35.71 %, respectively. In S180 ascites tumor model, AMC and AAC (50 mg/kg BW) treatment exhibited a significant ascites fluid growth inhibition of 31.23 % and 22.72 %. Furthermore, the ascites tumor cell viability ratio in AMC and AAC groups reduced to 50.89 % and 51.69 %, respectively. The life span of AMC and AAC administrated groups increased by 55.28 % and 35.77 % compared to control. Quantitative real-time PCR analysis demonstrated that the administration of AMC and AAC down-regulated the expression of Bcl-2, Bcl-xL, while on the other hand, up-regulated Bax, Cytochrome c, caspase-9 and caspase-3 mRNA level of the S180 ascites tumor cells. It was concluded that AMC and AAC should have potential anti-tumor activity both in vitro and in vivo by inducing apoptosis through the mitochondria-mediated apoptosis pathway. AAC seemed to be more effective than AMC in vitro but less potent in vivo. It may depend on the structural differences in their fatty acid groups and sphingoid bases.
Nonalcoholic fatty liver disease (NAFLD) is a prevalent chronic liver disease in industrialized countries. The present study was undertaken to explore the preventive effect of dietary sea cucumber cerebroside (SCC) extracted from Acaudina molpadioides in fatty liver rats.
Male Wistar rats were randomly divided into four groups including normal control group, NAFLD model group, and two SCC-treated groups with SCC at 0.006% and 0.03% respectively. The fatty liver model was established by administration of 1% orotic acid (OA) to the rats. After 10d, serum and hepatic lipid levels were detected. And the serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activities were also determined. Besides, to gain the potential mechanism, the changes of key enzymes and gene expressions related to the hepatic lipid metabolism were measured.
Dietary SCC at the level of 0.006% and 0.03% ameliorated the hepatic lipid accumulation in fatty liver rats. SCC administration elevated the serum triglyceride (TG) level and the ALT, AST activities in OA-fed rats. The activities of hepatic lipogenic enzymes including fatty acid synthase (FAS), malic enzyme (ME) and glucose-6-phosphatedehydrogenase (G6PDH) were inhibited by SCC treatment. And the gene expressions of FAS, ME, G6PDH and sterol-regulatory element binding protein (SREBP-1c) were also reduced in rats fed SCC. However, dietary SCC didn't affect the activity and mRNA expression of carnitine palmitoyltransferase (CPT) in liver. Besides, suppression of microsomal triglyceride transfer protein (MTP) activity was observed in SCC-feeding rats.
These results suggested that dietary SCC could attenuate hepatic steatosis due to its inhibition of hepatic lipogenic gene expression and enzyme activity and the enhancement of TG secretion from liver.
The neuropathological hallmarks of Alzheimer disease (AD) include “positive” lesions such as amyloid plaques and cerebral amyloid angiopathy, neurofibrillary tangles, and glial responses, and “negative” lesions such as neuronal and synaptic loss. Despite their inherently cross-sectional nature, postmortem studies have enabled the staging of the progression of both amyloid and tangle pathologies, and, consequently, the development of diagnostic criteria that are now used worldwide. In addition, clinicopathological correlation studies have been crucial to generate hypotheses about the pathophysiology of the disease, by establishing that there is a continuum between “normal” aging and AD dementia, and that the amyloid plaque build-up occurs primarily before the onset of cognitive deficits, while neurofibrillary tangles, neuron loss, and particularly synaptic loss, parallel the progression of cognitive decline. Importantly, these cross-sectional neuropathological data have been largely validated by longitudinal in vivo studies using modern imaging biomarkers such as amyloid PET and volumetric MRI.
Thyroid dysfunction has a great impact on lipids as well as a number of other cardiovascular risk factors. Hypothyroidism is relatively common and is associated with an unfavorable effect on lipids. Substitution therapy is beneficial for patients with overt hypothyroidism, improving lipid profile. However, whether subclinical hypothyroidism should be treated or not is a matter of debate. On the other hand, hyperthyroidism can be associated with acquired hypocholesterolemia or unexplained improvement of lipid profile. Overall, thyroid dysfunction should be taken into account when evaluating and treating dyslipidemic patients.
