Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “Pathways”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 487 records · Page 27Linked to original sources
PubMed2004

The Ras/protein kinase A pathway acts in parallel with the Mob2/Cbk1 pathway to effect cell cycle progression and proper bud site selection.

In Saccharomyces cerevisiae, Ras proteins connect nutrient availability to cell growth through regulation of protein kinase A (PKA) activity. Ras proteins also have PKA-independent functions in mitosis and actin repolarization. We have found that mutations in MOB2 or CBK1 confer a slow-growth phenotype in a ras2Delta background. The slow-growth phenotype of mob2Delta ras2Delta cells results from a G1 delay that is accompanied by an increase in size, suggesting a G1/S role for Ras not previously described. In addition, mob2Delta strains have imprecise bud site selection, a defect exacerbated by deletion of RAS2. Mob2 and Cbk1 act to properly localize Ace2, a transcription factor that directs daughter cell-specific transcription of several genes. The growth and budding phenotypes of the double-deletion strains are Ace2 independent but are suppressed by overexpression of the PKA catalytic subunit, Tpk1. From these observations, we conclude that the PKA pathway and Mob2/Cbk1 act in parallel to determine bud site selection and promote cell cycle progression.

Actins↗
PubMed1995

A lacZ reporter fusion method for the genetic analysis of regulatory mutations in pathways of fungal secondary metabolism and its application to the Aspergillus nidulans penicillin pathway.

Secondary metabolism, usually superfluous under laboratory conditions, is intrinsically elusive to genetic analysis of its regulation. We describe here a method of analyzing regulatory mutations affecting expression of secondary metabolic genes, with an Aspergillus nidulans penicillin structural gene (ipnA [encoding isopenicillin N-synthase]) as a model. The method is based on a targeted double integration of a lacZ fusion reporter gene in a chromosome different from that containing the penicillin gene cluster. The trans-acting regulatory mutations simultaneously affect lacZ expression and penicillin biosynthesis. One of these mutations (npeE1) has been analyzed in detail. This mutation is recessive, prevents penicillin production and ipnA'::'lacZ expression, and results in very low levels of the ipnA message at certain times of growth. This indicates that npeE positively controls ipnA transcription. We also show that this tandem reporter fusion allows genetic analysis of npeE1 by using the sexual and parasexual cycles and that lacZ expression is an easily scorable phenotype. Haploidization analysis established that npeE is located in chromosome IV, but npeE1 does not show meiotic linkage to a number of known chromosome IV markers. This method might be of general applicability to genetic analysis of regulation of other fungal secondary metabolic pathways.

Aspergillus nidulans↗
PubMed1982

Bio-inorganic regulation of pathways of carbohydrate and lipid metabolism. 1. Effect of iron and manganese on the enzyme profile of pathways of carbohydrate metabolism in adipose tissue during development.

The effect of Fe2+ and Mn2+ on the pattern of emergence of enzymes in adipose tissue was studied in weaned rats given a high-fat diet; comparison was made with groups given a high-carbohydrate diet for 3 weeks. The addition of Fe2+ resulted in increased activity of key enzymes of glycolysis, the pentose phosphate pathway and lipogenesis, while further supplementation with Mn2+ enhanced these changes. The Mn2+ treatment thus appeared partially to overcome the regulatory feedback mechanisms of the high-fat diet and to provide a signal for the increase in enzymes involved in glucose oxidation and lipogenesis.

Adipose Tissue↗
PubMed1984

In situ estrogen production via the estrone sulfatase pathway in breast tumors: relative importance versus the aromatase pathway.

