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PubMed2006

Olfactory mucosa-expressed organic anion transporter, Oat6, manifests high affinity interactions with odorant organic anions.

We have characterized the expression of organic anion transporter 6, Oat6 (slc22a20), in olfactory mucosa, as well as its interaction with several odorant organic anions. In situ hybridization reveals diffuse Oat6 expression throughout olfactory epithelium, yet olfactory neurons laser-capture microdissected from either the main olfactory epithelium (MOE) or the vomeronasal organ (VNO) did not express Oat6 mRNA. These data suggest that Oat6 is expressed in non-neuronal cells of olfactory tissue, such as epithelial and/or other supporting cells. We next investigated interaction of Oat6 with several small organic anions that have previously been identified as odortype components in mouse urine. We find that each of these compounds, propionate, 2- and 3-methylbutyrate, benzoate, heptanoate, and 2-ethylhexanoate, inhibits Oat6-mediated uptake of a labeled tracer, estrone sulfate, consistent with their being Oat6 substrates. Previously, we noted defects in the renal elimination of odortype and odortype-like molecules in Oat1 knockout mice. The finding that such molecules interact with Oat6 raises the possibility that odorants secreted into the urine through one OAT-mediated mechanism (Eraly et al., JBC 2006) are transported through the olfactory mucosa through another OAT-mediated mechanism. Oat6 might play a direct or indirect role in olfaction, such as modulation of the availability of odorant organic anions at the mucosal surface for presentation to olfactory neurons or facilitation of delivery to a distal site of chemosensation, among other possibilities that we discuss.

Animals↗
PubMed2005

In vivo characterization of a novel inhibitor of CNS nicotinic receptors.

There are multiple types of nicotine acetylcholine receptors (nAChR) in the brain associated with synaptic function, signal processing, or cell survival. The therapeutic targeting of nicotinic receptors in the brain will benefit from the identification of drugs, which may be selective for their ability to activate or inhibit a limited range of these receptor subtypes. We previously identified a family of bis-tetramethylpiperidine compounds as selective inhibitors of neuronal-type nicotinic receptors. In the present study we describe the in vivo effects and properties of 2,2,6,6-tetramethylpiperidin-4-yl heptanoate (TMPH), a novel inhibitor of neuronal nicotinic receptors. Delivered systemically, this drug can block central nervous system effects of nicotine, indicating that this drug is able to cross the blood-brain barrier and access sites in the brain. Unlike the prototype CNS-active nicotinic inhibitor, mecamylamine, TMPH blocked some but not all of the CNS effects of nicotine, indicating that it has a unique selectivity for specific receptor subtypes in the brain. The nAChR subtypes that mediate the locomotor effects and hypothermic effects of nicotine appear to be less sensitive to TMPH than those which mediate analgetic effects and discriminative stimuli. These results indicate that TMPH may possess unique selectivity for specific nicotinic receptor subtypes.

Analgesics↗
PubMed2000

Human internal mammary artery contraction by isoprostaglandin f(2alpha) type-III [8-iso-prostaglandin F(2alpha)].