Metabolomics studies hold promise for the discovery of pathways linked to disease processes. Cardiovascular disease (CVD) represents the leading cause of death and morbidity worldwide. Here we used a metabolomics approach to generate unbiased small-molecule metabolic profiles in plasma that predict risk for CVD. Three metabolites of the dietary lipid phosphatidylcholine--choline, trimethylamine N-oxide (TMAO) and betaine--were identified and then shown to predict risk for CVD in an independent large clinical cohort. Dietary supplementation of mice with choline, TMAO or betaine promoted upregulation of multiple macrophage scavenger receptors linked to atherosclerosis, and supplementation with choline or TMAO promoted atherosclerosis. Studies using germ-free mice confirmed a critical role for dietary choline and gut flora in TMAO production, augmented macrophage cholesterol accumulation and foam cell formation. Suppression of intestinal microflora in atherosclerosis-prone mice inhibited dietary-choline-enhanced atherosclerosis. Genetic variations controlling expression of flavin monooxygenases, an enzymatic source of TMAO, segregated with atherosclerosis in hyperlipidaemic mice. Discovery of a relationship between gut-flora-dependent metabolism of dietary phosphatidylcholine and CVD pathogenesis provides opportunities for the development of new diagnostic tests and therapeutic approaches for atherosclerotic heart disease.
The integrity of central and peripheral nervous system myelin is affected in numerous lipid metabolism disorders. This vulnerability was so far mostly attributed to the extraordinarily high level of lipid synthesis that is required for the formation of myelin, and to the relative autonomy in lipid synthesis of myelinating glial cells because of blood barriers shielding the nervous system from circulating lipids. Recent insights from analysis of inherited lipid disorders, especially those with prevailing lipid depletion and from mouse models with glia-specific disruption of lipid metabolism, shed new light on this issue. The particular lipid composition of myelin, the transport of lipid-associated myelin proteins, and the necessity for timely assembly of the myelin sheath all contribute to the observed vulnerability of myelin to perturbed lipid metabolism. Furthermore, the uptake of external lipids may also play a role in the formation of myelin membranes. In addition to an improved understanding of basic myelin biology, these data provide a foundation for future therapeutic interventions aiming at preserving glial cell integrity in metabolic disorders.
The transcription factor NF-kappaB has diverse functions in the nervous system, depending on the cellular context. NF-kappaB is constitutively activated in glutamatergic neurons. Knockout of p65 or inhibition of neuronal NF-kappaB by super-repressor IkappaB resulted in the loss of neuroprotection and defects in learning and memory. Similarly, p50-/- mice have a lower learning ability and are sensitive to neurotoxins. Activated NF-kappaB can be transported retrogradely from activated synapses to the nucleus to translate short-term processes to long-term changes such as axon growth, which is important for long-term memory. In glia, NF-kappaB is inducible and regulates inflammatory processes that exacerbate diseases such as autoimmune encephalomyelitis, ischemia, and Alzheimer's disease. In summary, inhibition of NF-kappaB in glia might ameliorate disease, whereas activation in neurons might enhance memory. This review focuses on results produced by the analysis of genetic models.
Microglia, brain resident macrophages, are activated in brain injuries and several neurodegenerative diseases. However, microglial activators that are produced in the brain are not yet defined. In this study, we showed that gangliosides, sialic acid-containing glycosphingolipids, could be a microglial activator. Gangliosides induced production of nitric oxide (NO) and tumor necrosis factor-alpha (TNF-alpha) and expression of cyclooxygenase-2 (COX-2). The effect of gangliosides on NO release increased dose-dependently in the range of 10-100 microgram/ml; however, the effect decreased at concentrations higher than 200 microgram/ml. Specific types of gangliosides showed differential effects on microglial activation. Similar to gangliosides, GT1b induced production of NO and TNF-alpha and expression of COX-2. However, GM1 and GD1a induced expression of COX-2 but had little effect on NO and TNF-alpha release. The effect of gangliosides and GT1b on NO release was reduced in the presence of neuraminidase, which removes sialic acid residues from gangliosides and GT1b. Gangliosides activated extracellular signal-regulated kinase significantly but activated c-jun N-terminal kinase/stress-activated protein kinase and p38 relatively weakly. The inhibition of extracellular signal-regulated kinase by PD98059 reduced NO release from both gangliosides- and GT1b-treated microglia whereas inhibition of p38 by SB203580 increased it rather slightly. Gangliosides activated NF-kappaB, and N-acetyl cystein, an inhibitor of NF-kappaB, reduced NO release. These results suggest that gangliosides could be a microglial activator that functions via activation of mitogen-activated protein kinase and NF-kappaB.
