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1.
Chinese Journal of Preventive Medicine ; (12): 649-653, 2023.
Article in Chinese | WPRIM | ID: wpr-985457

ABSTRACT

Objective: To investigate the relationship between serum lysophosphatidylcholine (LPC) level and the health index of the elderly. Methods: A total of 251 subjects were selected from the 2016 baseline survey of the Yongfu Longevity Cohort in Guangxi Province among whom 66, 63 and 122 were in the young and middle-aged group (≤59 years old), the young group (60-89 years old) and the longevity group (≥90 years old), respectively. Demographic data were collected and related indicators of height, weight, blood pressure and lipid metabolism were measured. The cognitive and physical functions of the elderly were assessed by the results of the simple mental state scale and the daily living activity scale to construct the health index of the elderly. The serum levels of LPC16∶0, LPC18∶0, LPC18∶1 and LPC18∶2 were determined by liquid chromatography-tandem mass spectrometry, and the differences among different ages and health status groups were compared. The logistic regression model was used to analyze the relationship between the serum LPC level and the health index of the elderly. Results: With the increase in age, the proportion of female subjects increased, and the rate of smoking and drinking decreased. BMI, TC, TG, LDL-C, diastolic blood pressure, and the four LPCs levels decreased with the increase of age, and systolic blood pressure levels increased with the increase of age (all P values<0.05). There was no significant difference in HDL-C levels among age groups (P>0.05). With the decline of health status in the elderly, serum levels of LPC16∶0, LPC18∶0, LPC18∶1 and LPC18∶2 showed a downward trend (all P values<0.001). After adjusting for age and gender, only LPC18∶0 was associated with the health status in old age [OR (95%CI): 0.48 (0.25-0.92)]. For every 1 standard deviation (16.87 nmol/L) increase in serum LPC18∶0 concentration, the risk of poor health status in old age decreased by 52%. Conclusion: Serum LPC18∶0 was associated with the health status in old age independent of age and sex.


Subject(s)
Aged , Middle Aged , Humans , Female , Aged, 80 and over , Lysophosphatidylcholines , Risk Factors , China , Longevity , Surveys and Questionnaires , Triglycerides
2.
Neuroscience Bulletin ; (6): 247-260, 2018.
Article in English | WPRIM | ID: wpr-777042

ABSTRACT

The differentiation and maturation of oligodendrocyte precursor cells (OPCs) is essential for myelination and remyelination in the CNS. The failure of OPCs to achieve terminal differentiation in demyelinating lesions often results in unsuccessful remyelination in a variety of human demyelinating diseases. However, the molecular mechanisms controlling OPC differentiation under pathological conditions remain largely unknown. Myt1L (myelin transcription factor 1-like), mainly expressed in neurons, has been associated with intellectual disability, schizophrenia, and depression. In the present study, we found that Myt1L was expressed in oligodendrocyte lineage cells during myelination and remyelination. The expression level of Myt1L in neuron/glia antigen 2-positive (NG2) OPCs was significantly higher than that in mature CC1 oligodendrocytes. In primary cultured OPCs, overexpression of Myt1L promoted, while knockdown inhibited OPC differentiation. Moreover, Myt1L was potently involved in promoting remyelination after lysolecithin-induced demyelination in vivo. ChIP assays showed that Myt1L bound to the promoter of Olig1 and transcriptionally regulated Olig1 expression. Taken together, our findings demonstrate that Myt1L is an essential regulator of OPC differentiation, thereby supporting Myt1L as a potential therapeutic target for demyelinating diseases.


Subject(s)
Animals , Mice , Cell Differentiation , Physiology , Demyelinating Diseases , Lysophosphatidylcholines , Toxicity , Mice, Inbred C57BL , Nerve Tissue Proteins , Metabolism , Oligodendrocyte Precursor Cells , Cell Biology , Metabolism , Oligodendroglia , Cell Biology , Metabolism , Remyelination , Physiology , Transcription Factors , Metabolism
3.
The Korean Journal of Physiology and Pharmacology ; : 399-408, 2018.
Article in English | WPRIM | ID: wpr-727579

ABSTRACT

A lipidomic study on extensive plasma lipids in bacterial peritonitis (cecal ligation and puncture, CLP)-induced sepsis in mice was done at 24 h post-CLP. The effects of administration of lysophosphatidylcholine (LPC) and lysophosphatidic acid (LPA), compounds known to have beneficial effects in CLP, on the sepsis-induced plasma lipid changes were also examined. Among the 147 plasma lipid species from 13 lipid subgroups (fatty acid [FA], LPA, LPC, lysophosphatidylethanolamine [LPE], phosphatidic acid [PA], phosphatidylcholine [PC], phosphatidylethanolamine [PE], phosphatidylinositol [PI], monoacylglyceride [MG], diacylglyceride [DG], triacylglyceride [TG], sphingomyelin [SM], and ceramide [Cer]) analyzed in this study, 40 and 70 species were increased, and decreased, respectively, in the CLP mice. Treatments with LPC and LPA affected 14 species from 7 subgroups, and 25 species from 9 subgroups, respectively. These results could contribute to finding the much needed reliable biomarkers of sepsis.


