Lysophosphatidic acid (LPA) and sphingosine-1-phosphate (S1P) are members of the phospholipid growth factor family. A major limitation in field to date has been a lack receptor subtype-specific agonists antagonists. Here, we report that dioctylglycerol pyrophosphate dioctylphosphatidic selective antagonists LPA(1) LPA(3) receptors, but prefer by an order magnitude. Neither molecule had agonistic or antagonistic effect on LPA(2) receptor. Consistent with this subtype selectivity, inhibited...

A more complete understanding of the physiological and pathological role lysophosphatidic acid (LPA) requires receptor subtype-specific agonists antagonists. Here, we report synthesis pharmacological characterization fatty alcohol phosphates (FAP) containing saturated hydrocarbon chains from 4 to 22 carbons in length. Selection FAP as lead structure was based on computational modeling a minimal that satisfies two-point pharmacophore developed earlier for interaction LPA with its receptors....

Abstract Colorectal cancer (CRC) is a major cancer, and its precise diagnosis especially important for the development of effective therapeutics. In series metabolome analyses, levels very long chain fatty acids (VLCFA) were shown to be elevated in CRC tissues, although endogenous form VLCFA has not been fully elucidated. this study we analyzed amount nonesterified acids, acyl-CoA species, phospholipids neutral lipids such as cholesterylesters using liquid-chromatography–mass spectrometry....

Sphingolipids, including sphingomyelin (SM) and glucosylceramide (GlcCer), are generated by the addition of a polar head group to ceramide (Cer). Sphingomyelin synthase 1 (SMS1) (GCS) key enzymes that catalyze conversion Cer SM GlcCer, respectively. GlcCer synthesis has been postulated occur mainly in

Abstract Morphine is the drug of choice to treat intractable pain, although prolonged administration often causes undesirable side‐effects including analgesic tolerance. It speculated that voltage‐dependent Ca 2+ channels (VDCCs) play a key role in morphine analgesia and To examine subtype specificity VDCCs these processes, we analysed mice lacking N‐type (Ca v 2.2) or R‐type 2.3) VDCCs. Systemic exposure warm water swim‐stress, known induce endogenous opioid release, resulted greater 2.3...

Lysophosphatidic acid (LPA) is a ligand for three endothelial differentiation gene family G protein-coupled receptors, LPA(1-3). We performed computational modeling-guided mutagenesis of conserved residues in transmembrane domains 3, 4, 5, and 7 LPA(1-3) predicted to interact with the glycerophosphate motif LPA C18:1. The mutants were expressed RH7777 cells, efficacy (E(max)) potency (EC(50)) LPA-elicited Ca(2+) transients measured. Mutation alanine R3.28 universally decreased both...

Although considerable evidence indicates neuronal Ca channels play significant roles in pain perception, their possible importance hypersensitization after acute inflammation has not been investigated.Using carrageenan for inducing hypersensitization, the authors investigated analgesic effects of intrathecally administered N- and P/Q-type channel blockers, omega-conotoxin GVIA omega-agatoxin IVA, respectively, also examined level N-type expression.Acute inflammation, produced by injection a...

LPPs (lipid phosphate phosphatases) are members of a family enzymes that catalyse the dephosphorylation lipid phosphates. The only known form regulation this is via de novo expression LPP isoforms in response to growth factors. In respect, we evaluated effect moderate increases recombinant LPP1 on signal transduction by both G-protein-coupled receptors and receptor tyrosine kinases. We present evidence for novel role reducing PDGF (platelet-derived factor)- lysophosphatidic acid-induced...

Abstract The ratio of C 26:0 /C 22:0 fatty acids in patient lipids is widely accepted as a critical clinical criterion peroxisomal diseases, such Zellweger syndrome and X‐linked adrenoleukodystrophy (X‐ALD). However, phospholipid molecular species with very long chain (VLCFA) have not been precisely characterized. In the present study, structures molecules fibroblasts X‐ALD were examined using LC–ESI–MS/MS analysis. from patients, large number VLCFA‐containing detected several classes well...

Abstract ABCD1 is a gene responsible for X‐linked adrenoleukodystrophy (X‐ALD), and critical the transport of very long‐chain fatty acids (VLCFA) into peroxisomes subsequent β‐oxidation. VLCFA‐containing lipids accumulate in X‐ALD patients, although effect ABCD1‐deficiency on each lipid species central nervous system has not been fully characterized. In this study, phospholipid lysophospholipid Abcd1 ‐deficient mice brains were profiled by liquid chromatography‐mass spectrometry. Among that...

