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This study examined the effect of dietary lysolecithin on growth performance, nutrient digestibility, haematobiochemistry, and oxidative status in finisher broiler chickens. In a completely randomized design (CRD), 300 21-day-old Chikun strain chicks were randomly allocated to 30 pens in which they were allotted to 5 dietary treatments as follows TI (0 g /100kg), T2 (100 g /100kg), T3 (200 g /100kg), T4 (300 g /100kg), T5 (400 g /100kg) of feed with 6 replicates pens of 10 during the finisher phase (28 days). Results showed that dietary supplementation with lysolecithin increased the final body weight (FBW) (quadratic P = 0.0178), body weight gain (BWG) (quadratic P = 0.0232), whilst it decreased the total feed intake (TFI) (linear P = 0.0104). Similarly, it linearly increased the retention of dry matter (P = 0.0324); crude protein (P = 0.0029), crude fibre (P = 0.0147), and crude fat (P = 0.0002). Furthermore, it increased the superoxide dismutase (linear P < 0.001), glutathione peroxidase (quadratic P < 0.001), glutathione (linear P < 0.001), whilst it decreased malondialdehyde (linear P = 0.003), without affecting (P > 0.05) the haematobiochemistry parameters. Therefore, dietary lysolecithin could be supplemented up to 400 g /100 kg without compromising performance, nutrient retention, haemato-biochemistry, and oxidative status in finisher broiler diets., (© 2024. The Author(s).)

Lysophosphatidylcholine (LPC) is immunomodulatory in nonruminants; however, the actions of LPC on immunity in cattle are undefined. Our objective was to study the effects of LPC administration on measures of immunity, liver health, and growth in calves. Healthy Holstein heifer calves (n = 46; age 7 ± 3 d) were randomly assigned to 1 of 4 treatments (n = 10 to 11 calves/treatment): a milk replacer diet unsupplemented with lecithin in the absence (CON) or presence of subcutaneously (s.c.) administered mixed (mLPC; 69% LPC-16:0, 25% LPC-18:0, 6% other) or pure LPC (pLPC; 99% LPC-18:0), or a milk replacer diet supplemented with 3% lecithin enriched in lysophospholipids containing LPC in the absence of s.c.-administered LPC (LYSO) for 5 wk. Calves received 5 s.c. injections of vehicle (10 mL of phosphate-buffered saline containing 20 mg of bovine serum albumin/mL; CON and LYSO) or vehicle containing mLPC or pLPC to provide 10 mg of total LPC per kilogram of BW per injection every 12 h during wk 2 of life. Calves were fed a milk replacer containing 27% crude protein and 24% fat at 1.75% of BW per day (dry matter basis) until wk 6 of life (start of weaning). Starter grain and water were provided ad libitum. Body measurements were recorded weekly, and clinical observations were recorded daily. Blood samples were collected weekly before morning feeding and at 0, 5, and 10 h, relative to the final s.c. injection of vehicle or LPC. Data were analyzed using a mixed model, with repeated measures including fixed effects of treatment, time, and their interaction. Dunnett's test was used to compare treatments to CON. Peak rectal temperatures were higher in mLPC or pLPC, relative to CON. Plasma LPC concentrations were greater in mLPC and LYSO calves 5 h and 10 h after the final injection, relative to CON. Calves receiving mLPC and pLPC also had higher circulating serum amyloid A concentrations, relative to CON. Calves receiving mLPC had greater serum aspartate aminotransferase, γ-glutamyltransferase, and glutamate dehydrogenase concentrations, relative to CON. Calves provided mLPC experienced lower average daily gain (ADG) after weaning, relative to CON. The LYSO treatment did not modify rectal temperatures, ADG, or measures of liver health, relative to CON. We conclude that LPC administered as s.c. injections induced an acute febrile response, modified measures of liver and immune function, and impaired growth in calves., (The Authors. Published by Elsevier Inc. on behalf of the American Dairy Science Association®. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).)

Objective: Cardiac arrest (CA) is a major health burden with brain damage being a significant contributor to mortality. We found lysophosphatidylcholine (LPC), including a species containing docosahexaenoic acid (LPC-DHA), was significantly decreased in plasma post-CA, supplementation of which significantly improved neurological outcomes. The aim of this study is to understand the protective role of LPC-DHA supplementation on the brain post-CA., Methods: We first evaluated associations between the plasma level of LPC-DHA and neurological injury and outcomes of human patients with CA. We then utilized a rat CA model and cell cultures to investigate therapeutic and mechanistic aspects of plasma LPC-DHA supplementation., Results: We found that decreased plasma LPC-DHA was strongly associated with neurological outcomes and disappearance of the difference between gray and white matter in the brain after CA in human patients. In rats, the decreased plasma LPC-DHA was associated with decreased levels of brain LPC-DHA after CA, and supplementing plasma LPC-DHA normalized brain levels of LPC-DHA and alleviated neuronal cell death, activation of astrocytes, and expression of various inflammatory and mitochondrial dynamics genes. We also observed deceased severity of metabolic alterations with LPC-DHA supplementation using untargeted metabolomics analysis. Furthermore, LPC treatment showed a similar protective effect for neurons and astrocytes in mixed primary brain cell cultures., Interpretation: The observed neuroprotection accompanied with normalized brain LPC-DHA level by plasma supplementation implicate the importance of preventing the decrease of brain LPC-DHA post-CA for attenuating brain injury. Furthermore, the data supports the causative role of decreased plasma LPC-DHA for brain damage after CA. ANN NEUROL 2022;91:389-403., (© 2022 American Neurological Association.)

Nerve-glia (NG2) glia or oligodendrocyte precursor cells (OPCs) are distributed throughout the gray and white matter and generate myelinating cells. OPCs in white matter proliferate more than those in gray matter in response to platelet-derived growth factor AA (PDGF AA), despite similar levels of its alpha receptor (PDGFRα) on their surface. Here we show that the type 1 integral membrane protein neuropilin-1 (Nrp1) is expressed not on OPCs but on amoeboid and activated microglia in white but not gray matter in an age- and activity-dependent manner. Microglia-specific deletion of Nrp1 compromised developmental OPC proliferation in white matter as well as OPC expansion and subsequent myelin repair after acute demyelination. Exogenous Nrp1 increased PDGF AA-induced OPC proliferation and PDGFRα phosphorylation on dissociated OPCs, most prominently in the presence of suboptimum concentrations of PDGF AA. These findings uncover a mechanism of regulating oligodendrocyte lineage cell density that involves trans-activation of PDGFRα on OPCs via Nrp1 expressed by adjacent microglia.

Lysophosphatidylcholine (LPC) is a bioactive lysolipid known to contribute to the development of lung allergic diseases. However, it remains unknown whether LPC possesses proinflammatory properties in the skin as well. Here, we investigated this issue by injection of LPC into the murine contact hypersensitivity (CHS) model induced by 2,4-dinitrofluorobenzene (DNFB). LPC increased the expression of IL17, recruited more neutrophils, and eventually aggravated the CHS in the skins. Moreover, the effects of LPC diminished after neutralizing IL17 or depleting neutrophils. Mechanistically, LPC upregulated not only IL17 but also CXCL1 and CXCL2 in a G2A-dependent manner. Taken together, our study demonstrated that the upregulation of LPC could contribute to allergic skin inflammation by increasing IL17 expression and neutrophil recruitment via G2A receptor. [BMB Reports 2021; 54(4): 203-208].

Docosahexaenoic acid (DHA) is one of the most important fatty acids that plays a critical role in maintaining proper brain function and cognitive development. Deficiency of DHA leads to several neurodegenerative disorders and, therefore, dietary supplementations of these fatty acids are essential to maintain cognitive health. However, the complete picture of how DHA is incorporated into the brain is yet to be explored. In general, the de novo synthesis of DHA is poor, and targeting the brain with specific phospholipid carriers provides novel insights into the process of reduction of disease progression. Recent studies have suggested that compared to triacylglycerol form of DHA, esterified form of DHA (i.e., lysophosphatidylcholine [lysoPC]) is better incorporated into the brain. Free DHA is transported across the outer membrane leaflet of the blood-brain barrier via APOE4 receptors, whereas DHA-lysoPC is transported across the inner membrane leaflet of the blood-brain barrier via a specific protein called Mfsd2a. Dietary supplementation of this lysoPC specific form of DHA is a novel therapy and is used to decrease the risk of various neurodegenerative disorders. Currently, structured glycerides of DHA - novel nutraceutical agents - are being widely used for the prevention and treatment of various neurological diseases. However, it is important to fully understand their metabolic regulation and mechanism of transportation to the brain. This article comprehensively reviews various studies that have evaluated the bioavailability of DHA, mechanisms of DHA transport, and role of DHA in preventing neurodegenerative disorders, which provides better insight into the pathophysiology of these disorders and use of structured DHA in improving neurological health., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Enriching brain DHA is believed to be beneficial for the prevention and treatment of several neurological diseases, including Alzheimer's disease. An impediment in assessing the effectiveness of the treatments is the lack of a reliable biomarker for brain DHA. The commonly used erythrocyte omega-3 index is not suitable for brain because of the involvement of unique transporter at the blood brain barrier (BBB). We recently showed that dietary lysophosphatidylcholine (LPC)-DHA significantly increases brain DHA, which results in increase of brain BDNF. Since there is bidirectional transport of BDNF through the BBB, we tested the hypothesis that plasma BDNF may be used as biomarker for brain DHA enrichment. We altered the brain DHA in rats and mice over a wide range using different dietary carriers of DHA, and the correlations between the increase in brain omega-3 index with the increases in plasma BDNF and the erythrocyte index were determined. Whereas the increase in brain omega-3 index positively correlated with the increase in plasma BDNF, it negatively correlated with the erythrocyte index. These results show that the plasma BDNF is more reliable than the erythrocyte index as biomarker for assessing the effectiveness of omega-3 supplements in improving brain function.