Subject(s)
Animals , Mice , Biomarkers , Ligation , Lysophosphatidylcholines , Peritonitis , Phosphatidic Acids , Phosphatidylcholines , Phosphatidylinositols , Plasma , Punctures , Sepsis
4.
Cancer Research and Treatment ; : 883-893, 2018.
Article in English | WPRIM | ID: wpr-715969

ABSTRACT

PURPOSE: We sought to develop a matrix assisted laser desorption ionization-time of flight (MALDI-TOF)-based, ovarian cancer (OVC), low-mass-ion discriminant equation (LOME) and to evaluate a possible supportive role for triple-TOF mass analysis in identifying metabolic biomarkers. MATERIALS AND METHODS: A total of 114 serum samples from patients with OVC and benign ovarian tumors were subjected to MALDI-TOF analysis and a total of 137 serum samples from healthy female individuals and patients with OVC, colorectal cancer, hepatobiliary cancer, and pancreatic cancer were subjected to triple-TOF analysis. An OVC LOME was constructed by reference to the peak intensity ratios of discriminatory low-mass ion (LMI) pairs. Triple-TOF analysiswas used to select and identify metabolic biomarkers for OVC screening. RESULTS: Three OVC LOMEs were finally constructed using discriminatory LMI pairs (137.1690 and 84.4119 m/z; 496.5022 and 709.7642 m/z; and 524.5614 and 709.7642 m/z); all afforded accuracies of > 90%. The LMIs at 496.5022 m/z and 524.5614 m/z were those of lysophosphatidylcholine (LPC) 16:0 and LPC 18:0. Triple-TOF analysis selected seven discriminative LMIs; each LMI had a specificity > 90%. Of the seven LMIs, fourwith a 137.0455 m/z ion atretention times of 2.04-3.14 minuteswere upregulated in sera from OVC patients; the ion was identified as that derived from hypoxanthine. CONCLUSION: MALDI-TOF–based OVC LOMEs combined with triple-TOF–based OVC metabolic biomarkers allow reliable OVC screening; the techniques are mutually complementary both quantitatively and qualitatively.


Subject(s)
Female , Humans , Biomarkers , Colorectal Neoplasms , Hypoxanthine , Lysophosphatidylcholines , Mass Screening , Mass Spectrometry , Ovarian Neoplasms , Pancreatic Neoplasms , Sensitivity and Specificity
5.
Chinese Journal of Contemporary Pediatrics ; (12): 241-244, 2015.
Article in Chinese | WPRIM | ID: wpr-346174

ABSTRACT

<p><b>OBJECTIVE</b>To study the association of ORMDL3 single nucleotide polymorphisms (SNP) with lysophosphatidylcholine (LysoPC) and apolipoprotein B (apoB) levels.</p><p><b>METHODS</b>A total of 300 children diagnosed with bronchial asthma between January 2010 and December 2012 were selected for the asthma group, and 298 children diagnosed with upper respiratory tract infection in the same period were selected for the control group. Serum LysoPC and apoB levels were measured using enzyme-linked immunosorbent assay. Genotype analysis was performed using the TaqMan probe.</p><p><b>RESULTS</b>LysoPC and apoB levels were significantly higher in the asthma group than in the control group (P<0.01). Among children with various genotypes of ORMDL3 gene at locus rs12603332, the asthma group had significantly higher LysoPC and apoB levels than the control group (P<0.01). Among the children with asthma, those with CC genotype had significantly higher LysoPC and apoB levels than those with CT and TT genotypes (P<0.01).</p><p><b>CONCLUSIONS</b>LysoPC and apoB may intervene in the pathological process of asthma. Pro-inflammatory gene ORMDL3 SNP rs12603332 may be associated with high LysoPC and apoB levels, which leads to the occurrence of childhood asthma.</p>


Subject(s)
Child , Child, Preschool , Female , Humans , Male , Apolipoproteins B , Blood , Asthma , Blood , Genetics , Lysophosphatidylcholines , Blood , Membrane Proteins , Genetics , Polymorphism, Single Nucleotide
6.
Acta Pharmaceutica Sinica ; (12): 368-373, 2014.
Article in Chinese | WPRIM | ID: wpr-245075

ABSTRACT

A UPLC-MS/MS method based on metabonomic skills was developed to study the serum metabolic changes of rats after acute liver injury induced by CCl4 and to evaluate the action mechanism of Si-Ni-San. The integrated data were exported for principal components analysis (PCA) by using SIMCA-P software, in order to find the potential biomarkers. It showed that clear separation of healthy control group, model group, silymarin group, Si-Ni-San group was achieved by using the PCA method. Nine significantly changed metabolites were identified as potential biomarkers of acute liver injury. Compared with the health control group, the model group rats showed higher levels of phenylalanine, tryptophan and GCDCA together with lower levels of LPC 16 : 0, LPC 18 : 0, LPC 18 : 1, LPC 16 : 1, LPC 20 : 4 and LPC 22 : 6. These changes of serum metabolites suggested that the disorders of amino acid metabolism, lipid metabolism, bile acid biosynthesis and anti-oxidative damage were related to acute liver injury induced by CCl4. Si-Ni-San might have the anti-liver injury effect on all these four metabolic pathways.