Isoprostaglandin F(2alpha) type-III (formerly known as 8-iso-prostaglandin F(2alpha)) is produced in large quantities in vivo in clinical situations associated with oxidant stress such as atherosclerosis, hypercholesterolemia, and myocardial reperfusion. Isoprostaglandin F(2alpha) type-III may alter smooth muscle and platelet functions. The aim of this study was to evaluate the effects of isoprostaglandin F(2alpha) type-III on isolated human internal mammary arteries, and to characterise the signalling underlying mechanisms. In organ baths, concentration-dependent contractions of human internal mammary arteries were obtained in response to isoprostaglandin F(2alpha) type-III stimulation. The responses to isoprostaglandin F(2alpha) type-III were inhibited in a concentration-dependent manner by the thromboxane A(2) receptor antagonist, GR 32191 ([1R-[1 alpha(Z), 2beta,3beta,5 alpha(+)-7-[[1, 1'-biphenyl)-4-yl]methoxy]-3-hydroxy-2-(1-piperidinyl) cyclo pentyl]-4-4heptanoic acid], hydrochloride), 3x10(-9) to 3x10(-7) M). However, this effect was associated with a decreased maximal contraction. AH 6809 (6-isopropoxy-9-oxoxanthene-2-carboxylic acid, 10(-6) to 3x10(-5) M), an EP(1)-DP receptor antagonist had no effect on isoprostaglandin F(2alpha) type-III-induced contractions. The maximal responses to isoprostaglandin F(2alpha) type-III were significantly reduced in the presence of the cyclooxygenase inhibitor indomethacin (10(-5) M) (E(max): 147+/-20% vs. 213+/-19% in control group, P<0.05). Isoprostaglandin F(2alpha) type-III stimulated thromboxane B(2) release (5.7-fold increase) from human internal mammary arteries. Baicaleine, a non-specific lipoxygenase inhibitor, (10(-4) M) and AA 861 (2,3,5-trimethyl-6-(12-hydroxy-5, 10-dodecadiynyl)-1,4 benzoquinone), a 5-lipoxygenase inhibitor (10(-5) M) did not affect isoprostaglandin F(2alpha) type-III response. In conclusion, this study shows that (1) isoprostaglandin F(2alpha) type-III is a vasoconstrictor in human internal mammary arteries, with a potency equivalent to prostaglandin F(2alpha), (2) the contractions induced by isoprostaglandin F(2alpha) type-III are mediated by TP receptor but not EP(1)-DP-receptor activation, (3) thromboxane A(2) but not cysteinyl leukotrienes production is involved in the vascular effects of isoprostaglandin F(2alpha) type-III. Isoprostaglandin F(2alpha) type-III, produced at sites of free radical generation, may play an important role in internal mammary artery spasm in situations of oxidant stress such as coronary bypass surgery.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
PubMed2002

Conjugation of a magainin analogue with lipophilic acids controls hydrophobicity, solution assembly, and cell selectivity.

Our basic understanding of how to combat fungal infections has not kept pace with the recent sharp rise in life-threatening cases found particularly among immuno-compromised individuals. Current investigations for new potential antifungal agents have focused on antimicrobial peptides, which are used as a cell-free defense mechanism in all organisms. Unfortunately, despite their high antibacterial activity, most of them are not active toward fungi, the reason of which is not clear. Here, we present a new approach to modify an antibacterial peptide, a magainin analogue, to display antifungal activity by its conjugation with lipophilic acids. This approach has the advantage of producing well-defined changes in hydrophobicity, secondary structure, and self-association. These modifications were characterized in solution at physiological concentrations using CD spectroscopy, tryptophan fluorescence, and analytical ultracentrifugation. In order of increasing hydrophobicity, the attachment to the magainin-2 analogue of (i) heptanoic acid results in a monomeric, unordered structure, (ii) undecanoic acid yields concentration-dependent oligomers of alpha helices, and (iii) palmitic acid yields concentration-independent alpha-helical monomers, a novel lipopeptide structure, which is resistant to proteolytic digestion. Membrane-lipopeptide interactions and the membrane-bound structures were studied using fluorescence and ATR-FTIR in PC/PE/PI/ergosterol (5/2.5/2.5/1, w/w) SUV, which constitute the major components of Candida albicans bilayers. A direct correlation was found between oligomerization of the lipopeptides in solution and potent antifungal activity. These results provide insight to a new approach of modulating hydrophobicity and self-assembly of antimicrobial peptides in solution, without altering the sequence of the peptidic chain. These studies also provide a general means of developing a new group of lipopeptide candidates as therapeutic agents against fungal infections.

Amino Acid Sequence↗
PubMed1992

Synthesis and thromboxane A2/prostaglandin H2 receptor antagonistic activity of phenol derivatives.

