PubMed Health⌕ Search

Biomedical subjects

U Tibes

Publications and source records attributed to U Tibes.

At least 19 recordsLinked to original sources
PubMed2000

Inhibition of cytosolic phospholipase A(2) attenuates activation of mitogen-activated protein kinases in human monocytic cells.

Eicosanoids and platelet-activating factor generated upon activation of cytosolic phospholipase A(2) enhance activity of transcription factors and synthesis of proinflammatory cytokines. Here, we show that selective inhibitors and antisense oligonucleotides against this enzyme suppressed expression of the interleukin-1beta gene at the level of transcription and promoter activation in human monocytic cell lines. This inhibitory effect was due to failure of activation of mitogen-activated protein kinases (MAPK) through phosphorylation by upstream mitogen-activated protein kinase kinases (MKK). Consequently, phosphorylation and degradation of inhibitor-kappaBalpha (I-kappaBalpha) and subsequent cytoplasmic mobilization, DNA-binding and the transactivating potential of nuclear factor-kappaB (NF-kB), nuclear factor-interleukin-6 (NF-IL6), activation protein-1 (AP-1) and signal-transducer-and-activator-of-transcription-1 (STAT-1) were impaired. It is concluded, that lipid mediators promote activation of MAPKs, which in turn lead to phosphorylation and liberation of active transcription factors. Since inhibition of cytosolic phospholipase A(2) ameliorates inflammation in vivo, this potency may reside in interference with the MAPK pathway.

Arachidonic Acid↗
PubMed1999

Activation of nuclear factor-kappaB by lipopolysaccharide in mononuclear leukocytes is prevented by inhibitors of cytosolic phospholipase A2.

In monocytes, lipopolysaccharide induces synthesis and activity of the 85-kDa cytosolic phospholipase A2. This enzyme releases arachidonic acid and lyso-phospholipids from membranes which are metabolized to eicosanoids and platelet-activating-factor. These lipid mediators increase activity of transcription factors and expression of cytokine genes indicating a function for cytosolic phospholipase A2 in signal transduction and inflammation. We have shown previously that trifluoromethylketone inhibitors of cytosolic phospholipase A2 suppressed interleukin-1beta protein and steady-state mRNA levels in human lipopolysaccharide-stimulated peripheral blood mononuclear leukocytes. In this study, the subcellular mechanisms were analyzed by which trifluoromethylketones interfere with gene expression. We found that they reduced the initial interleukin-1beta mRNA transcription rate through prevention of degradation of inhibitor-kappaB alpha. Consequently, cytosolic activation, nuclear translocation and DNA-binding of nuclear factor-kappaB were decreased. Trifluoromethylketones ameliorate chronic inflammation in vivo. Thus, this therapeutic potency may reside in retention of inactive nuclear factor-kappaB in the cytosol thereby abrogating interleukin-1beta gene transcription.

Animals↗
PubMed1999

Suppression of acute experimental inflammation by antisense oligonucleotides targeting secretory phospholipase A2 (sPLA2) in vitro and in vivo experiments.

In HepG2 cells phosphorothioate modified antisense oligonucleotides against a sequence in the Ca2+ binding domain (AS-Ca2+) of type II sPLA2 mRNA restrained IL-6-induced synthesis of sPLA2 protein, sPLA2 mRNA (northern blot), and abolished IL-6 stimulated PGE2 release. An antisense oligonucleotide corresponding to a sequence in the catalytic domain (AS-Cat) of sPLA2 was less effective. The antisense oligonucleotides did not affect albumin synthesis in HepG2 cells, additionally demonstrating their specificity. The corresponding AS-Ca2+ against a homologous part of the rat sPLA2 mRNA depressed rat carrageenin oedema for 60-70%. Identical suppression was achieved by specific low molecular weight inhibitors of sPLA2. Since cyclo- and 5-lipoxygenase inhibitors exerted similar reductions of carrageenin oedema type II sPLA2 dependent eicosanoid formation seems to be a key cascade in this type of inflammation.