NF-κB is widely known for its ubiquitous roles in inflammation and immune responses, as well as in control of cell division and apoptosis. These roles are apparent in the nervous system, but neurons and their neighboring cells employ the NF-κB pathway for distinctive functions as well, ranging from development to the coordination of cellular responses to injury of the nervous system and to brain-specific processes such as the synaptic signaling that underlies learning and memory. Here we discuss the regulation of NF-κB activity by neurotransmitters and neurotrophic factors and the physiological and pathological effects of NF-κB activation in neurons and glial cells. Based on work in animal models, it appears that manipulation of NF-κB signaling may prove valuable in treating such conditions as ischemic stroke, physical trauma to the brain or spinal cord, and neurodegenerative disorders, including Alzheimer’s disease and Parkinson’s disease.
Our objective was to determine whether dietary supplementation with phosphatidylcholine (PC) plus vitamin B12 could afford beneficial effects on biochemical and biophysical events in the brain of senescence-accelerated mouse (SAM) substrain SAMP8. We measured learning behaviour, hippocampal protein kinase C (PKC) activity, cerebral antioxidant status, phospholipid composition and fatty acid composition in 6-month-old SAMP8 and in age-matched controls (SAM substrain SAMR1). In comparison with SAMR1, SAMP8 showed a significant elevation in total grading score of senescence and a significant decline in acquisition SAMP8 had a lower hippocampal PKC activity and cerebral PKC-beta mRNA abundance than SAMR1. SAMP8 had increased cerebral lipid peroxide levels and proportion of sphingomyelin, and a lower proportion of 20 : 4n-6 and 22 : 6n-3 in cerebral phosphtidylethanolamine than SAMR1. SAMP8 fed the PC combined with vitamin B12 diet had an increased PKC activity and a higher proportion of 22 : 6n-3 than SAMP8 fed the control diet. These results indicate the potential benefit of PC combined with vitamin B12 as a dietary supplement.
Rabbits maintained on high-cholesterol diets are known to show increased immunoreactivity for amyloid beta protein in cortex and hippocampus, an effect that is amplified by presence of copper in the drinking water. Hypercholesterolemic rabbits also develop sporadic neuroinflammatory changes. The purpose of this study was to survey microglial activation in rabbits fed cholesterol in the presence or absence of copper or other metal ions, such as zinc and aluminum.
Vibratome sections of the rabbit hippocampus and overlying cerebral cortex were examined for microglial activation using histochemistry with isolectin B4 from Griffonia simplicifolia. Animals were scored as showing either focal or diffuse microglial activation with or without presence of rod cells.
Approximately one quarter of all rabbits fed high-cholesterol diets showed evidence of microglial activation, which was always present in the hippocampus and not in the cortex. Microglial activation was not correlated spatially with increased amyloid immunoreactivity or with neurodegenerative changes and was most pronounced in hypercholesterolemic animals whose drinking water had been supplemented with either copper or zinc. Controls maintained on normal chow were largely devoid of neuroinflammatory changes, but revealed minimal microglial activation in one case.
Because the increase in intraneuronal amyloid immunoreactivity that results from administration of cholesterol occurs in both cerebral cortex and hippocampus, we deduce that the microglial activation reported here, which is limited to the hippocampus, occurs independent of amyloid accumulation. Furthermore, since neuroinflammation occurred in the absence of detectable neurodegenerative changes, and was also not accompanied by increased astrogliosis, we conclude that microglial activation occurs because of metabolic or biochemical derangements that are influenced by dietary factors.