Docosahexaenoic acid (DHA) is highly concentrated in the brain, and its deficiency is associated with several neurological disorders including Alzheimer's disease. However, the currently used supplements do not appreciably enrich brain DHA, although they enrich most other tissues. We tested the hypothesis that the ability of the dietary carrier to augment brain DHA depends upon the generation of DHA-lysophosphatidylcholine (LPC), the preferred carrier of DHA across the blood brain barrier. We compared the efficacy of DHA-triacylglycerol (TAG), di-DHA phosphatidylcholine (PC) and DHA-LPC to enrich brain DHA following their gavage to normal rats for 30 days, all at a dose of 10 mg DHA/day. The results show that DHA from TAG, which is released as free DHA or monoacylglycerol during digestion and is absorbed as TAG in chylomicrons, was incorporated preferentially into adipose tissue and heart but not into brain. In contrast, LPC-DHA increased brain DHA by up to 100% but had no effect on adipose tissue. Di-DHA PC, which generates both free DHA and LPC-DHA during the digestion, enriched DHA in brain, as well as in heart and liver. Brain-derived neurotrophic factor was increased by di-DHA PC and DHA-LPC, but not by TAG-DHA, showing that enrichment of brain DHA correlated with its functional effect. We conclude that dietary DHA from TAG or from natural PC (sn-2 position) is not suitable for brain enrichment, whereas DHA from LPC (at either sn-1 or sn-2 position) or from sn-1 position of PC efficiently enriches the brain and is functionally effective., (Published by Elsevier Inc.)

In this report, a novel redox-responsive liposomes based on disulfide derivative paclitaxel-ss-lysophosphatidylcholine prodrug (PTX-ss-PC) with high PTX loading was developed for triggering drug release. First of all, PTX-ss-PC was synthesized by a facile esterification and verified by MS, 1 H NMR and HPLC. After that, PTX-ss-PC derived liposomes (PTX-ss-PC liposomes) containing EPC:Chol:mPEG 2000 -DSPE components were prepared by the conventional film method. Moreover, physicochemical characterizations of the PTX-ss-PC liposomes were carried out by using transmission electron microscope (TEM), dynamic light scattering (DLS) and release test. It was demonstrated that the PTX-ss-PC liposomes possessed average diameter of 234.9 nm and zeta potential of -29.1 mV with highest PTX loading 7.97%. The PTX-ss-PC liposomes dissociated rapidly in a reduction medium, as confirmed by their triggered aggregation/disruption and rapid release of PTX in the presence of glutathione (GSH). Finally, in vitro cytotoxicity of the liposomes was checked against MCF-7 and A549 cells. It was found that the PTX-ss-PC liposomes exhibited favorable GSH-mediated anti-proliferative activity in comparison with the nonresponsive counterpart. Taken together, the novel PTX-ss-PC based liposomes possess improved loading capacity, reduction triggered release of PTX and efficient anti-proliferative activity, which should be valuable for further preclinical evaluation., (Copyright © 2019 Elsevier B.V. All rights reserved.)

The observation that amyloid radiotracers developed for Alzheimer's disease bind to cerebral white matter paved the road to nuclear imaging of myelin in multiple sclerosis. The lysolecithin (lysophosphatidylcholine (LPC)) rat model of demyelination proved useful in evaluating and comparing candidate radiotracers to target myelin. Focal demyelination following stereotaxic LPC injection is larger than lesions observed in experimental autoimmune encephalitis models and is followed by spontaneous progressive remyelination. Moreover, the contralateral hemisphere may serve as an internal control in a given animal. However, demyelination can be accompanied by concurrent focal necrosis and/or adjacent ventricle dilation. The influence of these side effects on imaging findings has never been carefully assessed. The present study describes an optimization of the LPC model and highlights the use of MRI for controlling the variability and pitfalls of the model. The prototypical amyloid radiotracer [ 11 C]PIB was used to show that in vivo PET does not provide sufficient sensitivity to reliably track myelin changes and may be sensitive to LPC side effects instead of demyelination as such. Ex vivo autoradiography with a fluorine radiotracer should be preferred, to adequately evaluate and compare radiotracers for the assessment of myelin content.

Obesity is one of the most important risk factors for chronic metabolic disorders. Molecular mechanisms underlying obesity-related metabolic disorders have not been completely elucidated. Peroxisome proliferator-activated receptors (PPARs) are members of the nuclear receptor superfamily and are key metabolic regulators of the whole-body energy metabolism. Certain enzymes involved in carbohydrate and lipid metabolism are directly regulated by PPARs via their interaction with specific response elements in their gene promoters. Many food factors act as ligands of PPARs and regulate carbohydrate and lipid metabolism by regulating the activities of these nuclear receptors, leading to the attenuation of obesity-related metabolic disorders. In this review, we describe our current knowledge of the role of PPARs in the regulation of whole-body energy metabolism and several examples of food factors that act as ligands of PPARs, which may be useful in the management of obesity and the accompanying energy metabolism abnormalities. Abbreviations: WAT: white adipose tissue; PPAR: Peroxisome proliferators-activated receptor; RXR: retinoid X receptors; mTORC1: mechanistic target of rapamycin complex 1; PPRE: PPAR-responsive regulatory elements; NAFLD: nonalcoholic fatty liver disease; LPL: lipoprotein lipase; FGF21: fibroblast growth factor 21; BAT: brown adipose tissue; UCP1: uncoupling protein 1; LPC(16:0): 1-palmitoyl lysophosphatidylcholine; C/EBP: CCAAT-enhancer binding proteins; STAT5A: signal transduction and activator of transcription 5A; APO apolipoptotein; CBP: cAMP response element-binding protein-binding protein; PGC1A: PPARγ coactivator protein 1a; HFD: high-fat diet; TG: triglyceride; VLDL: very low density lipoprotein; HDL: high density lipoprotein.

The possibility of improving brain function coupled with its preferential uptake in the brain has garnered attention for docosahexaenoic acid-bound lysophosphatidylcholine (DHA-LPC). However, studies focusing on the health benefits of dietary DHA-LPC are lacking. We prepared a dietary oil rich in DHA-LPC (DHA-LPC rich oil) via enzymatic modification of phospholipids (PL) extracted from squid (Todarodes pacificus) meal and purification of active carbon, ion exchange resin, and silica gel. We then examined the effects of dietary DHA-LPC rich oil on male Wistar rats by evaluating serum and liver lipid profiles, fatty acid (FA) metabolizing enzyme activity, and the FA composition of serum and brain. The rats were fed a basal diet containing either soybean oil alone (7%) or soybean oil (4.5%) with DHA-LPC rich oil (2.5%) for 28 days, and then evaluated. The rats fed the diet containing DHA-LPC rich oil showed reduced triacylglycerol concentration due, in part, to the enhancement of carnitine palmitoyltransferase 2 and acyl-CoA oxidase activities and suppression of acetyl-CoA carboxylase and glucose-6-phosphate dehydrogenase activities in the liver. Moreover, the dietary DHA-LPC rich oil moderately increased DHA in the FA composition of the rat hippocampus, which may be due to elevated DHA composition in serum LPC. These results suggest that DHA-LPC rich oil has hypolipidemic effect and moderate increase in hippocampal DHA amount in normal rats.

Curcumin has been introduced as effective anti-inflammatory agent in treatment of several inflammatory disorders. Despite the wide range pharmacological activities, clinical application of curcumin is restricted mainly due to the low water solubility of this substance. More recently, we could remarkably improve the aqueous solubility of curcumin by its encapsulation in chitosan-alginate-sodium tripolyphosphate nanoparticles (CS-ALG-STPP NPs). In this study, the anti-inflammatory and myelin protective effects of curcumin-loaded NPs were evaluated in lysolecithin (LPC)-induced focal demyelination model. Pharmacokinetic of curcumin was assessed using high performance liquid chromatography (HPLC). Local demyelination was induced by injection of LPC into corpus callosum of rats. Animals were pre-treated with intraperitoneal (i.p.) injections of curcumin or curcumin-loaded NPs at dose of 12.5 mg/kg, 10 days prior to LPC injection and the injections were continued for 7 or 14 days post lesion. Hematoxylin and eosin (H&E) staining and immunostaining against activated glial cells including astrocytes and microglia were carried out for assessment of inflammation level in lesion site. Myelin specific staining was performed to evaluate the effect of curcumin-loaded NPs on myelination of LPC receiving animals. HPLC results showed the higher plasma concentration of curcumin after administration of NPs. Histological evaluation demonstrated that, the extent of demyelination areas was reduced in animals under treatment of curcumin-loaded NPs. Furthermore, treatment with curcumin-loaded NPs effectively attenuated glial activation and inflammation in LPC-induced demyelination model compared to curcumin receiving animals. Overall; these findings indicate that treatment with curcumin-loaded NPs preserve myelinated axons through amelioration of glial activation and inflammation in demyelination context., (Copyright © 2018 Elsevier B.V. All rights reserved.)

