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At least 163 records · Page 9Linked to original sources
PubMed2002

Impaired lipoprotein metabolism in obese offspring of streptozotocin-induced diabetic rats.

The time course of changes in lipoprotein metabolism of obese offspring of mildly diabetic rats was studied with respect to serum lipoprotein composition as well as LCAT and tissue lipoprotein lipase (LPL) activities. Mild hyperglycemia in pregnant rats was induced by intraperitoneal injection of streptozotocin on day 5 of gestation. Control pregnant rats were injected with citrate buffer. At birth, obese pups had higher serum glucose, insulin, and lipoprotein (VLDL, LDL-HDL1, HDL(2-3)) levels than control pups. After 1 mon of life, all of these parameters in obese rats became similar to those of controls. However, LCAT, adipose tissue LPL, and hepatic triacylglycerol lipase activities were high. At 2 mon of age, VLDL-TAG levels were higher in obese females than in controls. By the age of 3 mon, obese offspring had developed insulin resistance with hyperglycemia, hyperinsulinemia, and higher serum lipoprotein concentrations. Indeed, qualitative abnormalities of lipoproteins were seen and were typical of obese and diabetic human beings. Fetal hyperinsulinemia should be considered as a risk factor for later metabolic diseases, including dyslipoproteinemia.

Adipose Tissue↗
PubMed1990

Effects of bepridil and CERM 4205 (ORG 30701) on the relation between cardiac cycle length and QT duration in healthy volunteers.

Bepridil is a calcium antagonist that prolongs the duration of ventricular repolarization, whereas CERM 4205, another calcium antagonist, seems to be devoid of any effect on QT interval. The aim of this study was to compare the effects of bepridil and CERM 4205 on the QT-RR relation at different heart rates during rest and exercise and the results of pharmacologic tests designed to vary neurovegetative tone. Twelve healthy men (21 to 37 years) participated in a placebo-controlled, randomized, crossover, double-blind study and received either bepridil (200 mg/day twice daily) or CERM 4205 (200 mg/day twice daily), or matching placebo during three 14-day treatment periods at 2-week intervals. Bepridil, but not CERM 4205, caused a significant prolongation of resting QT interval. The RR-QT relation was monoexponential for all subjects during resting and exercising physiologic conditions and remained unchanged after 14 days with placebo or CERM 4205. Bepridil significantly shifted the relation upward, resulting in a rate-dependent QT prolongation that predominated during bradycardia. After isoprenaline, QT no longer adapted to changes in heart rate, whereas atropine resulted in a rate-dependent shortening in QT. These results suggest that bepridil and CERM 4205 exert different effects on ventricular repolarization, since only bepridil significantly prolonged QT duration. Bepridil-induced prolongation of QT increased at slow heart rates, which could explain the greater incidence of torsades de pointes in bradycardia.

Adult↗
PubMed1993

Peptide hormone-membrane interactions. Intervesicular transfer of lipophilic gastrin derivatives to artificial membranes and their bioactivities.

Incorporation of di-fatty acylglycerol moieties at the N-terminus of human little-gastrin-(2-17) leads to self-aggregation of the resulting lipo-gastrins into stable, most probably fluid vesicles. Net intervesicular transfer of the lipo-gastrins to phosphatidyl-choline model bilayers occurs at high rates whereby the chain length of the gastrin lipid moiety was found to affect the transfer rate more decisively than the nature of the acceptor vesicle. Similarly, the bioactivity of the lipo-gastrins is again affected by the nature of the lipid moiety suggesting differentiated interdigitation with the natural bilayer components and thus, different two-dimensional migration rates to the target receptors. Embedment of the lipo-gastrins in phosphatidylcholine bilayers at high lipid/gastrin ratios as mimicry of the cell membrane bound state does not result in onset of ordered structure, but leads to full exposure of the gastrin in essentially randomly coiled form at the water/lipid interface. This may result from the artificial N-terminal anchorage of the gastrin molecules to the bilayers, but also from the relatively tight packing of the phosphatidylcholine vesicles. Nevertheless, this observation might suggest that in the present case membrane-induced conformation and orientation may not represent a pre-requisite for the hormone receptor binding process. However, the results of this study clearly confirm even for the non-amphiphilic hormone gastrin a membrane-bound pathway for receptor recognition and occupancy.

1,2-Dipalmitoylphosphatidylcholine↗
PubMed1993

Sequential modifications of topoisomerase I activity in a camptothecin-resistant cell line established by progressive adaptation.