Patients with cardiometabolic risk factors represent a group at high lifetime risk for CVD. These patients frequently have dyslipoproteinemia (low HDL cholesterol, increased triglycerides, and/or an increased number of small LDL particles). We recommend an assessment of global risk followed by a multifactorial risk reduction strategy for such individuals targeting each risk factor and emphasizing both lifestyle and pharmacologic therapy. In terms of dyslipoproteinemia, we recommend the following: Statin therapy for the majority of dyslipoproteinemic adult patients with CMR For patients with CMR on statin therapy, guiding therapy with measurements of apoB and treatment to apoB goals in addition to LDL cholesterol and non-HDL cholesterol assessments Treatment goals, summarized in Table 1, that address the high lifetime risk of patients with dyslipoproteinemia and CMR. Clinical trials to determine whether the pharmacologic therapy required to achieve very low levels of atherogenic lipoproteins is safe and cost-effective A concerted, multifaceted, public health effort, focused on lifestyle mod-ification, to reduce mean population levels of atherogenic lipoproteins to values well below current ones.
AIM: To investigate the signaling pathways implicated in phosphatidylethanolamine (PE)-induced apoptosis of human hepatoma HepG2 cells.
METHODS: Inhibitory effects of PE on human hepatoma HepG2 cells were detected by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Cell cycle, apoptosis and mitochondrial transmembrane potential (ΔΨm) were analyzed by flow cytometry. Immunocytochemical assay and Western blotting were used to examine Bcl-2, Bax and caspase-3 protein levels in HepG2 cells treated with PE.
RESULTS: PE inhibited the growth of HepG2 cells in a dose- and time- dependent manner. It did not affect the cell cycle, but induced apoptosis. PE significantly decreased δΨm at 0.25, 0.5 and 1 mmol/L, respectively, suggesting that PE induces cell apoptosis by decreasing the mitochondrial transmembrane potential. The Bcl-2 expression level induced by different concentrations of PE was lower than that in control groups. However, the Bax expression level induced by PE was higher than that in the control group. Meanwhile, PE increased the caspase-3 expression in a dose- and time-dependent manner.
CONCLUSION: Exogenous PE induces apoptosis of human hepatoma HepG2 cells via the bcl-2/bax pathway.
The maternal diet provides critical nutrients that can influence fetal and infant brain development and function. This review highlights the potential benefits of maternal dietary ganglioside supplementation on fetal and infant brain development. English-language systematic reviews, preclinical studies, and clinical studies were obtained through searches on PubMed. Reports were selected if they included benefits and harms of maternal ganglioside supplementation during pregnancy or ganglioside-supplemented formula after pregnancy. The potential benefits of ganglioside supplementation were explored by investigating the following: (1) their role in neural development, (2) their therapeutic use in neural injury and disease, (3) their presence in human breast milk, and (4) their use as a dietary supplement during or after pregnancy. Preclinical studies indicate that ganglioside supplementation at high doses (1% of total dietary intake) can significantly increase cognitive development and body weight when given prenatally. However, lower ganglioside supplementation doses have no beneficial cognitive effects, even when given throughout pregnancy and lactation. In human clinical trials, infants given formula supplemented with gangliosides showed increased cognitive development and an increase in ganglioside content. Ganglioside supplementation may promote brain development and function in offspring when administered at the optimum dosage. We propose that prenatal maternal dietary supplementation with gangliosides throughout pregnancy may promote greater long-term effects on brain development and function. Before this concept can be encouraged in preconception clinics, future research and clinical trials are needed to confirm the ability of dietary gangliosides to improve cognitive development, but available results already encourage this area of research.