Abstract Ceramide, the central molecule in sphingolipid synthesis, is a bioactive lipid that serves as regulatory anti-inflammatory responses, apoptosis, programmed necrosis, autophagy, and cell motility of cancer cells. In particular, authors have reported differences content colorectal tissues. The associations among genetic mutations, clinicopathological factors, metabolism (CRC) not been investigated. objective this study to investigate association between genes associated with...

Glycosphingolipids (GSLs) exist exclusively in the outer leaflet of plasma membrane mammalian cells and have diverse structures including different classes sugars various molecular species ceramide moieties. Establishing methods that measure each GSL should aid functional characterization GSLs reveal details about mechanism pathogenesis glycosphingolipidoses. Using an IF-3 chiral column has never been used for lipid analyses, we developed a liquid chromatography-mass spectrometry (LC-MS)...

An "A1 type" phospholipase activity with serine-phospholipid preference was released by rat activated platelets. It distinct from the secretory type II A2 [Horigome, K., Hayakawa, M., Inoue, and Nojima, S. (1987) J. Biochem. 101, 625-631] co-purified lysophosphatidylserine-selective lysophospholipase [Higashi, S., Kobayashi, T., Kudo, I., K. (1988) 103, 442-447]. Several lines of evidence indicated that a single protein responsible for A1 activities. Marked accumulation lysophospholipids...

Sphingolipid biosynthesis in synchronized HeLa cells was studied by pulse labeling with [ 14 C]Ser or l4 C]Gal and a simple TLC method. The major cell sphingolipids are ceramide (Cer), sphingomyelin, glucosylceramide (GlcCer), lactosylceramide (LacCer), globotriaosylceramide (Gb,Cer), N ‐acetylneuraminosylgangliotriaosylceramide (G M2 ) sialylparagloboside M1.Glc.NAc ). sphingolipid biosynthetic profiles of the G1, G1/S boundary, S G2 phases were similar, but significant changes occurred...

X-linked adrenoleukodystrophy (X-ALD) is an inherited disorder caused by deleterious mutations in the ABCD1 gene. The protein transports very long-chain FAs (VLCFAs) from cytosol into peroxisome where VLCFAs are degraded through β-oxidation. dysfunction leads to VLCFA accumulation individuals with X-ALD. activated esterification CoA before metabolic utilization. However, intracellular pools and profiles of individual acyl-CoA esters have not been fully analyzed. In this study, we profiled...

We describe a concise and reliable protocol for the precisely controlled tetradeuteration of straight-chain fatty acids (FAs) at α- β-positions that is generally applicable to variety FAs, including trans-FAs, polyunsaturated FAs (PUFAs), their oxidized derivatives. The introduction four deuterium atoms into enables persistent quantitative tracking by LC-MS/MS analysis based on molecular structures. In addition, phosphatidylcholine (PC) species prepared from tetradeuterated thus obtained...

Although the ceramide components of both glycosphingolipids (GSLs) and sphingomyelin (SM) in HL‐60 cells were identical, molecular species ceramides preferentially used biosynthesis quite different GSLs SM. When stimulated to differentiate into macrophage‐like by phorbol ester after their sphingolipids had been metabolically labeled with l ‐[3‐ 14 C]serine saturation point, marked changes radioactivities residues observed GSLs, showing activation a biosynthetic pathway ganglioside GM3. No...

Adrenoleukodystrophy (X-ALD) is an X-linked genetic disorder caused by mutation of the ATP-binding cassette subfamily D member 1 gene, which encodes peroxisomal membrane protein, adrenoleukodystrophy protein (ALDP). ALDP associated with transport very-long-chain fatty acids (VLCFAs; carbon chain length ≥ 24) into peroxisomes. Defective leads to accumulation saturated VLCFAs in plasma and tissues, results damage myelin adrenal glands. Here, we profiled glycosphingolipid (GSL) species...

In a previous study, we purified PAF-acetylhydrolase, which converts PAF to an inactive metabolite, lysoPAF, from peritoneal fluid of guinea pigs subjected experimental endotoxin shock and found that this enzyme had similar biochemical properties the plasma [Karasawa, K., Yato, M., Setaka, Nojima, S. (1994) J. Biochem. 116,374–379]. isolated homogeneous preparation pig using procedure. The molecular mass enzyme, as determined by SDS-PAGE was 58–63 kDa, larger than (43 kDa) human enzyme. To...