Subject(s)
Animals , Male , Rats , Carbon Tetrachloride Poisoning , Chemical and Drug Induced Liver Injury , Blood , Chromatography, High Pressure Liquid , Methods , Drugs, Chinese Herbal , Pharmacology , Glycodeoxycholic Acid , Blood , Lysophosphatidylcholines , Blood , Metabolomics , Phenylalanine , Blood , Plants, Medicinal , Chemistry , Principal Component Analysis , Random Allocation , Rats, Sprague-Dawley , Tandem Mass Spectrometry , Tryptophan , Blood
7.
Journal of Korean Diabetes ; : 65-70, 2014.
Article in Korean | WPRIM | ID: wpr-726903

ABSTRACT

Non-alcoholic fatty liver disease (NAFLD) is emerging as a world-wide health problem and is currently recognized as a hepatic manifestation of metabolic syndrome. It is an umbrella term to describe a wide range of diseases from simple steatosis to non-alcoholic hepatosteatosis (NASH) and NSAH-related liver cirrhosis. NAFLD is mainly associated with insulin resistance which allows increased free fatty acid (FFA) flux to the liver by increasing lipolysis from adipose tissue, triggering macrophage/immune activation, decreasing skeletal muscle glucose uptake, and increasing de novo lipogenesis. Increased FFA pool in the liver, in turn, increases lipotoxic intermediates, such as ceramides, diacylglycerols, and lysophosphatidylcholines, which are responsible for mitochondrial dysfunction and endoplasmic reticulum stress, resulting in inflammation of the liver. When inflammation is severe enough to affect stellate cells, hepatic fibrosis can be induced.


Subject(s)
Adipose Tissue , Ceramides , Diglycerides , Endoplasmic Reticulum Stress , Fatty Liver , Fibrosis , Glucose , Hepatic Stellate Cells , Inflammation , Insulin Resistance , Lipogenesis , Lipolysis , Liver , Liver Cirrhosis , Lysophosphatidylcholines , Muscle, Skeletal , Obesity
8.
Allergy, Asthma & Immunology Research ; : 61-65, 2014.
Article in English | WPRIM | ID: wpr-164119

ABSTRACT

PURPOSE: Asthma is a chronic inflammatory disease of the airways, and is associated with upregulation of phospholipase A2 (PLA2), the enzyme that hydrolyzes phosphatidylcholine, producing lysophosphatidylcholine (LPC) and free fatty acids. LPC is a lipid mediator with known pro-inflammatory and pro-atherogenic properties, and is believed to be a critical factor in cardiovascular diseases. We postulate that asthmatic subjects have an elevated content of LPC in the lung lining fluids. METHODS: Eight non-asthmatic controls and seven asthmatic subjects were recruited for broncho-alveolar lavage fluids (BALF) collection for analysis of LPC by high performance liquid chromatography-tandem mass spectrometry. RESULTS: LPC16:0 and LPC18:0 were significantly elevated in the BALF of asthmatics with impaired lung function characteristic of moderate asthma, but not mild asthma. The increased LPC content in BALF was accompanied by increased PLA2 activity. Furthermore, qRT-PCR analysis of the BALF cell fraction indicated increased secretory PLA2-X (sPLA2-X). CONCLUSIONS: The increased LPC content in the lung lining fluids is a potential critical lipid mediator in the initiation and/or progression of airway epithelial injury in asthma.


Subject(s)
Asthma , Cardiovascular Diseases , Fatty Acids, Nonesterified , Lung , Lysophosphatidylcholines , Mass Spectrometry , Phosphatidylcholines , Phospholipases A2 , Therapeutic Irrigation , Up-Regulation
9.
Allergy, Asthma & Immunology Research ; : 66-74, 2014.
Article in English | WPRIM | ID: wpr-164118

ABSTRACT

PURPOSE: In human subjects and animal models with acute and chronic lung injury, the bioactive lysophosphatidylcholine (LPC) is elevated in lung lining fluids. The increased LPC can promote an inflammatory microenvironment resulting in lung injury. Furthermore, pathological lung conditions are associated with upregulated phospholipase A2 (PLA2), the predominant enzyme producing LPC in tissues by hydrolysis of phosphatidylcholine. However, the lung cell populations responsible for increases of LPC have yet to be systematically characterized. The goal was to investigate the LPC generation by bronchial epithelial cells in response to pathological mediators and determine the major LPC species produced. METHODS: Primary human bronchial epithelial cells (NHBE) were challenged by vascular endothelial growth factor (VEGF) for 1 or 6 h, and condition medium and cells collected for quantification of predominant LPC species by high performance liquid chromatography-tandem mass spectrometry (LC-MS-MS). The cells were analyzed by quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) for PLA2. The direct effects of LPC in inducing inflammatory activities on NHBE were assessed by transepithelial resistance as well as expression of interleukin-8 (IL-8) and matrix metalloproteinase-1 (MMP-1). RESULTS: VEGF stimulation of NHBE for 1 or 6 h, significantly increased concentrations of LPC16:0, LPC18:0, and LPC18:1 in condition medium compared to control. The sPLA2-selective inhibitor (oleyloxyethyl phosphorylcholine) inhibited the VEGF-induced release of LPC16:0 and LPC18:1 and PLA2 activity. In contrast, NHBE stimulated with TNF did not induce LPC release. VEGF did not increase mRNA of PLA2 subtypes sPLA2-X, sPLA2-XIIa, cPLA2-IVa, and iPLA2-VI. Exogenous LPC treatment increased expression of IL-8 and MMP-1, and reduced the transepithelial resistance in NHBE. CONCLUSIONS: Our findings indicate that VEGF-stimulated bronchial epithelial cells are a key source of extracellular LPCs, which can function as an autocrine mediator with potential to induce airway epithelial inflammatory injury.