Estrone and estradiol concentrations in breast tumor tissue are an order of magnitude higher than circulating plasma levels in postmenopausal women with breast cancer. Local production of estrogen in the neoplastic tissue is one of several possible explanations for this plasma/tissue gradient. This study evaluated breast tumor estrogen production via the estrone sulfate to estrone (sulfatase) pathway and compared this with the androstenedione to estrone (aromatase) system in human and rodent mammary tumors. Estrogen production from estrone sulfate was related linearly with time and tissue concentrations, exhibited an apparent Km of 20 microM, and produced a linear Eadie-Hofstee kinetic plot consistent with a single class of enzymatic sites. Measurement of sulfatase in 35 human breast tumors using enzyme saturating conditions revealed estrone production ranging from 0.8-125 mumol/g protein . h. The corresponding range in host mammary tumors was 3.5-7.1 mumol/g protein . h. In human breast tumors, sulfatase activity did not correlate with the levels of estrogen receptor or progesterone receptor. Comparison of sulfatase with aromatase activity in human tumors at physiological levels of substrate revealed estrone formation via sulfatase of 2.8 pmol estrone produced/g protein . h, while aromatase produced only 0.27 pmol/g protein . h. In rat mammary tumors, sulfatase activity was similar to that in human tumors, whereas aromatase activity could not be detected, even with a highly sensitive assay. Thus, estrone sulfatase appears to be the enzyme primarily responsible for intratissue estrone production in hormone-dependent breast carcinomas.

Animals↗
PubMed2004

The TOR pathway interacts with the insulin signaling pathway to regulate C. elegans larval development, metabolism and life span.

The highly conserved target-of-rapamycin (TOR) protein kinases control cell growth in response to nutrients and growth factors. In mammals, TOR has been shown to interact with raptor to relay nutrient signals to downstream translation machinery. We report that in C. elegans, mutations in the genes encoding CeTOR and raptor result in dauer-like larval arrest, implying that CeTOR regulates dauer diapause. The daf-15 (raptor) and let-363 (CeTOR) mutants shift metabolism to accumulate fat, and raptor mutations extend adult life span. daf-15 transcription is regulated by DAF-16, a FOXO transcription factor that is in turn regulated by daf-2 insulin/IGF signaling. This is a new mechanism that regulates the TOR pathway. Thus, DAF-2 insulin/IGF signaling and nutrient signaling converge on DAF-15 (raptor) to regulate C. elegans larval development, metabolism and life span.

Adaptor Proteins, Signal Transducing↗
PubMed1974

Glucuronic acid pathway in alloxan diabetic rabbits. (I). Urinary excretion of metabolites related to the glucuronic acid pathway.

Studies on the activity of the glucuronic acid pathway in alloxan diabetic rabbits were carried out. Amount of D-glucaric acid, L-ascorbic acid, and D-glucuronic acid in urine increased in the case of the alloxan diabetic rabbits. The transformation from D-glucuronolactone to D-glucaric acid was higher than normal in the diabetic animals. The expired 14-CO2 decreased and urinary excretion of labeled L-gulonic acid increased after administration of 6-14-C-glucuronolactone in the diabetic rabbits. L-Gulonic acid dehydrogenase, lactonase II, and beta-glucuronidase activities were reduced, and UDPGA-pyrophosphatase, D-glucuronic acid-1-phosphatase, and UDPGA-transferase activities increased in the diabetic rabbit liver. From these results, it may be concluded that an increase of endogenous D-glucuronic acid in the diabetic states could be attributed to a metabolid defect in the step of L-gulonic acid dehydrogenation and to the enhancement of UDPGA-pyrophosphatase and D-glucuronic acid-1-phosphate phosphatase activities.

Adipates↗
PubMed1993

Expression of follistatin messenger ribonucleic acid in Sertoli cell-enriched cultures: regulation by epidermal growth factor and protein kinase C-dependent pathway but not by follicle-stimulating hormone and protein kinase A-dependent pathway.