1. The study aimed to investigate the effect of lysolecithin supplementation in low-energy diets on growth, nutrient digestibility and intestinal mucosa characteristics of broilers. 2. A total of 800 one-d-old Ross 308 broiler chickens were assigned to 4 dietary treatments consisting of 10 replicates of 20 broilers each. Broilers were fed with 4 different diets: (i) HE: positive control group broilers received a diet with unaltered energy; (ii) LE: negative control group broilers received a diet with lower energy of about 0.27 MJ/kg; (iii) LElys500: broilers received a diet similar to LE supplemented with 500 g/tn lysolecithin product (Lysoforte Booster Dry TM ); and (iv) LElys300: broilers received a diet similar to LE supplemented with 300 g/tn lysolecithin product. The experimental period was 42 d. 3. Body weight gain in treatments HE was higher than LE during the overall experimental period, while LElys500 and LElys300 had intermediate values. Feed conversion ratio was lower in HE and LElys500 than LE group, while the LElys300 had intermediate values. Fat digestibility was improved in both LElys 500 and LElys300 compared to the HE group. Apparent metabolisable energy (AMEn) was higher in HE, LElys500 and LElys300 than LE. Ileum viscosity at 42 d was also affected, being higher in LE group compared to HE. At 28 d mucosal thickness was lower both in LElys500 and LElys300 compared to HE and LE, while no difference occurred between treatment proliferation patterns of duodenal epithelial cells. 4. These findings indicated that lysolecithin supplementation at 500 g/tn of feed in low-energy diets maintained broiler performance. Supplementation of reformulated low-energy diets induced an increase in digesta viscosity. Lysolecithin supplementation resulted in variable alterations in the duodenum mucosal morphology.

For decades lysophosphatidylcholine (LPC, lysolecithin) has been used to induce demyelination, without a clear understanding of its mechanisms. LPC is an endogenous lysophospholipid so it may cause demyelination in certain diseases. We investigated whether known receptor systems, inflammation or nonspecific lipid disruption mediates LPC-demyelination in mice. We found that LPC nonspecifically disrupted myelin lipids. LPC integrated into cellular membranes and rapidly induced cell membrane permeability; in mice, LPC injury was phenocopied by other lipid disrupting agents. Interestingly, following its injection into white matter, LPC was cleared within 24 hr but by five days there was an elevation of endogenous LPC that was not associated with damage. This elevation of LPC in the absence of injury raises the possibility that the brain has mechanisms to buffer LPC. In support, LPC injury in culture was significantly ameliorated by albumin buffering. These results shed light on the mechanisms of LPC injury and homeostasis., (© 2017 Wiley Periodicals, Inc.)

Multiple sclerosis (MS) is a chronic autoimmune, inflammatory disease in the central nervous system (CNS) characterized by loss of oligodendrocytes, myelin axons, and neurons. Remyelination is an endogenous repair mechanism, which recovers the loss of myelin and is able to preserve functional axons. The hope is that the development of new treatments aiming at promoting remyelination will halt and potentially partially reverse the progressive neurological decline in MS. The development of such drugs requires adequate models. In this chapter, we will discuss the surgical procedure of injection of lysolecithin into ventral thoraco-lumbar spinal cord white matter of mice, which is particularly suitable for investigating remyelination using transgenic animals.

Remyelination is an endogenous regenerative process of myelin repair in the central nervous system (CNS) with limited efficacy in demyelinating disorders. As strategies enhancing endogenous remyelination become a therapeutic challenge, we have focused our study on α-secretase-induced sAPPα release, a soluble endogenous protein with neuroprotective and neurotrophic properties. However, the role of sAPPα in remyelination is not known. Therefore, we investigated the remyelination potential of α-secretase-induced sAPPα release following CNS demyelination in mice. Acute demyelination was induced by feeding mice with cuprizone (CPZ) for 5weeks. To test the protective effect and the remyelination potential of etazolate, an α-secretase activator, we designed two treatment protocols. Etazolate was administrated either during the last two weeks or at the end of the CPZ intoxication. In both protocols, etazolate restored the number of myelinated axons in corpus callosum with a corresponding increase in the amount of MBP, one of the major myelin proteins in the brain. We also performed ex vivo studies to decipher etazolate's mechanism of action in a lysolecithin-induced demyelination model using organotypic culture of cerebellar slices. Etazolate treatment was able to i) enhance the release of sAPPα in the culture media of demyelinated slices, ii) protect myelinated axons from demyelination, iii) increase the number of mature oligodendrocytes, iv) promote the reappearance of the paired Caspr + adjacent to the nodes of Ranvier and v) increase the percentage of myelinated axons with short internodes, an indicator of remyelination. Etazolate failed to promote all the aforementioned effects in the presence of GI254023X, an α-secretase inhibitor. Moreover, the protective effects of etazolate in demyelinated slices were mimicked by sAPPα treatment in a dose-dependent manner. In conclusion, etazolate-induced sAPPα release protects myelinated axons from demyelination while also promoting remyelination. This work, thus, highlights the therapeutic potential of strategies that enhance sAPPα release in demyelinating disorders., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Docosahexaenoic acid (DHA) is uniquely concentrated in the brain, and is essential for its function, but must be mostly acquired from diet. Most of the current supplements of DHA, including fish oil and krill oil, do not significantly increase brain DHA, because they are hydrolyzed to free DHA and are absorbed as triacylglycerol, whereas the transporter at blood brain barrier is specific for phospholipid form of DHA. Here we show that oral administration of DHA to normal adult mice as lysophosphatidylcholine (LPC) (40 mg DHA/kg) for 30 days increased DHA content of the brain by >2-fold. In contrast, the same amount of free DHA did not increase brain DHA, but increased the DHA in adipose tissue and heart. Moreover, LPC-DHA treatment markedly improved the spatial learning and memory, as measured by Morris water maze test, whereas free DHA had no effect. The brain derived neurotrophic factor increased in all brain regions with LPC-DHA, but not with free DHA. These studies show that dietary LPC-DHA efficiently increases brain DHA content and improves brain function in adult mammals, thus providing a novel nutraceutical approach for the prevention and treatment of neurological diseases associated with DHA deficiency, such as Alzheimer's disease.

Adding lysolecithin to feed has reportedly improved the performance of broiler chickens. Lysolecithin is generated by phospholipase catalyzed hydrolysis of lecithin. The enzymatic reaction converts various phospholipids into the corresponding lysophospholipids, with lysophosphatidylcholine (LPC) one of the primary products. Here we compared supplementation with a commercial lysolecithin (Lysoforte®) with comparable levels of highly purified LPC for effects on broilers. Despite no differences in weight gain during the starter period, we discovered a significant increase in average villus length with lysolecithin and an increase in villus width with purified LPC. High-throughput gene expression microarray analyses revealed many more genes were regulated in the epithelium of the jejunum by lysolecithin compared to purified LPC. The most up-regulated genes and pathways were for collagen, extracellular matrix, and integrins. Staining sections of the jejunum with Picrosirius Red confirmed the increased deposition of collagen fibrils in the villi of broilers fed lysolecithin, but not purified LPC. Thus, lysolecithin elicits gene expression in the intestinal epithelium, leading to enhanced collagen deposition and villus length. Purified LPC alone as a supplement does not mimic these responses. Feed supplementation with lysolecithin triggers changes in the intestinal epithelium with the potential to improve overall gut health and performance., (© 2017 Poultry Science Association Inc.)

Oligodendrocyte progenitor cells (OPCs) are the principal source of new myelin in the central nervous system. A better understanding of how they mature into myelin-forming cells is of high relevance for remyelination. It has recently been demonstrated that during developmental myelination, the DNA methyltransferase 1 (DNMT1), but not DNMT3A, is critical for regulating proliferation and differentiation of OPCs into myelinating oligodendrocytes (OLs). However, it remains to be determined whether DNA methylation is also critical for the differentiation of adult OPCs during remyelination. After lysolecithin-induced demyelination in the ventrolateral spinal cord white matter of adult mice of either sex, we detected increased levels of DNA methylation and higher expression levels of the DNA methyltransferase DNMT3A and lower levels of DNMT1 in differentiating adult OLs. To functionally assess the role of DNMT1 and DNMT3 in adult OPCs, we used mice with inducible and lineage-specific ablation of Dnmt3a and/or Dnmt1 (i.e., Plp-creER(t);Dnmt3a-flox , Plp-creER(t);Dnmt1-flox, Plp-creER(t);Dnmt1-flox;Dnmt3a-flox ). Upon lysolecithin injection in the spinal cord of these transgenic mice, we detected defective OPC differentiation and inefficient remyelination in the Dnmt3a null and Dnmt1/Dnmt3a null mice, but not in the Dnmt1 null mice. Taken together with previous results in the developing spinal cord, these data suggest an age-dependent role of distinct DNA methyltransferases in the oligodendrocyte lineage, with a dominant role for DNMT1 in neonatal OPCs and for DNMT3A in adult OPCs.