Consideration of possible structural similarities between thromboxane A2 and the hydroquinone form of (R)-(+)-7-(3,5,6-trimethyl-1,4-benzoquinon-2-yl)-7- phenylheptanoic acid (R-(+)-AA-2414) led to the development of a new series of thromboxane A2/prostaglandin H2 (TXA2/PGH2) receptor antagonists, namely 7-(4-fluorophenyl)-7-(2-hydroxyphenyl)heptanoic acids (I). These compounds were found to be potent TXA2/PGH2 receptor antagonists. Compounds having either a carbonyl or a hydroxymethyl group at the para-position of the phenolic hydroxy group exhibited most potent activities in this series. Compounds 14, 15, 18, and 26 inhibited the specific binding of [3H]U-46619 to guinea pig platelet membranes (IC50 = 4.4, 80, 32, and 13 nM, respectively), and also inhibited U-46619-induced human platelet aggregation (IC50 = 310, 69, 79, and 78 nM, respectively). Comparison of the UV spectra of the compounds with a carbonyl group at the para-position of phenolic hydroxy group revealed that the activity tended to increase in accordance with a decrease in the torsional angle between the carbonyl group and the phenol ring. These results suggested that the spacial location of the carbonyl and hydroxymethyl oxygen are important for significant increase in activity and that the carbonyl and hydroxymethyl oxygen at the para-position of the phenolic hydroxy group might interact with one of the TXA2/PGH2 receptor sites.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
PubMed1986

3-Hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors. 2. Structural modification of 7-(substituted aryl)-3,5-dihydroxy-6-heptenoic acids and their lactone derivatives.

A series of 7-(substituted aryl)-3,5-dihydroxy-6-heptenoic (heptanoic) acids and their lactone derivatives have been prepared and tested for inhibition of 3-hydroxy-3-methylglutaryl-coenzyme A reductase in vitro. A systematic exploration of the structure-activity relationships in this series led to the synthesis of (+)-trans-(E)-6-[2-[2,4-dichloro-6-[(4-fluorophenyl) methoxyl]phenyl]ethyl]-3,4,5,6-tetrahydro-4-hydroxy-2H-pyran-2-one (66(+)), which has one-half of the inhibitory activity of compactin.

Animals↗
PubMed2005

Effect of mono-CDNP substitution of lysine residues on the redox reaction of cytochrome c electrostatically adsorbed on a mercaptoheptanoic acid modified Au(111) surface.

The effect of charge-inverting modification of single surface lysine residue on the electron transfer (ET) reaction of horse heart cytochrome c (cyt c) is examined for 12 different types of mono-4-chloro-2,5-dinitrobenzoic acid substituted cyt c (mCDNPc) adsorbed on a Au(111) electrode modified with a self-assembled monolayer (SAM) of 7-mercapto-heptanoic acid (MHA). A negative shift in the redox potential by 10-35 mV as compared to that of native cyt c and a monolayer coverage in the range of 13-17 pmol cm(-2) are observed for electroactive mCDNPc's. The magnitude of the decrease in the ET rate constant (k(et)) of mCDNPc's compared with that of native cyt c depends on the position of the CDNP substitution. For mCDNPc's in which the modified lysine residue is outside of the interaction domain of cyt c with the SAM, the ratio of the k(et) of mCDNPc to that of native cyt c is correlated to the change in the dipole moment vector of cyt c due to the CDNP modification. This correlation suggests that the dipole moment of cyt c determines its orientation of adsorption on the SAM of MHA and significantly affects the rate of the ET. The CDNP modification of lysine residues at the interaction domain significantly decreases the rate, demonstrating the importance of the local charge environment in determining the rate of ET.

Adsorption↗
PubMed1996

Influence of carbon chain length on the hepatic effects of perfluorinated fatty acids. A 19F- and 31P-NMR investigation.