Acetates↗
PubMed1997

Suppression of cytokine synthesis, integrin expression and chronic inflammation by inhibitors of cytosolic phospholipase A2.

To define the isoform of phospholipases A2 active in inflammation we evaluated the effects of low-molecular-weight inhibitors of secretory and cytosolic phospholipases A2. We found that inhibitors of cytosolic phospholipase A2 had therapeutic efficacy in an in vivo model of chronic inflammation (rat adjuvant arthritis), whereas inhibitors of secretory phospholipase A2 had no beneficial effect. In vitro, inhibitors of cytosolic phospholipase A2 diminished surface expression of Mac-1 (CD11b/CD18) beta2-integrin on calcium ionophore-stimulated human blood granulocytes and suppressed synthesis of interleukin-1beta in lipopolysaccharide-stimulated human blood monocytes and U937 cells by reducing mRNA levels. Lipid mediators promote Mac-1 exocytosis and transcription of interleukin-1beta, which further enhances cytosolic phospholipase A2 activity and expression. Thus, superinduction of cytosolic phospholipase A2 may establish a positive feedback loop, converting acute inflammation into chronic inflammation. Consequently, inhibitors of cytosolic phospholipase A2 may prevent inflammation in vivo by interfering with cellular activation and infiltration. We conclude that cytosolic phospholipase A2 but not secretory phospholipase A2 is the predominant enzyme in inflammatory signalling.

Animals↗
PubMed1997

Phospholipase A2 inhibitors in development.

To date, three isoforms of phospholipase A2 (PLA2) have been identified. Of these, the two Ca2+-dependent isoforms, secretory (sPLA2) and cytosolic phospholipase A2 (cPLA2), are targets for new anti-inflammatory drugs. The catalytic mechanisms and functions of the third isoform, Ca2+-independent cytosolic phospholipase A2 (iPLA2), are unknown at present. sPLA2 and cPLA2 are both implicated in the release of arachidonic acid and prophlogistic lipid mediators. However, recent findings provide evidence that cPLA2 is the dominant isoform in various kinds of inflammation, such as T-cell-mediated experimental arthritis. A triple function of PLA2-derived lipid mediators has been suggested: causing immediate inflammatory signs, involvement in secondary processes, e.g., superoxide free radical (O2) generation, apoptosis, or tumour necrosis factor-alpha (TNF-alpha)-cytotoxicity, and controlling the expression and activation of pivotal proteins implicated in inflammation and cell development, e.g., cytokines, adhesion proteins, proteinases, NF-kappaB, fos/jun/AP-1, c-Myc, or p21ras. In the past, research predominantly focused on the development of sPLA2 inhibitors; however, present techniques enable discrimination of cPLA2, sPLA2, and iPLA2, and specific inhibitors of each of the three isoforms are likely to appear soon. Over the last decade, between 40 and 50 sPLA2 inhibitors have been described; and the list is growing. However, of these, few have the potential for clinical success, and those that do are predominantly active site-directed inhibitors, e.g., BMS-181162, LY311727, ARL-67974, FPL67047, SB-203347, Ro-23-9358, YM-26734, and IS-741. At present, there are no likely clinical candidates emerging from the ranks of cPLA2 and iPLA2 inhibitors in development. Indications for which PLA2 inhibitors are being pursued include, sepsis, acute pancreatitis, inflammatory skin and bowel diseases, asthma, and rheumatoid arthritis. The three main obstacles to the successful development of PLA2 inhibitors include, insufficient oral bioavailability, low affinity for the enzyme corresponding to low in vivo efficacy and insufficient selectivity.

Journal Article↗
PubMed1994

Induction of cytosolic phospholipase A2 in human leukocytes by lipopolysaccharide.