: Under experimental conditions optimal for the assay of D-galactosyl-N-acylsphingosine galactohydrolase (EC 3.2.1.46) activity, homog-enates of neurologically normal human brain tissue could transfer galactose from galactosyl ceramide (gal-cer), lactosyl ceramide (lac-cer), 4-methylumbelliferyl- β-galactoside (4-MU-gal), or p-nitrophenyl- β-galactoside (PNP-gal) to [1-14C]oleoyl sphingosine, but homogenates of brain tissue from patients with Krabbe's disease lacked this ability. The rate of hydrolysis of ganglioside GM1 and to a lesser extent, of PNP-gal by homogenates of Krabbe's brain tissue was also decreased. Activity of PNP- β-galactosidase in normal brain tissue, like that of cerebroside β-galactosidase from the same source, was considerably more heat-stable than the activity of either 4-MU- β-galactosidase or the predominant GM1β-D-galactosidase (EC 3.2.1.23). Lac-cer and GM1, as well as 4-MU-gal and PNP-gal, were competitive inhibitors of human-brain cerebroside β-galactosidase. These findings confirm the ability of mammalian cerebroside β-galactosidase to catalyze a transgalactosylation reaction and provide additional information on the substrate specificity of human brain cerebroside β-galactosidase.
A common feature of Alzheimer’s disease (AD) pathology is the abundance of reactive astrocytes and activated microglia in close proximity to neuritic plaques containing amyloid-beta protein (Aβ). The relationship between glial activation and neurodegeneration remains unclear, although several cytokines and inflammatory mediators produced by activated glia have the potential to initiate or exacerbate the progression of neuropathology. Assuming that glial activation plays a central role in the development and progression of AD, a prominent feature is to understand which stimuli drive this activation in senile plaques and to define their effects in vitro. There is a growing body of evidence to suggest that deposition of Aβ and expression of its associated molecules represent important trigger factors in glial activation leading to an inflammatory reaction in the brain. Thus, unraveling the mechanisms by which these proteins exert their effect on glial cells may provide significant insight into the pathophysiology of AD, and may lead to the identification of new strategies for AD treatment.
Phosphatidylserine (PS) and phosphatidylethanolamine (PE) are metabolically related membrane aminophospholipids. In mammalian cells, PS is required for targeting and function of several intracellular signaling proteins. Moreover, PS is asymmetrically distributed in the plasma membrane. Although PS is highly enriched in the cytoplasmic leaflet of plasma membranes, PS exposure on the cell surface initiates blood clotting and removal of apoptotic cells. PS is synthesized in mammalian cells by two distinct PS synthases that exchange serine for choline or ethanolamine in phosphatidylcholine (PC) or PE, respectively. Targeted disruption of each PS synthase individually in mice demonstrated that neither enzyme is required for viability whereas elimination of both synthases was embryonic lethal. Thus, mammalian cells require a threshold amount of PS. PE is synthesized in mammalian cells by four different pathways, the quantitatively most important of which are the CDP-ethanolamine pathway that produces PE in the ER, and PS decarboxylation that occurs in mitochondria. PS is made in ER membranes and is imported into mitochondria for decarboxylation to PE via a domain of the ER [mitochondria-associated membranes (MAM)] that transiently associates with mitochondria. Elimination of PS decarboxylase in mice caused mitochondrial defects and embryonic lethality. Global elimination of the CDP-ethanolamine pathway was also incompatible with mouse survival. Thus, PE made by each of these pathways has independent and necessary functions. In mammals PE is a substrate for methylation to PC in the liver, a substrate for anandamide synthesis, and supplies ethanolamine for glycosylphosphatidylinositol anchors of cell-surface signaling proteins. Thus, PS and PE participate in many previously unanticipated facets of mammalian cell biology. This article is part of a Special Issue entitled Phospholipids and Phospholipid Metabolism.