In this study the localization and regulation of steady-state follistatin messenger ribonucleic acid (mRNA) levels in testicular cell cultures were examined with a solution-hybridization assay using a specific 32P-labelled cytosolic RNA antisense probe for follistatin and a 35S-labelled cytosolic RNA antisense probe for cyclophilin as internal standard. Testes from immature rats were dispersed with collagenase and fractionated in Sertoli and Leydig cell-enriched cultures. Follistatin mRNA was mainly localized to the Sertoli cell-enriched fraction and the expression of follistatin mRNA could be stimulated in vitro with fetal calf serum, epidermal growth factor or phorbol-12-myristate-13-acetate (an activator of protein kinase C), whereas follicle-stimulating hormone and forskolin (an activator of protein kinase A) had no effect. Neither prostaglandin E2, the synthetic glucocorticoid RU 28362 or all-trans-retinoic acid, which all regulate follistatin mRNA levels in non-testicular cell types, nor extracellular adenosine triphosphate (a purinergic receptor agonist) or testosterone had any obvious influence on follistatin mRNA levels in Sertoli cell-enriched cultures. From this study it is concluded that Sertoli cells are likely to be the source of follistatin expression in the rat testis, that follistatin mRNA levels in Sertoli cell-enriched cultures are subjected to regulation by epidermal growth factor and the protein kinase C-dependent pathway but are not regulated by extracellular adenosine triphosphate, follicle-stimulating hormone, all-trans-retinoic acid, prostaglandin E2, forskolin, testosterone or the glucocorticoid RU 28362 and that the regulation of follistatin mRNA is sex- and tissue-specific.

Animals↗
PubMed2004

Cutting edge: TNFR-associated factor (TRAF) 6 is essential for MyD88-dependent pathway but not toll/IL-1 receptor domain-containing adaptor-inducing IFN-beta (TRIF)-dependent pathway in TLR signaling.

Signaling pathways from TLRs are mediated by the Toll/IL-1R (TIR) domain-containing adaptor molecules. TNF receptor-associated factor (TRAF) 6 is thought to activate NF-kappaB and MAPKs downstream of these TIR domain-containing proteins to induce production of inflammatory cytokines. However, the precise role of TRAF6 in signaling from individual TLRs has not been appropriately addressed. We analyzed macrophages from TRAF6-deficient mice and made the following observations. In the absence of TRAF6, 1) ligands for TLR2, TLR5, TLR7, and TLR9 failed to induce activation of NF-kappaB and MAPKs or production of inflammatory cytokines; 2) TLR4 ligand-induced cytokine production was remarkably reduced and activation of NF-kappaB and MAPKs was observed, albeit with delayed kinetics; and 3) in contrast with previously reported findings, TLR3 signaling was not affected. These results indicate that TRAF6 is essential for MyD88-dependent signaling but is not required for TIR domain-containing adaptor-inducing IFN-beta (TRIF)-dependent signaling.

Adaptor Proteins, Signal Transducing↗
PubMed2000

Inhibition of the mitogen activated protein kinase pathway potentiates radiation-induced cell killing via cell cycle arrest at the G2/M transition and independently of increased signaling by the JNK/c-Jun pathway.

The ability of low dose ionizing radiation (2 Gy) to modulate the activities of the mitogen activated protein kinase (MAPK) and c-Jun NH2-terminal kinase (JNK1) cascades in human monocytic leukemia (U937/pREP4) cells and in cells over-expressing dominant negative c-Jun (TAM67) (U937/TAM67) was investigated. Radiation exposure caused prolonged ( approximately 1 h) MAPK activations in U937 cells. In contrast, low dose irradiation weakly modulated JNK1 activity in these cells. Inhibition of the MAPK pathway by use of the specific MEK1/2 inhibitor (10 microM PD98059) in both U937/pREP4 and U937/TAM67 cells prior to radiation exposure permitted strong prolonged radiation-induced activations of JNK1. Expression of TAM67 decreased the ability of radiation to cause apoptosis compared to control transfected cells. However, combined MEK1/2 inhibition and radiation exposure in both cell types caused a large decrease in suspension culture growth and a large increase in apoptosis, when compared to either treatment alone. Reduced proliferation after combined irradiation and PD98059 treatment in both cell types correlated with prolonged cell cycle arrest in G2/M phase. Prolonged growth arrest was abolished when MEK1/2 inhibitor was removed 6 h following irradiation, which was associated with a reduction in apoptosis. The ability of MEK1/2 inhibition to cause prolonged G2/M growth arrest was reduced in U937 cells stably transfected with a p21Cip-1/WAF1 antisense construct (U937/p21AS). This data correlated with an enhancement of radiation-induced apoptosis and a reduced ability of MEK1/2 inhibition to potentiate apoptosis. Collectively our data demonstrate that inhibition of MEK1/2 function increases the radiation sensitivity of U937 cells, independently of c-Jun function, and decreases the ability of these cells to recover from the radiation-induced G2/M cell cycle checkpoint arrest. In addition, our data also demonstrate that the ability of MEK1/2 inhibition to potentiate radiation-induced cell death in U937 cells in part requires an ability of cells to express low levels of p21Cip-1/WAF1.