A previous study showed that stearoyl lysophosphatidylcholine (sLPC) suppressed extracellular high mobility group box 1 translocation in macrophages stimulated with lipopolysaccharide through AMP-activated protein kinase (AMPK) activation. In the present study, we investigated whether sLPC-induced AMPK activation could enhance macrophages phagocytosis of bacteria. We found that sLPC increased phosphorylation of AMPK and acetyl-CoA carboxylase, a downstream target of AMPK, in a time- and dose-dependent manner in macrophages. Furthermore, sLPC increased the uptake of FITC-conjugated Escherichia coli by macrophages in a dose-dependent manner, and treatment with an AMPK inhibitor (compound C) or siRNA to AMPKα1 reversed this uptake. sLPC increased the phosphorylation of p38 mitogen-activated protein kinase (MAPK), but inhibition of AMPK activity with compound C or siRNA to AMPKα1 prevented the sLPC-induced increase in p38 MAPK phosphorylation. SB203580, a p38 MAPK inhibitor, decreased sLPC-induced phagocytosis. In vivo, systemic administration of sLPC to mice led to increased AMPK and p38 MAPK activity in the lung and to increased phagocytosis of fluorescent E. coli in bronchoalveolar lavage cells. These results suggest that sLPC increases macrophages phagocytosis through activation of the AMPK/p38 MAPK pathway. Therefore, sLPC is a candidate pharmacological agent for the treatment of bacterial infections in clinically relevant conditions., (Copyright © 2016. Published by Elsevier B.V.)

Lysolecithins are added to poultry diets to promote the intestinal absorption of nutrients, in particular of dietary fats. Lysolecithins contain a mixture of phospho- and lysophospholipids and differ in composition depending on the conditions and source of the lecithin used for its production. The importance of the lysolecithin composition and its interaction with the fat type was investigated in vitro in a fat digestion model and in vivo in a digestibility trial with broilers (24 to 28 d age). The in vitro digestion of soybean oil and pig lard was investigated without and with the inclusion of soybean or rapeseed lysolecithin. Correspondingly, for the digestibility trial, 108 Ross 308 male broilers were assigned to 6 dietary treatments: a basal diet with either soybean oil (5.3%) or pig lard (5.8%), each basal diet supplemented with 250 ppm soybean lysolecithin, and each basal diet supplemented with 250 ppm rapeseed lysolecithin. In vitro pig lard digestibility was significantly lower compared to soybean oil digestibility. Although in vivo no significant difference was observed for crude fat digestibility, broilers fed the basal diet with pig lard had a lower (P < 0.05) DM digestibility, nitrogen retention, and AMEn compared to those fed the basal diet with soybean oil. Lysolecithin supplementation showed a significant interaction with the fat type, both in vitro and in vivo. The in vitro hydrolysis of pig lard, but not of soybean oil, increased (P < 0.001) with supplementation of soybean and rapeseed lysolecithin. Moreover, soybean and rapeseed lysolecithin supplementation improved (P < 0.05) DM digestibility of the basal diet with pig lard by 5.1 and 5.7%, respectively; nitrogen retention by 2.8 and 3.1 g/kg, respectively; and AMEn by 182 and 199 kcal/kg, respectively. Despite the major difference in molecular composition, there was, however, no impact of the lysolecithin composition on in vitro and in vivo fat digestibility. This study demonstrates that the improvements that can be made with lysolecithin supplementation are highly dependent on the fat incorporated in broiler feeds., (© 2015 Poultry Science Association Inc.)

Autotaxin (ATX) is an enzyme discovered in the conditioned medium of cultured melanoma cells and identified as a protein that strongly stimulates motility. This unique ectonucleotide pyrophosphatase and phosphodiesterase facilitates the removal of a choline headgroup from lysophosphatidylcholine (LPC) to yield lysophosphatidic acid (LPA), which is a potent lipid stimulator of tumorigenesis. Thus, ATX has received renewed attention because it has a prominent role in malignant progression with significant translational potential. Specifically, we sought to develop active site-targeted irreversible inhibitors as anti-cancer agents. Herein we describe the synthesis and biological activity of an LPC-mimetic electrophilic affinity label that targets the active site of ATX, which has a critical threonine residue that acts as a nucleophile in the lysophospholipase D reaction to liberate choline. We synthesized a set of quaternary ammonium derivative-containing vinyl sulfone analogs of LPC that function as irreversible inhibitors of ATX and inactivate the enzyme. The analogs were tested in cell viability assays using multiple cancer cell lines. The IC50 values ranged from 6.74 to 0.39 μM, consistent with a Ki of 3.50 μM for inhibition of ATX by the C16H33 vinyl sulfone analog CVS-16 (10b). A phenyl vinyl sulfone control compound, PVS-16, lacking the choline-like quaternary ammonium mimicking head group moiety, had little effect on cell viability and did not inhibit ATX. Most importantly, CVS-16 (10b) significantly inhibited melanoma progression in an in vivo tumor model by preventing angiogenesis. Taken together, this suggests that CVS-16 (10b) is a potent and irreversible ATX inhibitor with significant biological activity both in vitro and in vivo., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Multiple sclerosis is an inflammatory demyelinating disease of the central nervous system characterized by plaque formation containing lost oligodendrocytes, myelin, axons, and neurons. Remyelination is an endogenous repair mechanism whereby new myelin is produced subsequent to proliferation, recruitment, and differentiation of oligodendrocyte precursor cells into myelin-forming oligodendrocytes, and is necessary to protect axons from further damage. Currently, all therapeutics for the treatment of multiple sclerosis target the aberrant immune component of the disease, which reduce inflammatory relapses but do not prevent progression to irreversible neurological decline. It is therefore imperative that remyelination-promoting strategies be developed which may delay disease progression and perhaps reverse neurological symptoms. Several animal models of demyelination exist, including experimental autoimmune encephalomyelitis and curprizone; however, there are limitations in their use for studying remyelination. A more robust approach is the focal injection of toxins into the central nervous system, including the detergent lysolecithin into the spinal cord white matter of rodents. In this protocol, we demonstrate that the surgical procedure involved in injecting lysolecithin into the ventral white matter of mice is fast, cost-effective, and requires no additional materials than those commercially available. This procedure is important not only for studying the normal events involved in the remyelination process, but also as a pre-clinical tool for screening candidate remyelination-promoting therapeutics.

Lipids presented by the MHC class I-like molecule, CD1d, are recognized by NK T (NKT) cells, which can be broadly categorized into two subsets. The well-characterized type I NKT cells express a semi-invariant TCR and can recognize both α- and β-linked glycolipids, whereas type II NKT cells are less well studied, express a relatively diverse TCR repertoire, and recognize β-linked lipids. Recent structural studies have shown a distinct mode of recognition of a self-glycolipid sulfatide bound to CD1d by a type II NKT TCR. To further characterize Ag recognition by these cells, we have used the structural data and screened other small molecules able to bind to CD1d and activate type II NKT cells. Using plate-bound CD1d and APC-based Ag presentation assay, we found that phospholipids such as lysophosphatidylcholine (LPC) can stimulate the sulfatide-reactive type II NKT hybridoma Hy19.3 in a CD1d-dependent manner. Using plasmon resonance studies, we found that this type II NKT TCR binds with CD1d-bound LPC with micromolar affinities similar to that for sulfatide. Furthermore, LPC-mediated activation of type II NKT cells leads to anergy induction in type I NKT cells and affords protection from Con A-induced hepatitis. These data indicate that, in addition to self-glycolipids, self-lysophospholipids are also recognized by type II NKT cells. Because lysophospholipids are involved during inflammation, our findings have implications for not only understanding activation of type II NKT cells in physiological settings, but also for the development of immune intervention in inflammatory diseases., (Copyright © 2014 by The American Association of Immunologists, Inc.)

Mice deficient in group 1b phospholipase A2 have decreased plasma lysophosphatidylcholine and increased hepatic oxidation that is inhibited by intraperitoneal lysophosphatidylcholine injection. This study sought to identify a mechanism for lysophosphatidylcholine-mediated inhibition of hepatic oxidative function. Results showed that in vitro incubation of isolated mitochondria with 40-200μM lysophosphatidylcholine caused cyclosporine A-resistant swelling in a concentration-dependent manner. However, when mitochondria were challenged with 220μM CaCl2, cyclosporine A protected against permeability transition induced by 40μM, but not 80μM lysophosphatidylcholine. Incubation with 40-120μM lysophosphatidylcholine also increased mitochondrial permeability to 75μM CaCl2 in a concentration-dependent manner. Interestingly, despite incubation with 80μM lysophosphatidylcholine, the mitochondrial membrane potential was steady in the presence of succinate, and oxidation rates and respiratory control indices were similar to controls in the presence of succinate, glutamate/malate, and palmitoyl-carnitine. However, mitochondrial oxidation rates were inhibited by 30-50% at 100μM lysophosphatidylcholine. Finally, while 40μM lysophosphatidylcholine has no effect on fatty acid oxidation and mitochondria remained impermeable in intact hepatocytes, 100μM lysophosphatidylcholine inhibited fatty acid stimulated oxidation and caused intracellular mitochondrial permeability. Taken together, these present data demonstrated that LPC concentration dependently modulates mitochondrial microenvironment, with low micromolar concentrations of lysophosphatidylcholine sufficient to change hepatic oxidation rate whereas higher concentrations are required to disrupt mitochondrial integrity., (Copyright © 2013. Published by Elsevier B.V.)