Subject(s)
Humans , Epithelial Cells , Group X Phospholipases A2 , Hydrolysis , Interleukin-8 , Lung , Lung Injury , Lysophosphatidylcholines , Mass Spectrometry , Matrix Metalloproteinase 1 , Models, Animal , Phosphatidylcholines , Phospholipases A2 , Reverse Transcriptase Polymerase Chain Reaction , RNA, Messenger , Vascular Endothelial Growth Factor A
10.
Rio de Janeiro; s.n; 2013. xii,60 p. ilus, graf.
Thesis in Portuguese | LILACS | ID: lil-736929

ABSTRACT

A esquistossomose mansônica, endemia parasitária típica das Américas, Ásia e África, é causada pela infecção de trematódeos da espécie Schistosoma mansoni. A infecção por este trematódeo induz no hospedeiro a formação de granulomas e uma potente polarização da resposta imune para o tipo Th2. Os helmintos podem ser apresentados em diferentes estágios do seu ciclo de vida dentro de um hospedeiro humano, e cada estágio do desenvolvimento pode apresentar diferentes combinações de glicoconjugados reconhecidos de diferentes formas pelo hospedeiro. Estudos recentes do nosso grupo demonstraram que lipídeos de S. mansoni, incluindo a lisofosfatidilcolina, possuem atividade imunomoduladora. No presente trabalho investigamos o papel imunomodulador dos lipídeos de Schistosoma mansoni, em especial a LPC, na ativação de macrófagos e os possíveis mecanismos envolvidos neste processoDemonstramos que a lisofosfatidilcolina (LPC) esquistossomal estimula a formação de corpúsculos lipídicos de forma dependente de TLR2 em macrófagos peritoneais após 24 h de estimulação in vitro, ao mesmo tempo em que induz aumento na expressão desse receptor. Entretanto, a LPC não induz aumento na produção de óxido nítrico (NO) em macrófagos, e em altas concentrações foi capaz de inibir a indução de NO gerada por LPS. Além disso, a LPC esquistossomal induziu em macrófagos um perfil de ativação do tipo M2, observado pelo aumento da expressão de arginase-1 e produção de IL-10 e PGE2. A participação do receptor nuclear PPARgama na resposta de macrófagos frente a LPC esquistossomal foi investigada. Através de diferentes técnicas demonstramos que a LPC induz aumento da expressão de PPARgama em macrófagos...


Schistosomiasis mansoni, an endemic parasitic disease typical of the Americas, Asia andAfrica, is caused by infection of trematode species of Schistosoma mansoni. The trematodeinfection in the host induces the formation of granulomas and potent polarization of Th2-typeimmune response. Helminths can be presented in different stages of their life cycle in ahuman host, and each stage of development can have different combinations of differentforms of glycoconjugates recognized by the host. Recent studies from our group demonstratedthat lipids of S. mansoni, including lysophosphatidylcholine, have immunomodulatoryactivity. In the present work, we investigated the immunomodulatory role of lipids ofSchistosoma mansoni in the activation of macrophages and the possible mechanisms involvedin this process. We demonstrated that lysophosphatidylcholine (LPC) from S. mansonistimulates the formation of lipid bodies in peritoneal macrophages in a TLR2 dependentmanner after 24 h of in vitro stimulation, while it induces increased expression of thisreceptor. However, LPC failed to induce increased production of nitric oxide (NO) inmacrophages and in high concentrations was able to inhibit the induction of NO generated byLPS. Moreover, the schistosomal-derived LPC induced in macrophages an profile of M2activation observed by increased expression of arginase-1, and production of IL-10 andPGE2. Participation of the nuclear receptor PPAR gamma in macrophage response againstLPC was investigated. Through various techniques we demonstrated that the LPC inducesincreased expression of PPAR gamma in macrophages...


Subject(s)
Humans , Schistosomiasis mansoni/parasitology , Schistosomiasis mansoni/transmission , Lysophosphatidylcholines , Macrophages , Blotting, Western
11.
Chinese Journal of Pediatrics ; (12): 825-830, 2013.
Article in Chinese | WPRIM | ID: wpr-275614

ABSTRACT

<p><b>OBJECTIVE</b>To examine the effects of niacin on lysophosphatidylcholine (LPC)-induced intercellular adhesion molecule-1 (ICAM-1), and gained insight to the mechanisms.</p><p><b>METHOD</b>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.</p><p><b>RESULT</b>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).</p><p><b>CONCLUSION</b>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.</p>