Using nuclear magnetic resonance (NMR) spectroscopy, we investigated the importance of carbon chain length with regard to the hepatic effects associated with perfluoro-n-carboxylic acids. Male F-344 rats were administered a single intraperitoneal dose of either perfluoro-n-heptanoic acid (C7-PFA), perfluoro-n-nonanoic acid (C9-PFA), or perfluoro-n-undecanoic acid (C11-PFA). Data from previous studies involving perfluoro-n-octanoic acid (C8-PFA) and perfluoro-n-decanoic acid (C10-PFA) are included for comparison. Food consumption/body weight was monitored daily for all groups. C9- and C11-PFA treatment yields a prolonged hypophagic response while C7-PFA shows a more acute response. Fluorine-19 NMR spectra of urine and bile samples show no evidence of fluorometabolites and suggest that the distribution of perfluorocarbons into urine or bile is dependent upon carbon chain length. The aqueous solubility of C7-PFA appears to facilitate rapid urinary excretion, similar to that observed for C8-PFA. The relative hydrophobicity of C9- and C11-PFA appears to favor biliary enterohepatic recirculation, yielding a more protracted toxicity, similar to C10-PFA. Phosphorus-31 NMR studies of liver in vivo and liver extracts show that perfluorocarbons of > or = C9 carbons produce a significant increase in liver phosphocholine concentration. These data are discussed with regard to the impact of these chemicals on hepatic phospholipid metabolism. Hepatic peroxisomal fatty acyl CoA-oxidase activity (FAO) was measured to determine if C7-, C9-, and C11-PFA are peroxisome proliferators. Data indicate that the induction of peroxisomal enzyme activity by perfluorocarbons requires a chain length greater than seven carbons. In general, these results demonstrate the significance of carbon chain length in the hepatotoxic response and provide clues toward understanding the processes involved in the biological activities associated with exposure to these compounds.

Acyl-CoA Oxidase↗
PubMed2000

'Microsmatic' primates revisited: olfactory sensitivity in the squirrel monkey.

Using a conditioning paradigm, the olfactory sensitivity of three squirrel monkeys to nine odorants representing different chemical classes as well as members of a homologous series of substances was investigated. The animals significantly discriminated dilutions as low as 1:10,000 n-propionic acid, 1:30,000 n-butanoic acid and n-pentanoic acid, 1:100,000 n-hexanoic acid, 1:1Mio n-heptanoic acid, 1:30, 000 1-pentanol, 1:300,000 1,8-cineole, 1:1Mio n-heptanal and 1:30Mio amyl acetate from the near-odorless solvent, with single individuals scoring even slightly better. The results showed (i) the squirrel monkey to have an unexpectedly high olfactory sensitivity, which for some substances matches or even is better than that of species such as the rat or the dog, and (ii) a significant negative correlation between perceptibility in terms of olfactory detection thresholds and carbon chain length of carboxylic acids. These findings support the assumptions that olfaction may play a significant and hitherto underestimated role in the regulation of primate behavior, and that the concept of primates as primarily visual and 'microsmatic' animals needs to be revised.

Aldehydes↗
PubMed2002

Glucuronidation of statins in animals and humans: a novel mechanism of statin lactonization.

The active forms of all marketed hydroxymethylglutaryl (HMG)-CoA reductase inhibitors share a common dihydroxy heptanoic or heptenoic acid side chain. In this study, we present evidence for the formation of acyl glucuronide conjugates of the hydroxy acid forms of simvastatin (SVA), atorvastatin (AVA), and cerivastatin (CVA) in rat, dog, and human liver preparations in vitro and for the excretion of the acyl glucuronide of SVA in dog bile and urine. Upon incubation of each statin (SVA, CVA or AVA) with liver microsomal preparations supplemented with UDP-glucuronic acid, two major products were detected. Based on analysis by high-pressure liquid chromatography, UV spectroscopy, and/or liquid chromatography (LC)-mass spectrometry analysis, these metabolites were identified as a glucuronide conjugate of the hydroxy acid form of the statin and the corresponding delta-lactone. By means of an LC-NMR technique, the glucuronide structure was established to be a 1-O-acyl-beta-D-glucuronide conjugate of the statin acid. The formation of statin glucuronide and statin lactone in human liver microsomes exhibited modest intersubject variability (3- to 6-fold; n = 10). Studies with expressed UDP glucuronosyltransferases (UGTs) revealed that both UGT1A1 and UGT1A3 were capable of forming the glucuronide conjugates and the corresponding lactones for all three statins. Kinetic studies of statin glucuronidation and lactonization in liver microsomes revealed marked species differences in intrinsic clearance (CL(int)) values for SVA (but not for AVA or CVA), with the highest CL(int) observed in dogs, followed by rats and humans. Of the statins studied, SVA underwent glucuronidation and lactonization in human liver microsomes, with the lowest CL(int) (0.4 microl/min/mg of protein for SVA versus approximately 3 microl/min/mg of protein for AVA and CVA). Consistent with the present in vitro findings, substantial levels of the glucuronide conjugate (approximately 20% of dose) and the lactone form of SVA [simvastatin (SV); approximately 10% of dose] were detected in bile following i.v. administration of [(14)C]SVA to dogs. The acyl glucuronide conjugate of SVA, upon isolation from an in vitro incubation, underwent spontaneous cyclization to SV. Since the rate of this lactonization was high under conditions of physiological pH, the present results suggest that the statin lactones detected previously in bile and/or plasma following administration of SVA to animals or of AVA or CVA to animals and humans, might originate, at least in part, from the corresponding acyl glucuronide conjugates. Thus, acyl glucuronide formation, which seems to be a common metabolic pathway for the hydroxy acid forms of statins, may play an important, albeit previously unrecognized, role in the conversion of active HMG-CoA reductase inhibitors to their latent delta-lactone forms.