The DNA-topoisomerase I (Topo I) inhibitor, camptothecin (CPT), is a plant alkaloid with an important antitumor activity. In order to investigate the cellular mechanism leading to the development of the resistance to this agent, we have established by progressive adaptation a P388 subline resistant to CPT. After 5 months of continuous drug exposure, the resistance index reached a value of 20 and the resistant cell line, P388CPT0.3, was maintained in the presence of CPT. CPT-induced single strand breaks measured by alkaline elution were found drastically reduced in the resistant cell line. Topo I activity and CPT-induced DNA cleavage were measured on cells at different steps of resistance. We first observed that the Topo I activity was strongly decreased. In addition, the resistant cells recovered the ATP-independent relaxation activity after 3 months of exposure to CPT, but still kept a reduced CPT-induced DNA cleavage. Further evaluations at the final stage of the resistance induction have indicated that cells presented a CPT-resistant form of Topo I. Rearranged Topo I gene on one allele and a reduced Topo I transcription were also observed in resistant cells. The putative role of the rearrangement was discussed. These data show that the resistance mechanism has evolved from a decreased Topo I activity to an altered form of the enzyme, and suggest that multiple mechanisms of Topo I modifications could contribute to CPT resistance.

Animals↗
PubMed1994

A human small cell lung carcinoma cell line, resistant to 4'-(9-acridinylamino)-methanesulfon-m-anisidide and cross-resistant to camptothecin with a high level of topoisomerase I.

N417/AMSA cells, about 80-fold resistant to mAMSA [4'-(9-acridinylamino)-methanesulfon-m-anisidide], were obtained by serial passages of the parental human small cell lung carcinoma NCI-N417 (N417/p) in stepwise drug concentrations. The N417/AMSA cells were found to be 114-, 100-, and 9-fold cross-resistant to the topoisomerase II (Topo II) inhibitors VM26, VP16 and Doxorubicin (DXR); they showed a 2-fold decrease in Topo II activity. Interestingly, N417/AMSA cells which exhibited a 3-fold increase in topoisomerase I (Topo I) activity were 28-fold cross-resistant to camptothecin (CPT), a specific inhibitor of Topo I. In order to investigate the cellular mechanisms leading to the development of resistance, the effects of mAMSA and CPT on parental and resistant cell lines were analysed by alkaline elution. A decrease in DNA single-strand breaks (DNA-SSB) was observed in N417/AMSA cells treated with mAMSA or CPT compared to parental cells. Similar differences were obtained in isolated nuclei, suggesting that no modification of mAMSA and CPT accumulation occurred in resistant cells. Topo I was purified from N417/p (Topo I/p) and N417/AMSA (Topo I/AMSA) cells in the exponential phase of growth, and the inhibitory effects of CPT on relaxation activities were determined. Topo I/AMSA was found to be about 7-fold less sensitive to CPT than Topo I/p, suggesting the possible involvement of a mutation outside the gene region sequenced (codons 420 to 642) or post-translational modifications of the Topo I enzyme. These data indicate that increased Topo I activity cannot be related to CPT resistance, and suggest that mAMSA can generate multiple cellular modifications which may be involved in resistance to various drugs.

Amsacrine↗
PubMed1991

Cryosolvents effects on low temperature gel structure of denatured collagen.

Water flux and crystallization are major problems for cryopreservation. The gel approach relies on the concept that a biological gel network might sufficiently entrap fluid within its pores, so as to maintain its osmotically inactive under the stresses usually encountered in the course of cryopreservation and limit the extent of crystallization. It could even induce vitrification. The effects of some cryosolvents on the structure of denatured collagen gels were studied as a function of temperature by hydraulic conductivity measurements and electron microscopy observations, so as to explore the porosity and fluid behavior of the gels. Gels formed in the presence of methanol exhibit a large increase in pore size as gelation temperature drops, whereas almost no variation is detected with ethylene glycol, where the porosity is finer. Gels in the presence of ethylene glycol display a larger fluid content, smaller flow rates, and better pressure resistance than those in the presence of methanol. Electron micrographs confirm the variations in gel structures depending on the cryosolvent and the temperature. Rheological measurements also support these observations. Upon rapid cooling, vitrification occurs only in gels with ethylene glycol. Ethylene glycol seems to have a specific interaction with denatured collagen gels which induces a finer network better adapted for trapping fluid osmotically inactive in the course of cryopreservation.

Collagen↗
PubMed1994

S 14297, a novel selective ligand at cloned human dopamine D3 receptors, blocks 7-OH-DPAT-induced hypothermia in rats.