Objective: To examine the effects of niacin on lysophosphatidylcholine (LPC)-induced intercellular adhesion molecule-1 (ICAM-1), and gained insight to the mechanisms., Method: Human umbilical vein endothelial cell line was cultured using Medium 200 medium in incubator at 37 °C and 5% CO2 condition.Experimental groups:(1) the negative control group:medium; (2) LPC different time groups:the medium added with 20 µmol/L final concentration of LPC, were cultured for 10 min and 8 h, 24 h; (3) LPC+ p38-mitogen-activated protein kinase (p38MAPK) inhibitor (SB203580) group:the medium added with 10 µmol/L p38MAPK inhibitor (SB203580) was cultured for 1 h, then human umbilical vein endothelial cells (HUVECs) added with the LPC were cultured for 10 min, 8 h and 24 h.(4) LPC+different niacin dose group:after separately adding with 0.25, 0.5, 1 mmol/L niacin, the cells were cultured for 18 h, then HUVECs added with the LPC were cultured for 10 min, 8 h and 24 h. Cell concentration in each group was 5×10(5)/ml, inoculated in 6-well plates, each well 1 ml. Detected by Western blot analysis of pp38MAPK, ICAM-1 protein content, real-time quantitative PCR to detect endothelial cell ICAM-1 mRNA expression, cell immunofluorescence to detect LPC-induced ICAM-1 protein expression., Result: In LPC 24 h group, the expression of ICAM-1 protein was significantly increased 0.786 ± 0.02, the LPC+niacin group, ICAM-1 protein levels (0.487 ± 0.015) was significantly lower than the LPC 24 h group (P < 0.01), in LPC+SB203580 intervention group, ICAM-1 protein levels (0.461 ± 0.011) was significantly lower than that of the LPC 24 h group (P < 0.01), but did not reach the level of the control group. Adding LPC to culture for 10 min, phosphorylation of p38MAPK (pp38MAPK) reached its peak (0.47 ± 0.02), niacin could reduce the pp38MAPK (0.07 ± 0.02), SB203580 could also reduce its activity (0.11 ± 0.02). Adding LPC to culture for 8 h, ICAM-1 mRNA expression (8.16 ± 0.15) compared with the control group (1.00 ± 0.02) had a significant increase (t = 24.34, P < 0.01). Compared with the LPC 8 h, niacin reduced LPC-induced ICAM-1 mRNA expression (3.85 ± 0.14), and showed a dose-dependent manner (F = 8.06, P < 0.01), while SB203580 could not effectively reduce the ICAM-1 mRNA (8.09 ± 0.11)., Conclusion: Niacin prevented LPC-induced endothelial dysfunction by reducing expression of ICAM-1. These mechanisms appeared to be at least partly mediated by suppression of the pp38MAPK in endothelial cells. These pleiotropic effects of niacin may potentially contribute to the beneficial effects of risk reduction for atherosclerotic disease.

1. Rice bran lysolecithin (RBL) was evaluated in broiler chicken diets. In the first experiment, RBL was included in diet at 0, 0·5, 2, 8 and 32 g/kg and fed to 250 broiler chickens from 0 to 42 d of age. In the second experiment, RBL was fed at 0, 25 and 50 g/kg diet to 405 day-old broiler chickens until 21 d of age, while during the finisher phase (22-35 d of age) chickens receiving each concentration of RBL were given all three concentrations of RBL in a 3 × 3 factorial manner. The diets were isocaloric. 2. Body weight, food consumption and food conversion efficiency were unaffected by feeding RBL, while the weight of pancreas increased at ≥2 g/kg of RBL in diet (experiment 1). In experiment 2, body weight was greater in the chickens receiving RBL at either 25 or 50 g/kg (21 d) and 50 g/kg (35 d of age). At 21 d of age, food consumption was greater at 25 or 50 g RBL/kg diet, while food conversion efficiency improved with 50 g RBL/kg diet. 3. Fat digestibility increased with RBL at 32 g/kg (experiment 1) and ≤25 g/kg (experiment 2). Rice bran lysolecithin increased ready to cook weight at 50 g/kg during starter phase and decreased abdominal fat at 25 and 50 g/kg during finisher phase (experiment 2). Liver and meat fat content were not affected. 4. It is concluded that lysolecithin from rice bran oil could be used as energy supplement in broiler chicken diet.

Lysophosphatidylcholines (lysoPCs) have been known to be bioactive lipid mediators, which take part in various biological and pathological processes. In the present study, we examined the anti-inflammatory actions of 2-docosahexaenoyl lysophosphatidylcholine (2-docosahexaenoyl-lysoPC) in vitro as well as in vivo systems. When RAW 264.7 cells were treated with 2-docoshexaenoyl-lysoPC, a concentration-dependent decrease of LPS-induced formation of nitric oxide (NO), tumor necrosis factor alpha (TNF-α), or IL-6 was observed. Additionally, oral administration of 2-docosahexaenoyl-lysoPC was found to inhibit zymosan A-induced plasma leakage dose-dependently in mice with ED(50) value of 50 μg/kg and E (max) value of about 65%. Moreover, mechanistic study revealed that the anti-inflammatory action of 2-docosahexaenoyl-lysoPC seemed to be related largely to LTC(4) inhibition, but not PGE(2) inhibition. Moreover, 2-(17-hydroperoxydocosahexaneoyl)-lysoPC, intravenously administrated, was more effective than 2-docosahexaenoyl-lysoPC in the inhibition of zymosan A-induced plasma leakage, suggesting that 2-(17-hydroperoxydocosahexaneoyl)-lysoPC, a product from oxygenation of 2-docosahexaenoyl-lysoPC by 15-lipoxygenase (LOX), may be an active metabolite, intimately responsible for anti-inflammatory actions, generated from 2-docosahexaenoyl-lysoPC. In a related study, 2-docosahexaenoyl-lysoPC was found to be more efficient than 1-docosahexaenoyl-lysoPC or docosahexaenoic acid (DHA) as substrate for 15-lipoxygenases such as soybean LOX-1, leukocyte 12/15-LOX, and human 15-LOX-2. Taken altogether, it is suggested that 2-docosahexaenoyl-lysoPC and its oxygenation products may exert anti-inflammatory action after oral administration.

Background and Purpose: Lysophosphatidylcholines (lysoPCs) with polyunsaturated acyl chains are known to exert anti-inflammatory actions. 15-Lipoxygeanation is crucial for anti-inflammatory action of polyunsaturated acylated lysoPCs. Here, the anti-inflammatory actions of 1-(15-hydroxyeicosapentaenoyl)-lysoPC (15-HEPE-lysoPC) and its derivatives were examined in a mechanistic analysis., Experimental Approach: Anti-inflammatory actions of 15-HEPE-lysoPC in zymosan A-induced peritonitis of mice were examined by measuring plasma leakage and leucocyte infiltration, and determining levels of lipid mediators or cytokines., Key Results: When each lysoPC, administered i.v., was assessed for its ability to suppress zymosan A-induced plasma leakage, 15-HEPE-lysoPC was found to be more potent than 1-(15-hydroperoxyeicosapentaenoyl)-lysoPC or 1-eicosapentaenoyl-lysoPC. Separately, i.p. administration of 15-HEPE-lysoPC markedly inhibited plasma leakage, in contrast to 15-HEPE, which had only a small effect. 15-HEPE-lysoPC also decreased leucocyte infiltration. Moreover, it reduced the formation of LTC₄ and LTB₄, 5-lipoxygenation products, as well as the levels of pro-inflammatory cytokines. The time-course study indicated that 15-HEPE-lysoPC might participate in both the early inflammatory phase and resolution phase. Additionally, 15-HEPE-lysoPC administration caused a partial suppression of LTC₄-induced plasma leakage and LTB₄-induced leucocyte infiltration. In the metabolism study, peritoneal exudate was shown to contain lysoPC-hydrolysing activity, crucial for anti-inflammatory activity, and a system capable of generating lipoxin A from 15-hydroxy eicosanoid precursor., Conclusions and Implications: 15-HEPE-lysoPC, a precursor for 15-HEPE in target cells, induced anti-inflammatory actions by inhibiting the formation of pro-inflammatory leukotrienes and cytokines, and by enhancing the formation of lipoxin A. 15-HEPE-lysoPC might be one of many potent anti-inflammatory lipids in vivo., (© 2011 The Authors. British Journal of Pharmacology © 2011 The British Pharmacological Society.)