Plasmalogens are a unique class of membrane glycerophospholipids containing a fatty alcohol with a vinyl-ether bond at the sn-1 position, and enriched in polyunsaturated fatty acids at the sn-2 position of the glycerol backbone. These two features provide novel properties to these compounds. Although plasmalogens represent up to 20% of the total phospholipid mass in humans their physiological roles have been challenging to identify, and are likely to be particular to different tissues, metabolic processes and developmental stages. Their biosynthesis starts in peroxisomes, and defects at these steps cause the malformation syndrome, Rhizomelic Chondrodysplasia Punctata (RCDP). The RCDP phenotype predicts developmental roles for plasmalogens in bone, brain, lens, lung, kidney and heart. Recent studies have revealed secondary plasmalogen deficiencies associated with more common disorders and allow us to tease out additional pathways dependent on plasmalogen functions. In this review, we present current knowledge of plasmalogen biology in health and disease. This article is part of a Special Issue entitled: Metabolic Functions and Biogenesis of peroxisomes in Health and Disease.
It is generally accepted that the process of molecular facilitation (= Bahnung) of neuronal circuits by means of stabilization of synaptic contacts represents the structural basis for memory formation. On the basis of physiological, electron microscopic, biochemical, and physicochemical data, a concept is presented speaking in favor of the idea that interactions between brain gangliosides (= amphiphilic sialic acid-containing glycosphingolipids with peculiar physicochemical properties), calcium, and functional membraneous proteins (ion channels, ion pumps, receptors, kinases) play a crucial modulatory role in the transmission and storage of information.
A growing number of cell-surface receptors are now being shown to generate signals that trigger the hydrolysis of sphingomyelin to release diffusible ceramides. Ceramides have been implicated as key mediators in signaling pathways, with outcomes as diverse as cell proliferation, differentiation, growth arrest and apoptosis. The response depends on cell type, whether the signal is integrated with other signals originating from the same receptor and on the subcellular location of sphingomyelin hydrolysis and ceramide release.
Transcription factors provide the link between early membrane-proximal signalling events and changes in gene expression. NF-kappa B is one of the best-characterized transcription factors. It is expressed ubiquitously and regulates the expression of many genes, most of which encode proteins that play an important and often determining role in the processes of immunity and inflammation. Apart from its role in these events, evidence has begun to accumulate that NF-kappa B is involved in brain function, particularly following injury and in neurodegenerative conditions such as Alzheimer's disease. NF-kappa B might also be important for viral replication in the CNS. An involvement of NF-kappa B in neuronal development is suggested from studies that demonstrate its activation in neurones in certain regions of the brain during neurogenesis. Brain-specific activators of NF-kappa B include glutamate (via both AMPA/KA and NMDA receptors) and neurotrophins, pointing to an involvement in synaptic plasticity. NF-kappa B can therefore be considered as one of the most important transcription factors characterized in brain to date and it might be as crucial for neuronal and glial cell function as it is for immune cells.
Eukaryotic organisms as well as some prokaryotes and viruses contain sphingolipids, which are defined by a common structural feature, i.e. , a "sphingoid base" backbone such as D-erythro-1,3-dihydroxy, 2-aminooctadec-4-ene (sphingosine). The sphingolipids of mammalian tissues, lipoproteins, and milk include ceramides, sphingomyelins, cerebrosides, gangliosides and sulfatides; plants, fungi and yeast have mainly cerebrosides and phosphoinositides. The total amounts of sphingolipids in food vary considerably, from a few micromoles per kilogram (fruits) to several millimoles per kilogram in rich sources such as dairy products, eggs and soybeans. With the use of the limited data available, per capita sphingolipid consumption in the United States can be estimated to be on the order of 150-180 mmol (approximately 115-140 g) per year, or 0.3-0.4 g/d. There is no known nutritional requirement for sphingolipids; nonetheless, they are hydrolyzed throughout the gastrointestinal tract to the same categories of metabolites (ceramides and sphingoid bases) that are used by cells to regulate growth, differentiation, apoptosis and other cellular functions. Studies with experimental animals have shown that feeding sphingolipids inhibits colon carcinogenesis, reduces serum LDL cholesterol and elevates HDL, suggesting that sphingolipids represent a "functional" constituent of food. Sphingolipid metabolism can also be modified by constituents of the diet, such as cholesterol, fatty acids and mycotoxins (fumonisins), with consequences for cell regulation and disease. Additional associations among diet, sphingolipids and health are certain to emerge as more is learned about these compounds.