Stimulation of peripheral blood leukocytes with lipopolysaccharide results in the synthesis of inflammatory cytokines including interleukin-1 beta, interleukin-6, tumor necrosis factor-alpha and prostaglandin E2 correlating with an increase in phospholipase A2 activity. Mammalian cells contain several phospholipase A2 isoforms including the 14-kDa secretory isoform and the more recently described high-molecular-mass cytosolic isoform. It is commonly believed that during inflammatory responses secretory phospholipase A2 becomes activated. However, we could not detect secretory phospholipase A2 nor its corresponding mRNA after lipopolysaccharide-induced activation. By contrast, we found increased mRNA levels for cytosolic phospholipase A2 following activation of peripheral blood leukocytes when levels were compared to non-stimulated controls. Our results demonstrate that cytosolic phospholipase A2, rather than the secretory isoform may be the mediator of the lipopolysaccharide-induced inflammatory cascade in human peripheral blood leukocytes.

Base Sequence↗
PubMed1986

Fenetylline: new results on pharmacology, metabolism and kinetics.

In the fenetylline molecule, theophylline is covalently linked with amphetamine via an alkyl chain. The inclusion of amphetamine and results from early metabolic studies have led to speculation that fenetylline may be merely a prodrug for amphetamine and/or theophylline. Although previous studies are not consistent with this hypothesis, additional studies were conducted to comparatively evaluate the profiles of activity exhibited by fenetylline and its two postulated primary metabolites, (+/-)-amphetamine and theophylline. Investigations were also initiated using newly developed high pressure liquid chromatography (HPLC) techniques to further characterize the metabolic pattern that fenetylline undergoes and to examine the relationship between plasma pharmacokinetics and the pharmacodynamic actions of the drug. Fenetylline inhibits activity associated with amphetamine in certain test systems, an effect similar to that previously observed with fenfluramine. Only small amounts of the amphetamine theoretically available in the fenetylline molecule are released. Pharmacodynamic activity associated with fenetylline administration is more closely tied to plasma levels of the parent compound than to any (+/-)-amphetamine produced.

Amphetamines↗
PubMed1986

'Fingerprints' of central stimulatory drug effects by means of quantitative radioelectroencephalography in the rat (tele-stereo-EEG).

The new electrophysiological model earlier described as stereo-EEG is extended now to allow recording from the freely moving rat by means of a telemetric device. Chronic implantation of 4 electrodes into the brain allows simultaneous transmission of field potentials from frontal cortex, hippocampus, striatum and reticular formation. Frequency analysis of these potentials results in a drug-specific 'fingerprint' which cannot only be used to compare different chemicals with each other but also to detect onset and time dependence of drug actions. Application of the model to the question if fenetylline has its own intrinsic mode of action or merely develops its stimulatory effect after metabolic separation into its molecular moieties amphetamine and theophylline (prodrug hypothesis) revealed that fenetylline indeed displays its own stimulatory effect to the same extent and at a similar time course as amphetamine and theophylline. The 'fingerprint' as obtained by the analysis of the action of fenetylline in the rat resembles closely that obtained after the application of theophylline with respect to decreased alpha activity, but resembles amphetamine with respect to beta 1 activity. Thus the applied method allows studying structure function relationships as the action of fenetylline seems to reflect both its molecular moieties.

Amphetamine↗
PubMed1985

[Mechanism of action of the analgesic flupirtine].

To answer the questions of mode and site of action partly supplementary, partly new investigations with flupirtine (Katadolon) were carried out which are described below. The investigation for opiate receptor affinity of flupirtine in rat brain homogenate did not show any reduction in 3He-etorphine binding up to the highest concentration of flupirtine of 10(-5) mol/1. This result suggests that flupirtine either has a very low opiate receptor affinity or lacks it fully. Therefore the analgesic activity of flupirtine is not based on opiate mechanism. The intracerebroventricular and intrathecal administration of flupirtine and the other analgesics tested showed dose dependent analgesic activity in doses which, when applied systemically, did not cause any analgesia in rats. Thus these substances show cerebral or spinal analgesic activity. In relation to the effective doses (ED50 in micrograms/rat) flupirtine was of the same efficacy in both kinds of administration. Pethidine tested comparatively was found to be less potent by intrathecal than by intracerebroventricular application. On the other hand, morphine was weaker by intracerebroventricular than by intrathecal application. As in the experiments by oral administration, naloxone did not show any effect on the analgesic activity of flupirtine, neither by intracerebroventricular nor by intrathecal application. On the other hand, the analgesic effects of pethidine and morphine were completely suppressed by naloxone. These results demonstrate that the analgesic activity of flupirtine is not caused by the opiate mechanism.(ABSTRACT TRUNCATED AT 250 WORDS)

Aminopyridines↗
PubMed1979

Effects and post-effects of two-hour exhausting exercise on composition and gas transport functions of blood.