Objective: Previously we identified palmitoyl-lysophosphatidylcholine (LPC 16:0), as well as linoleoyl-, arachidonoyl- and oleoyl-LPC (LPC 18:2, 20:4 and 18:1) as the most prominent LPC species generated by the action of endothelial lipase (EL) on high-density lipoprotein (HDL). In the present study, the impact of EL and EL-generated LPC on interleukin-8 (IL-8) synthesis was examined in vitro in primary human aortic endothelial cells (HAEC) and in mice., Methods and Results: Adenovirus-mediated overexpression of the catalytically active EL, but not its inactive mutant, increased endothelial synthesis of IL-8 mRNA and protein in a time- and HDL-concentration-dependent manner. While LPC 18:2 was inactive, LPC 16:0, 18:1 and 20:4 promoted IL-8 mRNA- and protein-synthesis, differing in potencies and kinetics. The effects of all tested LPC on IL-8 synthesis were completely abrogated by addition of BSA and chelation of intracellular Ca(2+). Underlying signaling pathways also included NFkB, p38-MAPK, ERK, PKC and PKA. In mice, adenovirus-mediated overexpression of EL caused an elevation in the plasma levels of MIP-2 (murine IL-8 analogue) accompanied by a markedly increased plasma LPC/PC ratio. Intravenously injected LPC also raised MIP-2 plasma concentration, however to a lesser extent than EL overexpression., Conclusion: Our results indicate that EL and EL-generated LPC, except of LPC 18:2, promote endothelial IL-8 synthesis, with different efficacy and kinetics, related to acyl-chain length and degree of saturation. Accordingly, due to its capacity to modulate the availability of the pro-inflammatory and pro-adhesive chemokine IL-8, EL should be considered an important player in the development of atherosclerosis., (Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.)

Background: Although neuropathic pain is frequently observed in demyelinating diseases such as Guillain-Barré syndrome and multiple sclerosis, the molecular basis for the relationship between demyelination and neuropathic pain behaviors is poorly understood. Previously, we found that lysophosphatidic acid receptor (LPA1) signaling initiates sciatic nerve injury-induced neuropathic pain and demyelination., Results: In the present study, we have demonstrated that sciatic nerve injury induces marked demyelination accompanied by myelin-associated glycoprotein (MAG) down-regulation and damage of Schwann cell partitioning of C-fiber-containing Remak bundles in the sciatic nerve and dorsal root, but not in the spinal nerve. Demyelination, MAG down-regulation and Remak bundle damage in the dorsal root were abolished in LPA1 receptor-deficient (Lpar1-/-) mice, but these alterations were not observed in sciatic nerve. However, LPA-induced demyelination in ex vivo experiments was observed in the sciatic nerve, spinal nerve and dorsal root, all which express LPA1 transcript and protein. Nerve injury-induced dorsal root demyelination was markedly attenuated in mice heterozygous for autotaxin (atx+/-), which converts lysophosphatidylcholine (LPC) to LPA. Although the addition of LPC to ex vivo cultures of dorsal root fibers in the presence of recombinant ATX caused potent demyelination, it had no significant effect in the absence of ATX. On the other hand, intrathecal injection of LPC caused potent dorsal root demyelination, which was markedly attenuated or abolished in atx+/- or Lpar1-/- mice., Conclusions: These results suggest that LPA, which is converted from LPC by ATX, activates LPA1 receptors and induces dorsal root demyelination following nerve injury, which causes neuropathic pain.

Background: Poor gene transfer efficiency has been a major problem in developing an effective gene therapy for cystic fibrosis (CF) airway disease. Lysophosphatidylcholine (LPC), a natural airway surfactant, can enhance viral gene transfer in animal models. We examined the electrophysiological and physical effect of airway pre-treatment with variants of LPC on lentiviral (LV) vector gene transfer efficiency in murine nasal airways in vivo., Methods: Gene transfer was assessed after 1 week following nasal instillations of a VSV-G pseudotype LV vector pre-treated with a low and high dose of LPC variants. The electrophysiological effects of a range of LPC variants were assessed by nasal transepithelial potential difference measurements (TPD) to determine tight junction permeability. Any physical changes to the epithelium from administration of the LPC variants were noted by histological methods in airway tissue harvested after 1 hour., Results: Gene transduction was significantly greater compared to control (PBS) for our standard LPC (palmitoyl/stearoyl mixture) treatment and for the majority of the other LPC variants with longer acyl chain lengths. The LPC variant heptadecanoyl also produced significantly greater LV gene transfer compared to our standard LPC mixture. LV gene transfer and the transepithelial depolarization produced by the 0.1% LPC variants at 1 hour were strongly correlated (r2 = 0.94), but at the 1% concentration the correlation was less strong (r2 = 0.59). LPC variants that displayed minor to moderate levels of disruption to the airway epithelium were clearly associated with higher LV gene transfer., Conclusions: These findings show the LPC variants effect on airway barrier function and their correlation to the effectiveness of gene expression. The enhanced expression produced by a number of LPC variants should provide new options for preclinical development of efficient airway gene transfer techniques.

After central nervous system (CNS) demyelination-such as occurs during multiple sclerosis-there is often spontaneous regeneration of myelin sheaths, mainly by oligodendrocytes but also by Schwann cells. The origins of the remyelinating cells have not previously been established. We have used Cre-lox fate mapping in transgenic mice to show that PDGFRA/NG2-expressing glia, a distributed population of stem/progenitor cells in the adult CNS, produce the remyelinating oligodendrocytes and almost all of the Schwann cells in chemically induced demyelinated lesions. In contrast, the great majority of reactive astrocytes in the vicinity of the lesions are derived from preexisting FGFR3-expressing cells, likely to be astrocytes. These data resolve a long-running debate about the origins of the main players in CNS remyelination and reveal a surprising capacity of CNS precursors to generate Schwann cells, which normally develop from the embryonic neural crest and are restricted to the peripheral nervous system., (Copyright 2010 Elsevier Inc. All rights reserved.)

Nanomaterials released into the environment will interact with many materials including other contaminants. This may influence bioavailability and fate of both the nanoparticles and the other contaminants. The present study examined the effect of a combination of soluble copper and surface-modified single-walled carbon nanotubes (SWNTs) on Daphnia magna. Lysophosphatidylcholine (LPC) was used to modify the surface of SWNTs, reducing the surface hydrophobicity of the tubes and thereby producing a stable aqueous nanoparticle suspension. The toxicity of the nanoparticle-copper (Cu) mixture was determined to be additive. The addition of nontoxic concentration of LPC-SWNTs enhanced the uptake and toxicity of copper. Greater amounts of Cu were shown to accumulate in D. magna upon addition of 0.5 and 1.0 mg/L LPC-SWNTs.

Background: Cystic fibrosis (CF) is caused by a defect in cystic fibrosis transmembrane conductance regulator (CFTR) activity, often resulting in an incurable airway disease. Gene therapy into the conducting airway epithelium is a potential cure for CF; however, most gene vectors do not result in long-lived expression, and require re-dosing. Perversely, intrinsic host immune responses can then block renewed gene transfer., Methods: To investigate whether persistent gene expression could be achieved after a single dosing event, thus avoiding the issue of blocking host responses, we used a gene transfer protocol that combined an airway pretreatment using lysophosphatidylcholine with a human immunodeficiency virus type-1 (vesicular stomatitis virus G pseudotype) derived lentiviral vector to test whether an integrating vector could produce gene expression able to last for a substantial part of the lifetime of the laboratory mouse., Results: We found that a single dose of LV-LacZ produced immediate as well as lifetime mouse airway expression, confirming our hypothesis that use of an integrating vector extends transgene expression. Importantly, LV-CFTR dosing achieved at least 12 months of CFTR expression, representing partial functional correction of the CFTR defect in CF-null mice., Conclusions: These findings validate the potential of this methodology for developing a gene transfer treatment for CF airway disease.

This study investigated the influence of an eicosapentaenoic acid (EPA)- or a docosahexaenoic acid (DHA)-supplemented diet on the deleterious effects of lysophosphatidylcholine (LPC) on endothelium-dependent vasorelaxation of Golden Syrian hamster thoracic aorta. In a second step, LPC-modulated phospholipase A(2) (PLA(2))-derived ways of relaxation were investigated. Golden Syrian hamsters were fed for 6 weeks with a control diet or an EPA- or DHA-supplemented diet. Aortic fatty acid composition was analyzed by gas chromatography. Aortic rings were incubated for 20 minutes with LPC before constructing cumulative concentration-response curves for acetylcholine (ACh; 3 nmol/L-30 micromol/L) or sodium nitroprusside (3 nmol/L-30 micromol/L). The EPA- or DHA-supplemented diet increased n-3 polyunsaturated fatty acids in aortic fatty acids content because of the increase of EPA or DHA content, respectively, and decreased arachidonic acid aortic content. Lysophosphatidylcholine (1, 10, 15, and 20 micromol/L) induced a concentration-dependent inhibition of ACh-induced relaxation of preconstricted aortic rings in the control group, but did not influence sodium nitroprusside-induced aortic relaxation. The DHA- or EPA-supplemented diet worsened LPC (20 micromol/L) inhibitory effects on ACh-induced vasorelaxation. In the control diet group, ACh-induced relaxation was abolished by the nitric oxide synthase inhibitor (l-N(G)-nitro-arginine methyl ester; 100 micromol/L), whether LPC was added or not. The ACh-induced vasorelaxation was partially inhibited by PLA(2) inhibitors methyl arachidonyl fluorophosphonate (25 micromol/L) and arachidonyl trifluoromethyl ketone (20 micromol/L) as well as by the combination of 2 Ca(2+)-dependent potassium (K(Ca)) channel inhibitors charybdotoxin (0.1 micromol/L) plus apamin (0.3 micromol/L). In the presence of LPC (20 micromol/L), ACh-induced vasorelaxation was abolished by these inhibitors. These effects were not influenced by DHA or EPA diet. Our results suggested that EPA- or DHA-supplemented diet did not exhibit any beneficial effect against LPC-induced inhibition of endothelium-dependent aortic relaxation in Golden Syrian hamsters. These LPC effects were associated in our study not only with an inhibition of nitric oxide-dependent vasorelaxation, but also with a concomitant activation of a compensatory vasorelaxant pathway depending both on PLA(2) metabolites and on K(Ca) channel opening.