Animals↗
PubMed1997

Polyhydroxyalkanoate production in Rhodobacter capsulatus: genes, mutants, expression, and physiology.

Like many other prokaryotes, the photosynthetic bacterium Rhodobacter capsulatus produces high levels of polyhydroxyalkanoates (PHAs) when a suitable carbon source is available. The three genes that are traditionally considered to be necessary in the PHA biosynthetic pathway, phaA (beta-ketothiolase), phaB (acetoacetylcoenzyme A reductase), and phaC (PHA synthase), were cloned from Rhodobacter capsulatus. In R. capsulatus, the phaAB genes are not linked to the phaC gene. Translational beta-galactosidase fusions to phaA and phaC were constructed and recombined into the chromosome. Both phaC and phaA were constitutively expressed regardless of whether PHA production was induced, suggesting that control is posttranslational at the enzymatic level. Consistent with this conclusion, it was shown that the R. capsulatus transcriptional nitrogen-sensing circuits were not involved in PHA synthesis. The doubling times of R. capsulatus transcriptional nitrogen-sensing circuits were not involved in PHA synthesis. The doubling times of R. capsulatus grown on numerous carbon sources were determined, indicating that this bacterium grows on C2 to C12 fatty acids. Grown on acetone, caproate, or heptanoate, wild-type R. capsulatus produced high levels of PHAs. Although a phaC deletion strain was unable to synthesize PHAs on any carbon source, phaA and phaAB deletion strains were able to produce PHAs, indicating that alternative routes for the synthesis of substrates for the synthase are present. The nutritional versatility and bioenergetic versatility of R. capsulatus, coupled with its ability to produce large amounts of PHAs and its genetic tractability, make it an attractive model for the study of PHA production.

Acetone↗
PubMed1998

Cloning of the Nocardia corallina polyhydroxyalkanoate synthase gene and production of poly-(3-hydroxybutyrate-co-3-hydroxyhexanoate) and poly-(3-hydroxyvalerate-co-3-hydroxyheptanoate).

The polyhydroxyalkanoate (PHA) synthase gene (phaCNc) from Nocardia corallina was identified in a lambda library on a 6-kb BamHI fragment. A 2.8-kb XhoII subfragment was found to contain the intact PHA synthase. This 2.8-kb fragment was subjected to DNA sequencing and was found to contain the coding region for the PHA synthase and a small downstream open reading frame of unknown function. On the basis of DNA sequence, phaCNc is closest in homology to the PHA synthases (phaCPaI and phaCPaII) of Pseudomonas aeruginosa (approximately 41% identity and 55% similarity). The 2.8-kb XhoII fragment containing phaCNc was subcloned into broad host range mobilizable plasmids and transferred into Escherichia coli, Klebsiella aerogenes (both containing a plasmid bearing phaA and phaB from Ralstonia eutropha), and PHA-negative strains of R. eutropha and Pseudomonas putida. The recombinant strains were grown on various carbon sources and the resulting polymers were analyzed. In these strains, the PHA synthase from N. corallina was able to mediate the production of poly(3-hydroxybutyrate-co-3-hydroxyhexanoate) containing high levels of 3-hydroxyhexanoate when grown on hexanoate and larger even-chain fatty acids and poly(3-hydroxyvalerate-co-3-hydroxyheptanoate) containing high levels of 3-hydroxyheptanoate when grown on heptanoate or larger odd-chain fatty acids.