Subject(s)
Humans , Atherosclerosis , Metabolism , Cell Adhesion , Cells, Cultured , Enzyme Inhibitors , Pharmacology , Gene Expression Regulation , Human Umbilical Vein Endothelial Cells , Metabolism , Imidazoles , Pharmacology , Intercellular Adhesion Molecule-1 , Genetics , Metabolism , Lysophosphatidylcholines , Pharmacology , Niacin , Pharmacology , Pyridines , Pharmacology , RNA, Messenger , Genetics , Metabolism , Real-Time Polymerase Chain Reaction , Signal Transduction , p38 Mitogen-Activated Protein Kinases , Metabolism
12.
Journal of Korean Medical Science ; : 268-273, 2013.
Article in English | WPRIM | ID: wpr-25348

ABSTRACT

Although oxidized low-density lipoprotein (LDL) and lysophosphatidylcholine (LPC) have been proposed as important mediators of the atherosclerosis, the long-term contribution to the risk of cardiovascular disease (CVD) in hemodialysis patients has not been evaluated. This study investigated the relation between oxidized LDL and LPC levels with long term risk of CVD. Plasma oxidized LDL and LPC levels were determined in 69 Korean hemodialysis patients as a prospective observational study for 5 yr. During the observation period, 18 cardiovascular events (26.1%) occurred including 6 deaths among the hemodialysis patients. The low LPC level group ( 254 microM/L) (P = 0.01). However, serum levels of oxidized LDL were not significantly different between groups with and without CVD. In adjusted Cox analysis, previous CVD, (hazard ratio [HR], 5.68; 95% confidence interval [CI], 1.94-16.63, P = 0.002) and low LPC level (HR, 3.45; 95% CI, 1.04-11.42, P = 0.04) were significant independent risk factors for development of CVD. It is suggested that low LPC, but not oxidized LDL, is associated with increased risk of CVD among a group of Korean hemodialysis patients.


Subject(s)
Adult , Aged , Female , Humans , Male , Middle Aged , Asian People , Cardiovascular Diseases/diagnosis , Case-Control Studies , Follow-Up Studies , Kidney Failure, Chronic/blood , Lipoproteins, LDL/blood , Lysophosphatidylcholines/blood , Proportional Hazards Models , Prospective Studies , Renal Dialysis , Republic of Korea , Risk Factors
13.
Biomolecules & Therapeutics ; : 411-422, 2013.
Article in English | WPRIM | ID: wpr-202599

ABSTRACT

G-protein-coupled receptors (GPCR) are the largest superfamily of receptors responsible for signaling between cells and tissues, and because they play important physiological roles in homeostasis, they are major drug targets. New technologies have been developed for the identification of new ligands, new GPCR functions, and for drug discovery purposes. In particular, intercellular lipid mediators, such as, lysophosphatidic acid and sphingosine 1-phosphate have attracted much attention for drug discovery and this has resulted in the development of fingolimod (FTY-720) and AM095. The discovery of new intercellular lipid mediators and their GPCRs are discussed from the perspective of drug development. Lipid GPCRs for lysophospholipids, including lysophosphatidylserine, lysophosphatidylinositol, lysophosphatidylcholine, free fatty acids, fatty acid derivatives, and other lipid mediators are reviewed.


Subject(s)
Drug Discovery , Fatty Acids, Nonesterified , Homeostasis , Ligands , Lysophosphatidylcholines , Lysophospholipids , Receptors, G-Protein-Coupled , Sphingosine , Fingolimod Hydrochloride
14.
Journal of Korean Medical Science ; : 803-810, 2012.
Article in English | WPRIM | ID: wpr-210924

ABSTRACT

The balance between tissue-type plasminogen activator (t-PA) and plasminogen activator inhibitor type 1 (PAI-1) regulates fibrinolysis. PAI-1 expression increases in atherosclerotic arteries and vascular smooth muscle cells (VSMCs) are one of major constituents of atheroma. We investigated the impact of lysophosphatidylcholine (lysoPC), an active component of oxidized low-density lipoprotein, on the plasminogen activator system of the rat VSMCs. The lysoPC stimulated the protein and gene expressions of PAI-1 but did not affect the protein expression of t-PA. Fibrin overlay zymography revealed that lysoPC increased the activity of PAI-1 in the conditioned media, while concurrently decreasing that of free t-PA. Vitamin E inhibited the lysoPC-induced PAI-1 expression. Further, lysoPC increased the intracellular reactive oxygen species (ROS) formation. Caffeic acid phenethyl ester, an inhibitor of NF-kappaB, blocked this lysoPC effect. Indeed, lysoPC induced the NF-kappaB-mediated transcriptional activity as measured by luciferase reporter assay. In addition, genistein, an inhibitor of protein-tyrosine kinase (PTK), diminished the lysoPC effect, while 7,12-dimethylbenz[a]anthracene, a stimulator of PTK, stimulated PAI-1 production. In conclusion, lysoPC does not affect t-PA expression but induces PAI-1 expression in the VSMC by mediating NF-kappaB and the genistein-sensitive PTK signaling pathways via oxidative stress. Importantly, lysoPC stimulates the enzyme activity of PAI-1 and suppresses that of t-PA.