Lysophosphatidylcholine (lysoPC) stimulates the release of prostaglandins (PGs) in various cells and tissues. Cyclooxygenase (COX)-2 has recently emerged as a key regulator of PG synthesis. We investigated whether lysoPC regulates COX-2 expression in cultured rat vascular smooth muscle cells (VSMCs). LysoPC strongly increased the expression of COX-2 mRNA in a time- and dose-dependent manner. COX-2 protein expression also was increased by lysoPC. The p38 mitogen-activated protein kinase (MAPK) inhibitor SB203580 significantly suppressed lysoPC-induced COX-2 mRNA and protein expression, but not a p42/44MAPK kinase (MEK-1) inhibitor, PD98059. LysoPC did not increased the transcription of the COX-2 gene, as assayed with a COX-2 promoter/luciferase chimeric plasmid and suppressed the decay of COX-2 mRNA. SB203580 markedly enhanced the decay of COX-2 mRNA induced by lysoPC, implying that p38MAPK activated by lysoPC helps to regulate COX-2 by stabilizing its mRNA. The COX-2 specific inhibitor NS-398 attenuated lysoPC-stimulated DNA and protein synthesis as well as PGE(2) production by VSMCs. These results suggest that in rat VSMCs lysoPC regulates COX-2 expression and PG production and also modulates cell proliferation through p38MAPK-mediated signaling pathways.

In this research, Lysolecithin - a substance made with 100% natural ingredients - was given to ICR mice as medication to measure its periodic effect on the noradrenalin (NA), dopamine (DA), and serotonin (5-HT) levels of the brain. Both ICR and SAM mice were separated into two groups - control group and Lysolecithin (K. Lysolecithin: hydrolytic lysolecithin) medicated group, and given 1-week preparation period. The K. Lysolecithin group was given 500 mg/kg of K. Lysolecithin at 0.2 mL per dosage for 4 weeks, and the control group was given the same amount of dosage of water during the same period. NA, DA and 5-HT concentrations were measured from the blood before medication and 8 weeks/12 weeks/16 weeks after the first medication. For the SAM mice, 8 weeks after they were medicated with K .Lysolecithin, Morris Water Maze Test was conducted for 7 consecutive days and then the concentrations were measured by drawing blood from the heart. The K. Lysolecithin medicated group showed a tendency to have a statistically significant higher concentrations of 5-HT and NA in the blood. Also, periodic examination showed that the monoamine levels were highest in the 12th week and declined thereafter.

Reverse transcription of extracted cellular RNA combined with real-time PCR is now an established method for sensitive detection and quantification of specific mRNA level changes in experimental models of neurological diseases. To neutralize the impact of experimental error and make quantification more precise, normalization of test gene data using data from a constantly expressed gene, a reference gene that is tested along with the test gene, is required. There is no single gene constantly expressed under all experimental conditions. For a given set of conditions or a given disease model, identification of an unaffected reference gene is necessary. In this report, we present our findings from evaluation and validation of the genes encoding hypoxanthine guanine phosphoribosyl transferase 1 (HPRT1) and glyceraldehyde phosphate dehydrogenase (GAPDH) as individual reference genes in mRNA level studies involving four murine neurological disease models. We find both genes are suitable as a reference gene with these four models, provided quantification of subtle changes are avoided. We furthermore demonstrate that above a certain threshold of test mRNA level changes and given high quality RNA processing, normalization to total RNA alone provides for equally reliable quantitative mRNA level results.

The discovery of new adjuvants that can stimulate the immune response to protein antigens is a major issue for the development of subunit vaccines. Lipoprotein oxidation occurring during the acute phase response (APR) to aggression of the organism, provides signals of danger that are detected by dendritic cells (DC). Among other instructive molecules generated during the APR, lysophosphatidylcholine (LPC) promotes mature DC generation from differentiating human monocytes in vitro. It is shown here that LPC also controls the initiation of an adaptive immune response in vivo. LPC displays adjuvant properties when injected to mice in mixture with various antigens. Immunizations with LPC induced the production of antigen-specific antibodies with an efficiency similar to Alum, the reference adjuvant for human vaccination. Importantly, LPC also induced cytotoxic T cell responses, opening perspectives for vaccine development. Therefore, LPC is a natural adjuvant for the immune system, inducing humoral and cellular immune responses.

The bioavailability of lutein solubilized in mixed micelles containing either phosphatidylcholine (PC) or lysophosphatidylcholine (lysoPC) was evaluated in male rats. Mixed micelles contained 2.5 mM monooleoylglycerol, 7.5 mM oleic acid, 12 mM sodium taurocholate and 200 microM lutein either with 3 mM PC or lysoPC. To study lutein bioavailability, single and repeated dose experiments were conducted. For single dose study, group of rats (n = 30/group) were fed single dose of lutein solubilized in lysoPC (LPC group), PC (PC group) and no phospholipids (NoPL group) in micellar form. Each group was further divided in to five sub-groups (n = 6/sub group) to measure lutein bioavailability over time up to 9 h. For repeated dose study, group of rats (n = 6/group) were fed daily for 10 days a dose of lutein in mixed micelles with NoPL, PC and LPC. A separate group (n = 6) not fed mixed micelles was considered as zero-time control. In both the experiments, mixed micelles (0.2 ml/rat) were fed to the rat by direct intubation to the stomach. Results of single dose studies showed that the mean lutein levels in the plasma and liver of the PC group was significantly lower (p < 0.05) than those of the other two groups. Moreover, the average lutein level in the plasma and liver was significantly (p < 0.05) different among the groups in the order LPC > NoPL > PC. But, repeated dose experiment followed the order LPC > PC > NoPL. The level of lutein excreted through urine and feces of PC group was significantly higher (p < 0.05) than those of the other two groups. Thus, the results indicate that the PC in the mixed micelles suppressed the intestinal uptake of lutein after single dose but not after repeated dose and that lysoPC enhanced the absorption. In both the experiments, plasma and liver level of lutein was higher in LPC compared with PC group. Results also suggest that the luminal hydrolysis of PC to lysoPC is necessary for intestinal uptake of lutein solubilized in mixed micelles.

Lysophosphatidylcholine is increased in the airway of bronchial asthma, but its role is not clear. We investigated the role of lysophosphatidylcholine in asthma in anaesthetized, mechanically ventilated guinea pigs. Pressure at the airway opening was measured as an index of bronchial response. Increasing doses of lysophosphatidylcholine (1--10 mg/ml) were inhaled and then bronchoalveolar lavage was carried out. 100 and 200 microg/ml methacholine were inhaled 10 min after inhalation of 2.5 mg/ml lysophosphatidylcholine, 10 mg/ml dipalmitoyl phosphatidylcholine and 10 mg/ml glycerophosphocholine, all of which per se did not change the pressure at the airway opening. Effect of 1.0 microg/kg salbutamol, or 60 mg/kg diphenhydramine on the lysophosphatidylcholine-induced increase in the pressure at the airway opening was investigated. Inhalation of lysophosphatidylcholine dose-dependently increased the pressure at the airway opening and increased bronchial responsiveness to methacholine. On the other hand, inhalation of dipalmitoyl phosphatidylcholine decreased the pressure at the airway opening and decreased bronchial responsiveness to methacholine. Intravenously administered salbutamol, but not diphenhydramine, prevented the lysophosphatidylcholine-induced increase in the pressure at the airway opening. The percentage of leukocytes in bronchoalveolar lavage fluid did not change significantly at least within 20 min after the lysophosphatidylcholine inhalation. Lysophosphatidylcholine causes bronchoconstriction and enhances bronchial responsiveness without inducing leukocyte infiltration in the airway, suggesting that lysophosphatidylcholine may be a new bronchoconstrictor mediator in bronchial asthma.