Apoptosis↗
PubMed2003

Flavopiridol induces apoptosis in glioma cell lines independent of retinoblastoma and p53 tumor suppressor pathway alterations by a caspase-independent pathway.

Flavopiridol is a synthetic flavone, which inhibits growth in vitro and in vivo of several solid malignancies such as renal, prostate, and colon cancers. It is a potent cyclin-dependent kinase inhibitor presently in clinical trials. In this study, we examined the effect of flavopiridol on a panel of glioma cell lines having different genetic profiles: five of six have codeletion of p16(INK4a) and p14(ARF); three of six have p53 mutations; and one of six shows overexpression of mouse double minute-2 (MDM2) protein. Independent of retinoblastoma and p53 tumor suppressor pathway alterations, flavopiridol induced apoptosis in all cell lines but through a caspase-independent mechanism. No cleavage products for caspase 3 or its substrate poly(ADP-ribose) polymerase or caspase 8 were detected. The pan-caspase inhibitor Z-VAD-fmk did not inhibit flavopiridol-induced apoptosis. Mitochondrial damage measured by cytochrome c release and transmission electron microscopy was not observed in drug-treated glioma cells. In contrast, flavopiridol treatment induced translocation of apoptosis-inducing factor from the mitochondria to the nucleus. The proteins cyclin D(1) and MDM2 involved in the regulation of retinoblastoma and p53 activity, respectively, were down-regulated early after flavopiridol treatment. Given that MDM2 protein can confer oncogenic properties under certain circumstances, loss of MDM2 expression in tumor cells could promote increased chemosensitivity. After drug treatment, a low Bcl-2/Bax ratio was observed, a condition that may favor apoptosis. Taken together, the data indicate that flavopiridol has activity against glioma cell lines in vitro and should be considered for clinical development in the treatment of glioblastoma multiforme.

Antineoplastic Agents↗
PubMed2003

Flamingo, a cadherin-type receptor involved in the Drosophila planar polarity pathway, can block signaling via the canonical wnt pathway in Xenopus laevis.

The Flamingo gene encodes a seven-pass transmembrane receptor of the cadherin super family and is one of a growing number of components identified as being necessary for the establishment of planar polarity in the Drosophila wing. Although vertebrate homologues of Flamingo have been identified in both man and mice, no function has as yet been ascribed to them. Here, we report the cloning of the Xenopus homologue of Flamingo (XFmi). XFmi is expressed in the dorsal ectoderm during gastrulation and in the forebrain and midbrain subsequently. We show that ectopic expression of the murine Flamingo gene can prevent the wnt mediated posteriorisation of the neural plate by interfering with the canonical wnt signalling pathway.

Animals↗
PubMedDate not supplied

Metabolic and endocrine modulation of anabolic and catabolic pathways of glucose and fatty acids. I. Chemical anatomy of the major metabolic pathways of the energogenic general function.