Eleven male sport students (age 23.3 +/- 1.7 years) exercised for 2 h on a bicycle ergometer (60 rpm), the braking force of which was regulated to yield a constant pulse rate (156 +/- 3 min-1). Before, at end of, and 3 and 6 h after exercise blood was sampled from a cubital vein and an earlobe for measurement of hemoglobin (Hb) concentration, hematocrit (Hct) value, osmolality (Osm), plasma protein (Prot), sodium (Na+), potassium (K+), inorganic phosphate (Pi), and lactate (Lac) concentrations, red cell 2,3-diphosphoglycerate (DPG) and adenosin triphosphate (ATP) concentrations, acid base status and half saturation pressure (P50) of the oxygen dissociation curve. At end of exercise [Hb], Hct, [Prot], Osm, [K+], [Pi] and [Lac] were significantly elevated, pH in ear lobe (+ 0.04) and venous blood (+ 0.08) was also increased by both respiratory and nonrespiratory effects (BE + 1.4 mmol/l). The oxygen dissociation curve showed an unexplained slight right shift (standard P50 + 0.19 kPa). During the post-exercise period most parameters approximated to control values after only 3 h. [Prot] and especially [Pi], however, remained elevated while [DPG] slightly rose during the post-exercise period. It is suggested that these changes are first signs of adaptation to exercise, perhaps caused by endocrine stimulation.

Acid-Base Equilibrium↗
PubMed1977

Effect of contraction on lymphatic, venous, and tissue electr-lytes and metabolites in rabbit skeletal muscle.

The effect of muscle contraction on lymphatic and plasma [K+], [Na+], [Ca2+], [Mg2+], [Cl-], [Pi], [lactate] ([Lac-]); [creatine] ([Cr]), ideal osmolality (OSM), and [protein] was evaluated in femoral venous blood and lymph specimens sampled from the calf muscles of rabbits before, in the course of, and after contractions. In addition, total [K+], [Na+], [Ca2+], [Mg2+], [Cl-], and [H2O] were analyzed in the muscle tissue. To facilitate lymph sampling both hind limbs were passively flexed and extended, in imitation of natural running movements, by an electrically driven crank. The muscles of one side also performed superimposed rhythmic isotonic contractions. Before contractions, lymphatic [K+], [Na+], [Ca2+], [Mg2+], [Lac-], [Cr], and OSM did not significantly differ from corresponding femoral venous concentrations, [Cl-], and [Pi] were significantly higher, [protein] significantly lower in the lymph than in the plasma. During contractions lymphatic [K+], OSM, [Lac-], and [Pi] were raised significantly more in the lymph compared with the plasma concentrations. [Na+], [Cl-], [Ca2+], and [Mg2+] showed only small changes in the course of contractions and thereafter, and they were altered in a similar way in the lymph and plasma. It was suggested that lymphatic and interstitial concentrations were in equilibrium. Comparing inactive with active muscles, the latter lost K+ but gained Na+, Cl-, and H2O, whereas minimal changes occurred in the [Ca2+] and [Mg2+]. The changes were discussed in connection with the hypothesis that electrolyte shifts might be involved in the activation of the muscular non-proprioceptive interstitial nerve endings which appear to play a role in reflexogenic cardiovascular and respiratory control.

Animals↗
PubMed1977

Heart rate and ventilation in relation to venous [K+], osmolality, pH, PCO2, PO2, [orthophosphate], and [lactate] at transition from rest to exercise in athletes and non-athletes.