Objective: Leptin inhibits appetite and reduces body weight. However, subcutaneous leptin administration is not very effective on weight reduction. The present studies were undertaken to test the hypotheses that nasally administered leptin effectively accesses to the brain and inhibits appetite., Methods: Recombinant leptin (0.5 mg/rat) was administered into the bilateral nasal spaces of rats (i.n.). Changes in serum immunoreactive leptin (IRL) and cerebrospinal fluid (CSF)-IRL concentrations after i.n. leptin administration were compared after intraperitoneal (i.p.) administration. The influence of 0.1 or 0.5% lysophosphatidylcholine (LPC) as an optimizer of leptin absorption was examined. The anorexic effects of i.n. leptin were compared with i.p. leptin in ad libitum fed rats., Results: The i.n. leptin increased CSF-IRL concentrations, although serum IRL concentrations of rats administered leptin i.n. were lower than those administered i.p. The addition of 0.1 and 0.5% LPC dose-dependently increased serum IRL concentrations, but did not modify CSF-IRL concentrations in i.n. leptin-treated rats. The i.n. leptin inhibited dark-time food consumption at 0-1 h and 3-6 h in ad libitum fed rats. In contrast, i.p. leptin reduced food consumption only for an hour. Phosphorylated signal transducer and activator of transcription (STAT) 3 immunoreactive cells increased in the arcuate nucleus (ARC) of the hypothalamus at 3 h only following i.n. leptin., Conclusion: The present study demonstrated that i.n. leptin caused longer inhibition of appetite and phosphorylation of STAT3 in ARC. It is concluded that the trans-nasal route may be useful for the selective access of leptin to the brain in obese people.

Background: Lysophosphatidylcholine (LPC) is a product of phosphatidylcholine hydrolysis by phospholipase A(2) and a mediator of the lipid-induced atherosclerotic changes. In this study, we determined the effects of LPC on vasomotor functions, oxidative stress, and endothelial nitric oxide synthase (eNOS) expression in porcine coronary arteries., Methods: Porcine coronary arteries were cut into 5-mm rings and were treated with LPC or antioxidant selenomethionine (SeMet). For the vasomotor studies, we used a myograph tension system. Levels of superoxide anion (O(2)(-)) were detected by the lucigenin-enhanced chemiluminescence method. The eNOS protein level was studied by immunohistochemistry with avidin-biotin complex immunoperoxidase procedure., Results: Endothelium-dependent relaxation in response to bradykinin was reduced by 36% and 81% for the rings treated with 12.5 and 25 mum of LPC, respectively, as compared with controls (P < 0.05). Endothelium-independent relaxation in response to sodium nitroprusside also was reduced by 63% after treatment with 25 mum LPC (P < 0.05). The O(2)(-) level was increased in the porcine arteries treated with 25 mum of LPC by 41% as compared with controls (P < 0.05). The antioxidant SeMet reversed the effects of LPC on vascular relaxation and O(2)(-) production. Immunoreactivity of eNOS in LPC-treated vessel rings also was reduced substantially., Conclusions: LPC impairs endothelium-dependent and endothelium-independent vasorelaxation. This effect is associated with increased superoxide radical production and decreased eNOS activity and is practically reversed with the use of the antioxidant SeMet.

Two experiments were conducted to evaluate the effect of lysolecithin on performance and nutrient digestibility of nursery pigs and to determine the effects of fat encapsulation by spray drying in diets fed in either meal or pelleted form. In Exp. 1, 108 pigs (21 d of age; 5.96 +/- 0.16 kg BW) were allotted to one of four dietary treatments (as-fed basis): 1) control with no added lard, 2) control with 5% added lard, 3) treatment 2 with 0.02% lysolecithin, and 4) treatment 2 with 0.1% lysolecithin in a 35-d experiment. Added lard decreased ADG (P = 0.02) and ADFI (P < 0.06) during d 15 to 35 and overall. Lysolecithin improved ADG linearly (P = 0.04) during d 15 to 35 and overall, but did not affect ADFI or G:F. Addition of lard decreased the digestibility of DM (P = 0.10) and CP (P = 0.05) and increased (P = 0.001) fat digestibility when measured on d 10. Lysolecithin at 0.02%, but not 0.10%, tended to improve the digestibility of fat (P = 0.10). On d 28, digestibilities of DM, fat, CP, P, (P = 0.001), and GE (P = 0.03) were increased with the addition of lard, and lysolecithin supplementation linearly decreased digestibilities of DM (P = 0.003), GE (P = 0.007), CP, and P (P = 0.001). In Exp. 2, 144 pigs (21 d of age, 6.04 +/- 0.16 kg BW) were allotted to one of six treatments in a 3 x 2 factorial randomized complete block design. Factors included 1) level (as-fed basis) and source of fat (control diet with 1% lard; control diet with 5% additional lard; and control diet with 5% additional lard from encapsulated, spray-dried fat) and 2) diet form (pelleted or meal). Addition of lard decreased feed intake during d 0 to 14 (P = 0.04), d 15 to 35 (P = 0.01), and overall (P = 0.008), and improved G:F for d 15 to 35 (P = 0.04) and overall (P = 0.07). Encapsulated, spray-dried lard increased ADG (P = 0.004) and G:F (P = 0.003) during d 15 to 28 compared with the equivalent amount of fat as unprocessed lard. Pelleting increased ADG (P = 0.006) during d 0 to 14, decreased feed intake during d 15 to 35 (P = 0.01), and overall (P = 0.07), and increased G:F during all periods (P < 0.02). Fat digestibility was increased (P = 0.001) with supplementation of lard, and this effect was greater when diets were fed in meal form (interaction, P = 0.004). Pelleting increased the digestibility of DM, OM, and fat (P < 0.002). Results indicate that growth performance may be improved by lysolecithin supplementation to diets with added lard and by encapsulation of lard through spray drying.

As the physiological roles of dietary lecithin have not yet been clearly defined, we examined the effects of lecithin on lipid absorption in male Wistar rats with a mesenteric lymph cannula. Lymphatic absorption was observed after the infusion of 1 ml emulsion containing 100 mg test oil emulsified with sodium taurocholate (10 g/l) in three separate experiments. Test oils (100 mg) were: soyabean oil (triacylglycerol (TG) source, SO) and soyabean oil+lecithin (75 mg soyabean oil+25 mg lecithin, LE) in Expt 1; SO, LE or soyabean oil+lysolecithin (75 mg soyabean oil plus 25 mg lysolecithin, LY) in Expt 2; hydrolysed soyabean oil (HSO) or HSO+lysolecithin (75 mg HSO+25 mg lysolecithin, HLY) in Expt 3. After LE and LY infusions, lymph flow and the lymphatic output of TG was higher than after SO infusion at 0-30 min and 0-90 min respectively (Expts 1 and 2). Lecithin-induced increases in lymph TG output remained constant when HSO was infused (Expt 3). There were no differences in the TG:phospholipid ratio in the lymph after infusion among the groups; nevertheless, the lymphatic output of TG was much higher after infusion with LE than with SO. Fatty acid was released more efficiently from SO than from LE and LY by in vitro digestion with rat bile-pancreatic juice. These present results demonstrate that a TG emulsion containing soyabean lecithin or its hydrolysates promote lymphatic TG output and suggest that the increases in TG absorption do not depend on TG digestion.

Previously, we have shown that uptake of carotenoids solubilized with mixed micelles by human intestinal Caco-2 cells is enhanced by lysophosphatidylcholine (lysoPC) and suppressed by PC. This study determined the effect of PC and lysoPC in mixed micelles on the accumulation of beta-carotene and lutein in mice in order to elucidate the roles of micellar phospholipid in the intestinal uptake of carotenoids in vivo. Mixed micelles were composed of 2.5 mM monooleoylglycerol, 7.5 mM oleic acid, 12 mM sodium taurocholate, 200 microM carotenoid, and 3 mM phospholipid in PBS. The mice were fed single doses of beta-carotene or lutein solubilized in PC (PC group), lysoPC (LPC group), and no phospholipid (NoPL group) micelles. The beta-carotene responses in the plasma and liver of the PC group were markedly lower than those of the other two groups, whereas no differences were noticed between the LPC and NoPL groups. The average level of lutein in the plasma of the PC group after administration was significantly (P < 0.05) lower than those of the other groups. Moreover, the average level of lutein in the liver was significantly (P < 0.05) different among the groups in the order of LPC > NoPL > PC. Thus, the results clearly indicate that PC suppressed the accumulation of beta-carotene and lutein in plasma and liver and that lysoPC enhanced the accumulation of lutein in liver. These results suggest that the hydrolysis of PC to lysoPC plays an important role in the intestinal uptake of carotenoids solubilized in mixed micelles.

The permeability-enhancing effects of the two surfactants, 1-palmitoyl-2-lyso-sn-gycero-3-phosphocholine (lysoPPC) and palmitic acid (PA), on lipid membranes that at physiological temperatures are in the gel, fluid, and liquid-ordered phases were determined using the concentration-dependent self-quenching properties of the hydrophilic marker, calcein. Adding lysoPPC to lipid membranes in the gel-phase induced a time-dependent calcein release curve that can be described by the sum of two exponentials, whereas PA induces a considerably more complex release curve. However, when lysoPPC and PA were added simultaneously in equimolar concentrations, a dramatic synergistic permeability-enhancing effect was observed. In contrast, when both lysoPPC and PA are added to liposomal membranes that are in the fluid or liquid-ordered phases, no effect on the transmembrane permeation of calcein was observed.