This study is an attempt to integrate the intermediary metabolism of energogenic substrates--glucose and fatty acids--within the framework of the energogenic general function (EGF), which is active in two distinct phases: anabolic and catabolic. EGF is a component of the metabolic general function (MGF), which together with the reproductive general function and the adaptation general function may be taken to represent three main "general functions of organisms" common to all beings, whether animal or vegetal. This initial paper presents, descriptively and graphically, the main anabolic functions and pathways of glucose and fatty acids and, separately, the main catabolic ones, in other words, the "chemical anatomy" of EGF. The study begins with the anabolic "digestive" function of the digestive tract, concerning the digestion and absorption of carbohydrates and proteins. Conversion of the non-absorbable macromolecules of ingested carbohydrates into absorbable micromolecules of glucose, is shown to enable the latter, after absorption, to carry out the two characteristic anabolic processes: transmembrane "transport" and "condensation". Absorption and vehiculation of hydrophobic lipids is carried out by means of the major function of intestinal cells: synthesis of chylomicrons. Chylomicrons are hydrophilic special lipoprotein particles which are able to transport fats to the adipose tissue and cholesterol to the liver. In the liver the anabolic aspects of EGF are represented by two main functions: glycogeno-genesis, i.e. "non-reductive" condensation of glucose into glycogen stores, and lipoproteino-genesis, i.e. "reductive" condensation of glucose into lipoproteins or VLDL (very low density lipoproteins). VLDL are hydrophilic (vehiculable) spheric particles (containing triacylglycerols and cholesteryl esters in their core, and phospholipids, cholesterol and apolipoprotein-B at their surface), which are to be released into the general circulation. The anabolic phase in the muscles is characterized by the transmembrane "transport" of glucose and its "condensation" into intracellular glycogen stores; in the adipose tissue it is characterized by accumulation of triacylglycerols. The chemical anatomy of the "gluco-keto-productive" catabolic liver is clearly different from that of the "VLDL-productive" anabolic liver. Hepatic production of glucose (gluco-genesis) is achieved via glycogeno-lysis and via gluco-neo-genesis (GNG) from lactate, amino acids and glycerol. Hepatic production of ketone bodies (keto-genesis) is achieved through processing the fatty acids mobilized from the adipose tissue.(ABSTRACT TRUNCATED AT 400 WORDS)

Adipose Tissue↗
PubMed1995

Activation of the mitogen-activated protein kinase/cytosolic phospholipase A2 pathway in a rat mast cell line. Indications of different pathways for release of arachidonic acid and secretory granules.

The role of mitogen-activated protein (MAP) kinase in the release of arachidonic acid was examined in a mutated mast cell (RBL-2H3(m1)) line that expressed both native Fc epsilon R1 and the G protein-coupled muscarinic m1 receptor. Stimulation of these cells with Ag, carbachol, Ca(2+)-ionophore, or thapsigargin resulted in the phosphorylation of Raf1, MEK1, p42mapk MAP kinase, and the recently cloned cytosolic phospholipase A2 (PLA2) and increased activities of both MAP kinase and PLA2, as well as release of arachidonic acid. Because this cascade of reactions was inhibited by guanosine 5'-(2-thiodiphosphate), it appeared to be dependent on a GTP-binding protein(s). These reactions, however, were not dependent on protein kinase C; the cascade was totally resistant to the actions of a selective protein kinase C inhibitor, Ro31-7549, whereas release of the secretory granule marker, hexosaminidase, was blocked by this agent. Differences between the stimulatory pathways for release of arachidonic acid and hexosaminidase were evident also from the effects of the kinase inhibitor, quercetin. The above cascade of reactions, including release of arachidonic acid, was inhibited by 50% with approximately 5 microM quercetin, whereas secretion was inhibited only at higher concentrations of inhibitor. Moreover, inhibition of the activation of MAP kinase and release of arachidonic acid were closely correlated. This and previous findings suggested that release of arachidonic acid was attributable to the regulation of cytosolic PLA2 by MAP kinase (for activation of PLA2) and Ca2+ (for association of PLA2 with the membrane), whereas release of hexosaminidase was regulated primarily by Ca2+ and protein kinase C.

Animals↗
PubMed1994

Signal transduction pathway in human polymorphonuclear leukocytes for chemotaxis induced by a chemotactic factor. Distinct from the pathway for superoxide anion production.