Subject(s)
Animals , Rats , Benz(a)Anthracenes/pharmacology , Caffeic Acids/pharmacology , Cells, Cultured , Genistein/pharmacology , Lipoproteins, LDL/metabolism , Lysophosphatidylcholines/pharmacology , Muscle, Smooth, Vascular/cytology , NF-kappa B/antagonists & inhibitors , Oxidative Stress/drug effects , Phenylethyl Alcohol/analogs & derivatives , Plasminogen Activator Inhibitor 1/agonists , Protein Kinase Inhibitors/pharmacology , Protein-Tyrosine Kinases/antagonists & inhibitors , Rats, Sprague-Dawley , Reactive Oxygen Species/metabolism , Signal Transduction/drug effects , Tissue Plasminogen Activator/metabolism , Transcription, Genetic/drug effects , Up-Regulation/drug effects , Vitamin E/pharmacology
15.
Journal of Korean Society for Clinical Pharmacology and Therapeutics ; : 175-181, 2012.
Article in Korean | WPRIM | ID: wpr-138499

ABSTRACT

BACKGROUND: Metformin is an effective oral antihyperglycaemic agent for type 2 diabetes mellitus, with a variety of metabolic effects. In addition to controlling blood glucose level, it has been appeared to decrease the long-period complications of diabetes, including macrovascular disease. Few reports have addressed the metabolite profiling of metformin. The study was to evaluate if targeted metabolic profiling approach is sensitive enough to predict the therapeutic effects of metformin after a single oral dose. METHODS: A randomized, open-label, single-dose study was conducted in twenty eight healthy Korean male volunteers. To determine the concentrations of endogenous metabolites in their pre-dose and post-dose plasma samples, blood samples were collected before and at 2 and 6 h after a single oral dose of 500 mg metformin. Both Modular P/Modular D analyzer and ultra-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS)-based metabolic profiling was performed. RESULTS: We quantified pre-dose and post-dose creatinine, blood urea nitrogen (BUN), lactic acid, 7 amino acids (lysine, glutamic acid, alanine, valine, leucine, phenylalanine, tryptophan), and 5 lysophosphatidylcholines (14:0, 16:0, 17:0, 18:0, and 18:1) using autoanalyser and UPLC-MS/MS. The postdose levels of alanine, lactic acid, glutamic acid, lysine, valine, leucine, phenylalanine, tryptophan, and lysoPC (18:1) were slightly decreased with statistical significance, but there is no clinical significance. CONCLUSION: In order to explore the potential endogenous metabolites associated with the therapeutic effects of metformin, further study including non-targeted (global) metabolite profiling is needed.


Subject(s)
Humans , Male , Alanine , Amino Acids , Blood Glucose , Blood Urea Nitrogen , Chromatography, Liquid , Creatinine , Diabetes Mellitus, Type 2 , Glutamic Acid , Lactic Acid , Leucine , Lysine , Lysophosphatidylcholines , Metformin , Phenylalanine , Plasma , Tandem Mass Spectrometry , Tryptophan , Valine
16.
Journal of Korean Society for Clinical Pharmacology and Therapeutics ; : 175-181, 2012.
Article in Korean | WPRIM | ID: wpr-138498

ABSTRACT

BACKGROUND: Metformin is an effective oral antihyperglycaemic agent for type 2 diabetes mellitus, with a variety of metabolic effects. In addition to controlling blood glucose level, it has been appeared to decrease the long-period complications of diabetes, including macrovascular disease. Few reports have addressed the metabolite profiling of metformin. The study was to evaluate if targeted metabolic profiling approach is sensitive enough to predict the therapeutic effects of metformin after a single oral dose. METHODS: A randomized, open-label, single-dose study was conducted in twenty eight healthy Korean male volunteers. To determine the concentrations of endogenous metabolites in their pre-dose and post-dose plasma samples, blood samples were collected before and at 2 and 6 h after a single oral dose of 500 mg metformin. Both Modular P/Modular D analyzer and ultra-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS)-based metabolic profiling was performed. RESULTS: We quantified pre-dose and post-dose creatinine, blood urea nitrogen (BUN), lactic acid, 7 amino acids (lysine, glutamic acid, alanine, valine, leucine, phenylalanine, tryptophan), and 5 lysophosphatidylcholines (14:0, 16:0, 17:0, 18:0, and 18:1) using autoanalyser and UPLC-MS/MS. The postdose levels of alanine, lactic acid, glutamic acid, lysine, valine, leucine, phenylalanine, tryptophan, and lysoPC (18:1) were slightly decreased with statistical significance, but there is no clinical significance. CONCLUSION: In order to explore the potential endogenous metabolites associated with the therapeutic effects of metformin, further study including non-targeted (global) metabolite profiling is needed.