To evaluate to what metabolci event in contracting muscles heart rate (HR) and VE are related, time courses of femoral and cubital venous [K=], osomolality (OSM), pH, POC2, PO2, [lactate], and [orthophosphate] ([Pi]) at onset of exercise were studied in athletes (TR) and non-athletes (UT) and compared to time courses of HR and VE. During ischaemic work with the calf muscles it could be shown that most of these blood constituents were only released from contracting muscles. Thus their time courses reflected the metabolic events in working muscles being not essentially disturbed by non-working parts of the body. Ischaemic work induced, however, substantial increases of HR and VE. In the course of non-ischaemic bicycle work HR and VE rose more rapidly in TR than in UT but were lower in TR during the steady state. During non-ischaemic work only the increased of femoral venous [K=1 closely mimicked the cardiorespiratory transients in TR as well as in UT. None of the other femoral venous substances showed such a rapid change or such typical variations between TR and UT. Cubital venous [K=1 and [Pi] approached femoral venous concentrations only in second minute after start whereas pH, PCO2, and OSM increased mainly in venous outflow from contracting muscles. PO2 decreased in femoral venous blood of TR and UT, but in cubital venous blood it remained depressed only in UT. It was discussed that the cardiorespiratory adjustment during the initial stages of work was related to K+ release in working muscles and not to O2 consuming or H+ producing processes, nor to release of Pi or increase of OSM.

Blood↗
PubMed1976

Red cell hemoglobin, hydrogen ion and electrolyte concentrations during exercise in trained and untrained subjects.

Red cell concentrations of hemoglobin (MCHC), H+, Na+, K+, Mg++, cl- were measured in femoral venous blood of six untrained (UT), six endurance trained (TR) and three semitrained (ST) subjects during graded increasing work (4, 8, 12, 18 and 24 mkp/s, 10-15 min on each step) on a bicycle ergometer. Before exercise no significant differences were detected for the measured variables when comparing UT and TR. During exercise MCHC, [Na+], [K+] and [Mg++] remained constant indicating lack of water shift into the erythrocytes in spite of a marked acidosis (lowest pH Blood value 7.225). This lack resulted from an elevated extracellular osmolality. [H+]Ery and [Cl-]Ery maximally increased by 2.0 X 10(-8) eq/kg H2O and 10 meq/l, respectively. The change was markedly greater in UT than in TR at equal load. However, if [H+] Ery and [Cl-] Ery were related to pH of whole blood, differences between groups, almost disappeared and the ions were distributed as predictable from in vitro experiments (Fitzsimmons and Sendroy, 1961). Behaviour of H+ and Cl- may be of importance for oxygen dissociation under in vivo conditions.

Adult↗
PubMed1976

Relationships of femoral venous [K+], PO2, osmolality, and [orthophosphate) with heart rate, ventilation, and leg blood flow during bicycle exercise in athletes and non-athletes.

The relationship of femoral venous [K+], [H+], osmolality (OSM), PO2, and [inorganic phosphate] ([Pi]) with heart rate (HR), ventilation (VE), and calculated leg blood flow (Q) were investigated during bicycle exercise in endurance trained (TR) and untrained (UT) test subjects. At a given VO2 the increases of [K+], OSM, [Pi] and the decrease of PO2 were significantly lower in TR than in UT. In the same proportion the increases of HR, VE, and Q were diminished. Thus in TR and UT identical and highly significantly correlated regression lines of [K+], [H+], OSM, [Pi] and PO2 with HR, VE, and Q were obtained. These constituents changed in the same proportion as the relative VO2 in TR and UT. No relationships with [Na+], [Ca++], and [ Mg++] were found. By means of a multiple regression analysis the partial influence of K+, H+, OSM, PO2, and Pi upon the total change of HR, VE and Q was estimated to compare with data from infusion experiments. The findings were discussed in view of the hypothesis that these candidates may provide linkage between metabolic events, circulatory, and ventilatory adjustments during work.

Adult↗