Acyltransferases↗
PubMed2006

Parenteral and enteral metabolism of anaplerotic triheptanoin in normal rats.

A new chronic treatment for inherited disorders of long-chain fatty acid oxidation involves administering up to one-third of dietary calories as triheptanoin, a medium-odd-chain triglyceride (Roe CR, Sweetman L, Roe DS, David F, and Brunengraber H. J Clin Invest 110: 259-269, 2002). Heptanoate and C(5)-ketone bodies derived from its partial oxidation in liver are precursors of anaplerotic propionyl-CoA in peripheral tissues. It was hypothesized that increasing anaplerosis in peripheral tissues would boost energy production. In the present study, we tested the potential of a triheptanoin emulsion as an intravenous nutrient. Normal rats were infused with triheptanoin intravenously or intraduodenally at up to 40% of caloric requirement. The blood concentration ratio (heptanoate/C(5)-ketone bodies) was high with intravenous and low with intraduodenal triheptanoin infusion. During intravenous infusion of triheptanoin, lipolysis was stimulated but appeared compensated by fatty acid reesterification. During intraduodenal infusion of triheptanoin, lipolysis was not stimulated. Our data support the hypothesis that intravenous triheptanoin could be used to treat decompensated patients with long-chain fatty acid oxidation disorders.

Animals↗
PubMed1980

Vasopressin-stimulated water flow is decreased by thromboxane synthesis inhibition or antagonism.

The time course of vasopressin stimulation of water flow and immunoreactive thromboxane B2 (iTXB2) and prostaglandin E (iPGE) biosynthesis was studied in the isolated toad urinary bladder. Vasopressin (25 mU/ml) significantly stimulated iTXB2 synthesis within 8 min, synthesis reaching a maximum rate by 17 min. iPGE synthesis was significantly stimulated within 8 min, remaining unchanged for 24 min. Maximum vasopressin-stimulated water flow was reached between 16 and 24 min. 7-(1-Imidazolyl)-heptanoic acid (7IHA), a thromboxane synthetase inhibitor, inhibited both vasopressin-stimulated water flow and iTXB2 synthesis in a dose-dependent fashion, but did not affect iPGE synthesis. Vasopressin-stimulated water flow and iTXB2 synthesis were significantly correlated (r = 0.75, n = 24, P less than 0.001). 13-Azaprostanoic acid (13APA), a thromboxane antagonist, inhibited vasopressin-stimulated water flow in a dose-dependent fashion. Inhibition of arachidonic acid metabolism abolished the effects of 7IHA and 13APA on vasopressin-stimulated water flow. 7IHA and 13APA had no effect on cAMP-stimulated water flow. These results confirm that vasopressin stimulates TXA2 and PGE synthesis and support the hypothesis that TXA2 is a positive modulator of vasopressin-stimulated water flow in the toad urinary bladder.

Animals↗
PubMed1992

Regulation of glycolytic metabolism during long-term primary culture of renal proximal tubule cells.

Adequate oxygenation was a major factor regulating the induction of glycolytic metabolism in primary cultures of rabbit renal proximal tubule cells during short-term (less than 1 day) and long-term (1-7 day) culture. As measured by cellular lactate content, glucose consumption, and lactate dehydrogenase activity, less glycolytic metabolism was induced in cultured cells that were constantly aerated than in cells that were held stationary. When oxidative metabolism is supported by providing 2-10 mM heptanoate (HEP) as a metabolic substrate glycolytic metabolism further decreased during short-term, but not long-term culture. Cellular proliferation did not play a major role in regulating the induction of glycolytic metabolism, since glycolytic metabolism increased before cell growth had occurred, did not decline once logarithmic cell growth had ceased, and was stimulated less by cell growth than by inadequate oxygenation. Fructose-1,6-bisphosphatase and alkaline phosphatase, representative markers of gluconeogenic and brush-border membrane enzyme activities, respectively, declined during culture regardless of culture conditions or the presence of HEP. Therefore, glycolytic metabolism can be effectively minimized by constantly aerating cultured proximal tubule cells and can be further reduced by the addition of HEP during short-term culture.