Gangliosides induce apoptosis in the cells of the IL-2-dependent cytotoxic mouse line CTLL-2. Upon incubation with gangliosides for 24 h, their effect resulting in appearance of apoptotic cells, falls in a series GM2 > GM3 > GM1 > GD1a > GD1b > GT1b. In the presence of rIL-2, apoptosis induced by GM1 is suppressed, whereas that induced by GM2 is enhanced (the effect of intracellular agent C2-Cer is independent of this cytokine). The GM1-induced apoptosis is cancelled by the caspase I inhibitor. The gangliosides under study are not able to induce apoptosis in the promyelocyte leukemia cell line HL-60. Physiological aspects of the phenomenon found are discussed.
In analyzing the regulation of neurotrophin production/secretion from microglia, C8-ceramide (D-erythro-sphingosine, N-octanoyl-) was found to induce secretion of brain-derived neurotrophic factor (BDNF) from microglia in vitro. In the present study, the action of C8-ceramide in secreting neurotrophic and harmful factors was investigated and compared with the effects of lipopolysaccharide (LPS). C8-ceramide as well as LPS enhanced the production/secretion of BDNF but, different from LPS, did not induce tumor necrosis factor alpha, interleukin-1beta, or nitric oxide. The C8-ceramide-induced BDNF release was significantly suppressed by protein kinase C (PKC) inhibitor, bisindolylmaleimide, which targets PKC isoforms, alpha, beta, gamma, delta and epsilon. However, it was not suppressed by a specific inhibitor of PKCalpha. Furthermore, PKCbeta and gamma were undetected in the microglia. Therefore, PKCdelta and/or epsilon appear to be functioning PKC isoforms. In contrast, none of the mitogen-activated protein kinases (MAPKs) and none of the transcription factors, including the cAMP response element-binding transcription factor (CREB) and nuclear factor kappaB (NFkappaB) were activated in the microglia in response to C8-ceramide. These results indicate that ceramide-induced BDNF release in microglia is mediated by a signaling pathway associated with PKCdelta and/or epsilon, but not with activation of MAPKs, CREB and NFkappaB.
Ganglioside function in eukaryotic cells encompasses a variety of modulatory interactions related to both development and mature cellular behavior. In relation to the nervous system this includes induction of neurite outgrowth and trophic/neuroprotective phenomena; more generally this applies to ganglioside effects on receptor function, adhesion reactions, and signal transduction mechanisms in neural and extraneural systems. Underlying many of these trophic effects are ganglioside-induced changes in cellular calcium, accomplished through modulation of Ca2+ influx channels, Ca2+ exchange proteins, and various Ca2+-dependent enzymes that are altered through association with gangliosides. A clear distinction needs to be drawn between intrinsic functions of gangliosides as naturally expressed by the cell and activities created by application of exogenous ganglioside(s) that may or may not reflect natural function. This review attempts to summarize findings in this area and point to possible future directions of research.
Glycation has been implicated in the endothelial dysfunction that contributes to both diabetes- and aging-associated vascular complications. The aim of the present study was to determine whether Amadori-glycated phosphatidylethanolamine (Amadori-PE), a lipid-linked glycation compound that is formed at an increased rate in hyperglycemic states, affected proliferation, migration and tube formation of cultured human umbilical vein endothelial cells (HUVEC). Amadori-PE at a low concentration of less than 5 microM significantly enhanced these three factors involved in angiogenesis. Furthermore, stimulation of HUVEC with Amadori-PE resulted in secretion of matrix metalloproteinase 2 (MMP-2), a pivotal enzyme in the initial step of angiogenesis. Our results demonstrated for the first time that Amadori-PE may be an important compound that promotes vascular disease as a result of its angiogenic activity on endothelial cells. We also demonstrated that MMP-2 is a primary mediator of Amadori-PE-driven angiogenesis.