The tyrosine kinase inhibitors erbstatin and herbimycin A inhibited the chemotactic response to FMLP (2 x 10(-7) M) and the superoxide anion (O2-) production stimulated by FMLP (1 x 10(-6) M) in human polymorphonuclear leukocytes (PMN) in similar manners. These compounds also inhibited phospholipase D (PLD)-catalyzed breakdown of phosphatidyl choline, suggesting a possible link between tyrosine kinase and PLD. In the presence of propranolol (phosphatidic acid (PA) phosphohydrolase inhibitor), or ethanol, the activation of PLD results in the modulation of PA and/or diglyceride (DG) generation, producing an irregularity in O2- production. However, PMN motility was not affected in these conditions. These results suggest that PLD is a downstream effector of FMLP-induced tyrosine kinase activation that leads to activation of the PMN superoxide release but not to chemotactic migration. In contrast, the tyrosine kinase inhibitors did not inhibit inositol 1,4,5-triphosphate generation and increase of intracellular concentration of free calcium. Furthermore, a protein kinase C inhibitor, 1-(5-isoquinolinesulfonyl)-2-methylpiperazine dihydrochloride (H-7), did not affect the migration of PMN and the activation of PLD induced by FMLP at concentrations of less than 50 microM. These results support the premise that there is a specific signaling pathway for chemoattractant-induced PMN locomotion.

1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗
PubMed1995

Protein kinase C-dependent and -independent pathways of signal transduction in prostate cancer cells: fibroblast growth factor utilization of a protein kinase C-independent pathway.

To examine the possibility that differences in protein tyrosine phosphorylation contributed to differences in fibroblast growth factor (FGF) responsiveness of clonally derived C3 (modestly responsive) and T5 (highly responsive) rat prostate cancer cells, we evaluated the ability of orthovanadate to affect prostate cancer cell thymidine incorporation. These analyses showed that C3 cell FGF insensitivity was not attributable to enhanced protein phosphotyrosine phosphatase activity. Analyses of acidic FGF (aFGF)-mediated protein phosphorylation showed mitogen-caused, time-dependent tyrosine phosphorylation of C3 and T5 cell FGF receptors (FGFRs) and other proteins having a mass of 190, 150, 120, 100, 90, 80, 74, 60/62, 50, 42, or 28 kilodaltons. Although marked differences characterized aFGF mediated intensity of tyrosine phosphorylation, the notable commonality of tyrosine phosphorylation and the mass of the phosphorylated proteins suggested that C3 and T5 cells may use the ras and/or protein kinase C (PKC) pathways for FGF-mediated signal transduction. The PKC agonist 12-O-tetradecanoyl-phorbol-13-acetate (TPA) caused concentration-dependent increases in T5 cell thymidine incorporation. In contrast, TPA did not enhance thymidine incorporation of C3 cells or mitogen-sensitive NRK cells included as a nonneoplastic control. TPA also significantly enhanced T5 cell proliferation, whereas identical treatment did not affect proliferation of either C3 or NRK cells. Either 12 or 24 h treatment with 200 or 2000 ng/ml TPA caused complete PKC alpha and partial PKC delta down-regulation in C3, T5, and NRK cells. Consequently, the failure of TPA to affect C3 or NRK cell thymidine incorporation or proliferation was not attributable to potential TPA ineffectiveness in these cells. Survey immunological analyses showed that all three cell lines lacked PKC beta, PKC eta, and PKC theta. In contrast, T5 cells contained abundant amounts of PKC epsilon, whereas the PKC epsilon content of C3 and NRK cells was near the limit of detection. TPA treatment of T5 cells evoked only partial PKC epsilon down-regulation. Both aFGF and basic FGF (bFGF) promoted concentration-dependent enhancement of TPA-pretreated T5 cell thymidine incorporation, and the effects of combined TPA and either aFGF or bFGF treatment were additive. Neither aFGF nor bFGF was able to enhance thymidine incorporation of TPA-pretreated C3 cells beyond the modest effects elicited by FGF treatment of C3 controls.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1995

In vitro studies to elucidate the metabolic pathway of (+)-S-145, a thromboxane A2 receptor antagonist, in rats. Evidence for two independent pathways in peroxisomal beta-oxidation.