Subject(s)
Humans , Male , Alanine , Amino Acids , Blood Glucose , Blood Urea Nitrogen , Chromatography, Liquid , Creatinine , Diabetes Mellitus, Type 2 , Glutamic Acid , Lactic Acid , Leucine , Lysine , Lysophosphatidylcholines , Metformin , Phenylalanine , Plasma , Tandem Mass Spectrometry , Tryptophan , Valine
17.
The Journal of Korean Society of Menopause ; : 139-146, 2012.
Article in Korean | WPRIM | ID: wpr-95785

ABSTRACT

OBJECTIVES: To investigate the cytotoxic effects of lysophosphatidylcholine (lysoPC), an active component of oxidized low-density lipoproteins (LDL), on vascular smooth muscle cells (VSMCs). METHODS: VSMCs were derived from rat aorta. Cell death was assessed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide (MTT) assay, lactic dehydrogenase (LDH) assay, and DNA fragmentation assay. Apoptosis was quantified by propidium iodide staining and fluorescent activated cell sorting (FACS) analysis, and intracellular free radical production was determined using 2',7'-dichlorofluorescin diacetate (DCF-DA). In addition, the changes in caspases, bcl-2 and bax proteins were evaluated by western blot analysis. RESULTS: LysoPC over 25 microM induced more than 50% of the cell death at 10 hours on MTT assay with no change in the level of LDH. The DNA ladder pattern showed that cell death induced by lysoPC was caused by apoptosis, which was associated with increased free radical production. Vitamin E, a potent antioxidant and caffeic acid phenylethyl ester (CAPE), an inhibitor of nuclear factor-kappaB (NF-kappaB), blocked apoptosis. The casepase-3 precursor decreased and the active form of caspase-8 increased. Total bcl-2 and bax proteins did not change with lysoPC treatment, but translocation of bax from cytosole to the mitochondria membrane was observed. CONCLUSION: LysoPC induces apoptosis in VSMCs via an oxidant mechanism, dependent on NF-kappaB.


Subject(s)
Animals , Rats , Aorta , Apoptosis , Atherosclerosis , bcl-2-Associated X Protein , Blotting, Western , Caffeic Acids , Caspase 8 , Caspases , Cell Death , Cytosol , DNA , DNA Fragmentation , Fluoresceins , Lipoproteins, LDL , Lysophosphatidylcholines , Membranes , Mitochondria , Muscle, Smooth, Vascular , NF-kappa B , Oxidoreductases , Propidium , Vitamin E , Vitamins
18.
Chinese Journal of Pediatrics ; (12): 139-145, 2011.
Article in Chinese | WPRIM | ID: wpr-286157

ABSTRACT

<p><b>OBJECTIVE</b>To investigate the potential preventive effects of metformin on non-alcoholic fatty liver disease (NAFLD) and roles of phospholipase A2/lysophosphatidylcholine pathway in hepatocyte lipoapoptosis in a rat NAFLD model induced by high-fat diet.</p><p><b>METHOD</b>Male SD rats (n = 36) were randomly divided into three groups with 12 rats in each and treated with different diet and drugs: group I: ordinary diet, group II: high-fat diet, group III: high-fat diet and metformin. Ten weeks later, the rats were sacrificed and their body weight and liver weight were obtained, serum lipid metabolic indexes, insulin resistance indexes and secretory phospholipase A2 (sPLA2), lysophosphatidylcholine (LPC) levels and other parameters were measured. Phospholipase A2 mRNA expression levels were measured by quantitative reverse transcription-polymerase chain reaction (RT-PCR). In addition, the histological changes of liver tissue were analyzed.</p><p><b>RESULT</b>Compared to ordinary diet group, the rat's liver weight (g) (16.92 ± 2.49 vs. 12.16 ± 0.82), hepatic exponent (0.034 ± 0.004 vs. 0.026 ± 0.002), serum alanine aminotransferase (U/L) (45.43 ± 9.73 vs. 29.42 ± 6.73), triglyceride (mmol/L) (1.22 ± 0.24 vs. 0.85 ± 0.19), cholesterol (mmol/L) (2.00 ± 0.37 vs. 1.49 ± 0.33), lipoprotein(a) (mmol/L) (743.86 ± 32.19 vs. 648.42 ± 78.87), low-density lipoprotein (mmol/L) (1.31 ± 0.35 vs. 0.65 ± 0.22), insulin (mmol/L) (22.16 ± 5.16 vs. 16.86 ± 5.35), insulin resistance index(5.10 ± 1.45 vs. 3.59 ± 0.99), free fatty acid (mEq/L) (0.57 ± 0.10 vs. 0.35 ± 0.07), sPLA2 [µmol/(min·ml)] (0.130 ± 0.016 vs. 0.098 ± 0.024), lysophosphatidylcholine (µmol/L) (707.26 ± 92.48 vs. 508.87 ± 96.50), leptin (pg/ml (80.08 ± 17.73 vs. 65.11 ± 14.09), liver triglyceride (mg/g) (13.57 ± 0.65 vs. 12.03 ± 1.14), cholesterol (mg/g) (2.19 ± 0.15 vs. 1.94 ± 0.12) (P < 0.05) were significantly increased in high-fat diet group. Moreover, degree of hepatic steatosis was significantly higher and sPLA2 mRNA expression was also significantly increased. Secondly, in comparison with high-fat diet group, early metformin treatment significantly reduced the rat's body weight (g) (394.40 ± 33.10 vs. 491.86 ± 26.45), liver weight (g) (13.24 ± 1.16 vs. 16.92 ± 2.49), serum alanine aminotransferase (U/L) (30.40 ± 4.50 vs. 45.43 ± 9.73), triglyceride (mmol/L) (0.75 ± 0.19 vs. 1.22 ± 0.24), cholesterol (mmol/L) (1.61 ± 0.38 vs. 2.00 ± 0.37), insulin (mmol/L) (16.96 ± 5.60 vs. 22.16 ± 5.16), insulin resistance index (3.75 ± 1.41 vs. 5.10 ± 1.45), sPLA2 [µmol/(min·ml)] (0.101 ± 0.009 vs. 0.130 ± 0.016), lysophosphatidylcholine (µmol/L) (549.92 ± 90.78 vs. 707.26 ± 92.48), liver triglyceride (mg/g) (11.23 ± 1.70 vs. 13.57 ± 0.65), cholesterol (mg/g) (1.97 ± 0.20 vs. 2.19 ± 0.15) (P < 0.05). Moreover, degree of hepatic steatosis was significantly lower and sPLA2 mRNA expression was also significantly decreased by metformin. Thirdly, when compared to ordinary diet group, metformin could also significantly increase hepatic exponent (0.034 ± 0.004 vs. 0.026 ± 0.002) and low-density lipoprotein level (mmol/L) (0.96 ± 0.34 vs. 0.65 ± 0.22) (P < 0.05). However, it had no impact on hepatic steatosis and sPLA2 expression (P > 0.05).</p><p><b>CONCLUSION</b>It was indicated that metformin has potent effects on improving lipid metabolism and insulin resistance in high-fat diet induced non-alcoholic fatty liver disease rat model. The liver protective mechanisms of metformin in non-alcoholic fatty liver disease may be contributed to down-regulation of secretory phospholipase A2 mRNA expression, decrease in serum secretory phospholipase A2, lysophosphatidylcholine, lower inflammatory response and protect mitochondrial function.</p>