Gangliosides participate in various cellular events of the central nervous system and have been closely implicated in many neuronal diseases. However, the precise molecular mechanisms underlying the pathological activity of gangliosides are poorly understood. Here we report that toll-like receptor 4 (TLR4) may mediate the ganglioside-triggered inflammation in glia, brain resident immune cells. Gangliosides rapidly altered the cell surface expression of TLR4 in microglia and astrocytes within 3 hours. Using TLR4-specific siRNA and a dominant-negative TLR4 gene, we clearly demonstrate the functional importance of TLR4 in ganglioside-triggered activation of glia. Inhibition of TLR4 expression by TLR4-siRNA suppressed nuclear factor (NF)-kappaB-binding activity, NF-kappaB-dependent luciferase activity, and transcription of inflammatory cytokines after exposure to gangliosides. Transient transfection of dominant-negative TLR4 also attenuated NF-kappaB-binding activity and interleukin-6 promoter activity. In contrast, these activities were slightly elevated in cells with wild-type TLR4. In addition, CD14 was required for ganglioside-triggered activation of glia, and lipid raft formation may be associated with ganglioside-stimulated signal propagation. Taken together, these results suggest that TLR4 may provide an explanation for the pathological ability of gangliosides to cause inflammatory conditions in the brain.
There is increasing evidence that microglial activation is one of the major pathogenic factors for Alzheimer's disease (AD) and the inhibition of the inflammatory activation of the microglia thus appears to be neuroprotective and a potentially useful treatment for AD. Phospholipids such as phosphatidylserine (PS) and phosphatidylcholine (PC) have been reported to modulate the immune function of phagocytes. In addition, PS has been reported to be a nootropics that can be used as nonprescription memory or cognitive enhancers. We therefore evaluated the effects of liposomes, which comprise both PS and PC (PS/PC liposomes), on the microglial production of tumor necrosis factor-alpha (TNF-alpha), nitric oxide (NO), and superoxide (*O(2)-) induced by amyloid beta (Abeta) and interferon-gamma (IFN-gamma). Pretreatment of microglia with PS/PC liposomes considerably inhibited the TNF-alpha, NO and *O(2)- production induced by Abeta/IFN-gamma. These results suggest that PS/PC liposomes have both neuroprotective and antioxidative properties through the inhibition of microglial activation, thus supporting the nootropic and antidementia effect of PS.
Alzheimer's disease sufferers have been found to have a lack of the enzyme responsible for converting choline into acetylcholine within the brain. Lecithin is a major dietary source of choline, so extra consumption may reduce the progression of dementia.
To determine the efficacy of lecithin in the treatment of dementia or cognitive impairment.
The Cochrane Dementia and Cognitive Improvement Group's Specialized Register was searched on 15 May 2002 using the terms lecithin and phosphaditylcholine. This contains records from all major databases and many trials databases. Reference lists and relevant books have been examined.
All unconfounded, randomized trials comparing lecithin with placebo in a treatment period longer than one day, in patients with dementia of the Alzheimer type, vascular dementia, mixed vascular and Alzheimer's disease, unclassified or other dementia or unclassified cognitive impairment not fulfilling the criteria for dementia are eligible for inclusion.
Data were extracted by two independent reviewers and cross-checked. Meta-analyses were performed when more than one trial provided data on a comparable outcome on sufficiently similar patients. Random effects analyses were performed whenever heterogeneity between results appeared to be present. Standardised differences in mean outcome measures were used due do the use of different scales and periods of treatment. Odds ratios for dichotomous data were pooled using the Mantel-Haenszel or DerSimonian and Laird methods.
Twelve randomized trials have been identified involving patients with Alzheimer's disease (265 patients), Parkinsonian dementia (21 patients) and subjective memory problems (90 patients). No trials reported any clear clinical benefit of lecithin for Alzheimer's disease or Parkinsonian dementia. Few trials contributed data to meta-analyses. The only statistically significant result was in favour of placebo for adverse events, based on one trial, which appears likely to be a spurious result. A dramatic result in favour of lecithin was obtained in a trial of subjects with subjective memory problems.
Evidence from randomized trials does not support the use of lecithin in the treatment of patients with dementia. A moderate effect cannot be ruled out, but results from the small trials to date do not indicate priority for a large randomized trial.
Lipid rafts: Bringing order to chaos
- Pike