Animals↗
PubMed2005

Ingested medium-chain fatty acids are directly utilized for the acyl modification of ghrelin.

Ghrelin, an acylated brain and gut peptide, is primarily produced by endocrine cells of the gastric mucosa for secretion into the circulation. The major active form of ghrelin is a 28-amino-acid peptide containing an n-octanoyl modification at serine that is essential for activity. Studies have identified multiple physiological functions for ghrelin, including GH release, appetite stimulation, and metabolic fuel preference. Until now, there has not been any report detailing the mechanism of ghrelin acyl modification. Here we report that ingestion of either medium-chain fatty acids (MCFAs) or medium-chain triacylglycerols (MCTs) increased the stomach concentrations of acylated ghrelin without changing the total (acyl- and des-acyl-) ghrelin amounts. After ingestion of either MCFAs or MCTs, the carbon chain lengths of the acyl groups attached to nascent ghrelin molecules corresponded to that of the ingested MCFAs or MCTs. Ghrelin peptides modified with n-butyryl or n-palmitoyl groups, however, could not be detected after ingestion of the corresponding short-chain or long-chain fatty acids, respectively. Moreover, n-heptanoyl ghrelin, an unnatural form of ghrelin, could be detected in the stomach of mice after ingestion of either n-heptanoic acid or glyceryl triheptanoate. These findings indicate that ingested medium-chain fatty acids are directly used for the acylation of ghrelin.

Acylation↗
PubMed1988

Effect of a new synthetic 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor on cholesterol synthesis and low density lipoprotein uptake by primary cultures of rat hepatocytes.

CS-514 ((+)-sodium (3R,5R)-3,5-dihydroxy-7-[(1S,2S,6S,8S,8aR)-6-hydroxy-2- methyl-8-[(S)-2-methyl-butyryl]-1,2,6,7,8-hexahydro-1-naphthyl] heptanoate) which was recently synthesized as an inhibitor of 3-hydroxy-3-methyl-glutaryl coenzyme A reductase lowers serum cholesterol levels. This compound inhibited cholesterol synthesis dose-dependently from acetate in primary cultures of rat hepatocytes. At high concentration (0.5 and 5.0 mumol/l), but not at lower concentration, it inhibited bile formation from acetate. Low density lipoprotein (LDL)-[3H]-cholesteryl linoleate incorporation into hepatocytes was increased when the cells were preincubated with 0.5 or 5.0 mumol/l CS-514 for 12 h. Bile formation from LDL-[3H]-cholesterol linoleate was not affected by addition of CS-514. These results suggest that inhibition of de novo cholesterol synthesis by CS-514 enhanced LDL receptor function in primary cultures of rat hepatocytes and lowered LDL-cholesterol level.

Acetates↗
PubMed1993

[Inhibitory effects of AA-2414, a thromboxane (Tx) A2 receptor antagonist, on U-46619-, prostaglandin (PG) D2- and 9 alpha, 11 beta PGF2-induced contractions of guinea pig tracheas and isolated human bronchi].

The effects of a novel TXA2 receptor antagonist, AA-2414 [(+-)-7-(3,5,6-trimethyl-1,4-benzoquinone-2-yl)-7-phenyl-heptanoic acid], on U-46619-, PGD2- and 9 alpha, 11 beta-PGF2 alpha-induced contractions of isolated guinea pig tracheas and human bronchi were investigated. AA-2414 competitively inhibited the contractile responses of both human and guinea pig preparations induced by U-46619 with similar pA2 values (7.7 and 7.6, respectively). In addition, the compound also inhibited the contractions of both preparations caused by PGD2 and 9 alpha, 11 beta-PGF2 alpha, the IC50 values of which were 1.2 x 10(-7) and 1.8 x 10(-7) M in guinea pig tracheas and 2.8 x 10(-8) and 8.5 x 10(-8) M in human bronchi. These results suggest that AA-2414 may be a therapeutically useful drug for bronchial asthma.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