Subject(s)
Animals , Male , Rats , Apoptosis , Disease Models, Animal , Down-Regulation , Fatty Liver , Drug Therapy , Pathology , Insulin Resistance , Lipid Metabolism , Lysophosphatidylcholines , Metabolism , Metformin , Pharmacology , Non-alcoholic Fatty Liver Disease , Phospholipases A2 , Metabolism , Rats, Sprague-Dawley , Signal Transduction
19.
Journal of Southern Medical University ; (12): 578-581, 2011.
Article in Chinese | WPRIM | ID: wpr-307881

ABSTRACT

<p><b>OBJECTIVE</b>To investigate the effect of fluvastatin on lysophosphatidylcholine (LPC)-induced ventricular arrhythmias and its mechanism.</p><p><b>METHODS</b>Twenty male SD rats were randomly allocated into two equal groups, namely LPC treatment group and fluvastatin pretreatment group. Langendorff apparatus was used for cardiac perfusion ex vivo with 5 µmol/L LPC for 5 min followed by washing for 30 min in LPC treatment group, and in fluvastatin pretreatment group, a 30-min perfusion with 10 µmol/L fluvastatin was administered before LPC perfusion. The LPC-induced nonselective cation current (I(NSC)) in the ventricular myocytes was recorded using the whole-cell voltage-clamp method.</p><p><b>RESULTS</b>Fluvastatin significantly inhibited LPC-induced ventricular tachyarrhythmia/fibrillation and I(NSC). The small G-protein Rho inhibitor (C3) and Rho-kinase inhibitor (Y-27632) in the pipette solution also suppressed LPC-induced I(NSC).</p><p><b>CONCLUSION</b>Fluvastatin offers cardiac protection against LPC by inhibiting LPC-induced I(NSC). LPC induces fatal arrhythmia via a Rho/Rho-kinase-mediated pathway.</p>


Subject(s)
Animals , Male , Rats , Arrhythmias, Cardiac , Metabolism , Drug Antagonism , Fatty Acids, Monounsaturated , Pharmacology , Indoles , Pharmacology , Ion Channels , Lysophosphatidylcholines , Myocytes, Cardiac , Metabolism , Rats, Sprague-Dawley , rho-Associated Kinases , Metabolism
20.
Acta Physiologica Sinica ; (6): 601-610, 2011.
Article in Chinese | WPRIM | ID: wpr-335949

ABSTRACT

Autotaxin (ATX), a member of nucleotide pyrophosphatase/phosphodiesterase (NPP) family, is also named as phosphodiesterase Iα (PD-Iα) or NPP2. ATX is the unique member among the NPPs that can function as a lysophospholipase D (lysoPLD), converting lysophosphatidylcholine into lysophosphatidic acid (LPA). LPA acts on specific G-protein-coupled receptors to elicit a wide range of cellular response, including cell proliferation, cell migration and cell contraction, etc. As the major LPA-producing phospholipase, many ATX's features and functions are dependent on the production of LPA. ATX and LPA together form the ATX-LPA functional axis. The present review summarizes the current progress in function and biological activities of ATX-LPA axis.


Subject(s)
Animals , Humans , Cell Movement , Physiology , Cell Proliferation , Lysophosphatidylcholines , Metabolism , Lysophospholipids , Metabolism , Physiology , Phospholipases , Metabolism , Phosphoric Diester Hydrolases , Metabolism , Physiology , Receptors, G-Protein-Coupled , Physiology
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