The metabolism of (+)-S-145, a thromboxane A2 receptor antagonist, was investigated in vitro using isolated hepatocytes, liver homogenates, and subcellular fractions prepared from rats. The cofactor requirement and subcellular distribution of beta-oxidation and hydroxylation suggested that the chain shortening of the carboxyl side chain of (+)-S-145 was catalyzed by beta-oxidation enzyme systems in peroxisomes and hydroxylation at the C-5 and C-6 positions of the bicyclo ring was catalyzed by monooxygenases in microsomes, respectively. In the initial stage of metabolism of (+)-S-145, the potential of activation to its coenzyme A (CoA) thio ester was prominent, compared with that of the hydroxylation. The resulting (+)-S-145-CoA was beta-oxidized. There seems to be two metabolic pathways in the metabolism of (+)-S-145-CoA. One is the biotransformation of (+)-S-145-CoA to bisnor-(+)-S-145 and tetranor-(+)-S-145 in the beta-oxidation cycle, and the other is the reduction of (+)-S-145-CoA to dihydro-(+)-S-145-CoA by NADPH dependent delta 5-reductase followed by beta-oxidation to dihydrobisnor-(+)-S-145, which was scarcely beta-oxidized to tetranor-(+)-S-145. Finally, these beta-oxidized metabolites are hydroxylated by monooxygenases in microsomes at the 5- or 6-position of their bicyclo ring, whereas beta-oxidation activity of hydroxylated metabolites of (+)-S-145 was not observed in the light mitochondrial fraction nor in isolated hepatocytes.

Animals↗
PubMed1996

Initiation of the tissue factor pathway of coagulation in the presence of heparin: control by antithrombin III and tissue factor pathway inhibitor.

Activation of factor X by both the unactivated tissue factor:factor VII complex (TF:VII) and the activated tissue factor:factor VIIa complex (TF:VIIa) has been studied in the presence of tissue factor pathway inhibitor (TFPI), antithrombin III (ATIII), and heparin. At near-plasma concentrations of TFPI, ATIII, and factor X, factor X activation that occurs in response to TF:VII is essentially abolished in the presence of heparin (0.5 micromol/L). This effect requires both inhibitors, acting on different targets: (1) ATIII, which in the presence of heparin blocks the activation of TF:VII, and (2) TFPI, which inhibits the TF:VIIa that is generated. In the absence of ATIII, TFPI alone with heparin reduces but does not abolish factor X activation. Conversely, in the absence of TFPI, ATIII + heparin reduces but does not abolish TF:VIIa generation and allows continuing activation of factor X. These results indicated that when the unactivated TF:VII complex is the initiating stimulus, heparin-dependent reduction in the rate and extent of factor X activation requires both ATIII and TFPI. In contrast, if TF:VIIa is used to initiate activation, only TFPI is involved in its regulation.

Amino Acid Chloromethyl Ketones↗
PubMed1997

The importance of the binding of factor Xa to phospholipids in the inhibitory mechanism of tissue factor pathway inhibitor: the transmembrane and cytoplasmic domains of tissue factor are not essential for the inhibitory action of tissue factor pathway inhibitor.

To investigate the inhibitory mechanism of tissue factor pathway inhibitor (TFPI), an attempt was made to examine the inhibitory activity of TFPI toward the factor VIIa-truncated tissue factor (TF1-219) complex, which lacks its transmembrane and cytoplasmic domains. Factor VIIa-TF1-219 activity was significantly inhibited by TFPI-factor Xa complex in the presence of phospholipids, but was not in the absence of phospholipids. In addition, TFPI did not inhibit factor VIIa-TF1-219 activity in the presence of gamma-carboxyglutamic acid-domainless factor Xa. The ability of TFPI-factor Xa complex to inhibit factor VIIa-TF1-219 activity was totally dependent on the presence of phospholipids and was neutralized by prothrombin fragment 1 in a dose-dependent manner. These results indicate that the transmembrane and cytoplasmic domains of tissue factor are not essential for the inhibitory mechanism of TFPI and confirm that the binding of factor Xa to phospholipids through its gamma-carboxyglutamic acid domain is essential for this reaction.

Anticoagulants↗