The selective dopamine D3 receptor agonist, 7-OH-DPAT ((+)-7-hydroxy-2-(di-n-propylamino)tetralin) and the novel naphthofurane, S 14297 ((+)-[7-(N,N-dipropylamino)-5,6,7,8-tetrahydro- naphtho(2,3b)dihydro,2,3-furane]), bound with high affinity and selectivity to recombinant, human dopamine D3 versus D2 receptors stably transfected into Chinese hamster ovary cells: Ki values = 2 versus 103 nM for 7-OH-DPAT and 13 versus 297 nM for S 14297. In contrast, the putative dopamine D3 receptor antagonist, AJ 76 (cis-(+)-5-methoxy-1-methyl-2-(n- propylamino)tetralin), displayed low affinity and selectivity for dopamine D3 versus D2 sites (70 versus 154 nM). 7-OH-DPAT (0.01-0.16 mg/kg s.c.) provoked hypothermia in rats, an action abolished by S 14297 (0.04-0.63 mg/kg s.c.) and, less potently, by AJ 76 (0.16-2.5 mg/kg s.c.). S 14297 (20.0 mg/kg s.c.) did not modify prolactin secretion. These data suggest that dopamine D3 receptors mediate hypothermia in the rat and that S 14297 acts as a selective antagonist at these sites.

2-Naphthylamine↗
PubMed1995

In vitro and in vivo pharmacology of S 16474, a novel dual tachykinin NK1 and NK2 receptor antagonist.

Since tachykinins released from lung sensory nerve endings are thought to play a role in inflammatory diseases of airways via NK1 and NK2 receptors, dual tachykinin NK1 and NK2 receptor antagonists may have a great therapeutic potential. In vitro, the cyclopeptide S 16474 (cyclo-[Abo-Asp(D-Trp(Suc0Na)-Phe-N-(Me)Bzl)]) bound to both human tachykinin NK1 and NK2 receptors expressed in two lines of transfected Chinese hamster ovary cells (IC50 values 85 nM and 129 nM, respectively), while showing a poor affinity for the rat tachykinin NK1 receptor. S 16474 inhibited the contractions induced by substance P in isolated rabbit vena cava (pA2 7.0) and by neurokinin A in rabbit pulmonary artery (pA2 5.6). In vivo in anaesthetized guinea-pigs, S 16474 was found to dose dependently inhibit the bronchoconstrictions induced by intravenously administered substance P, neurokinin A and capsaicin. Plasma extravasation evoked in bronchi by endogenously released tachykinins under vagus nerve stimulation was abolished by S 16474 (10 mu mol/kg i.v.). These results demonstrate clearly that S 16474 is a tachykinin receptor antagonist exhibiting, in vitro and in vivo, a dual inhibitory effect on NK1 and NK2 receptors.

Animals↗
PubMed1984

Desensitization by histamine of H2 receptor-mediated adenylate cyclase activation in the human gastric cancer cell line HGT-1.

Short-term treatment of cultured HGT-1 cells with histamine produced a time-dependent (half-life: 20 min) and homologous desensitization of histamine H2 receptor activity mediating cAMP generation in HGT-1 cells and gastric acid secretion in normal gastric mucosa. Histamine treatment resulted in loss of response of the adenylate cyclase to histamine in purified plasma membranes, but had no effect on basal, vasoactive intestinal peptide (VIP)- or NaF-stimulated enzyme activities. We propose that the desensitization of gastric histamine H2 receptor by histamine evidenced in cellular or subcellular preparations from HGT-1 cells could be involved in the physiological regulation and pharmacological control of gastric cell function in man.

Adenylyl Cyclases↗
PubMed1993

Pentoxifylline inhibits the expression of tissue factor mRNA in endotoxin-activated human monocytes.

Tissue factor (TF) is a transmembrane glycoprotein which, in association with factor VII(a), is the main activator of coagulation. In illnesses such as Gram-negative endotoxemia, circulating monocytes synthesize and express substantial TF activity, resulting in extensive disseminated intravascular coagulation. We investigated the way in which TF is suppressed by pentoxifylline (PTX), and found that PTX down-regulates immunologic TF expression and specific mRNA production in response to LPS. Since TF mRNA stability is not altered, this effect appears to take place at the transcriptional level.

Endotoxins↗
PubMed1993

Interleukin-10 inhibits endotoxin-induced tissue factor mRNA production by human monocytes.

In Gram-negative septic shock, human monocytes synthesize and express on their cytoplasmic membrane tissue factor (TF), a potent activator of the coagulation cascades. The role of TF in triggering disseminated intravascular coagulation (DIC) in these patients appears to be clear. We report the suppressive effect of interleukin-10 (IL-10) on endotoxin-induced TF activity and antigen levels, and on the expression of TF mRNA levels in human monocytes. These results emphasize the potential therapeutic value of this cytokine in septic shock, a condition still associated with a high mortality rate.

Humans↗
PubMed1994

Interleukin-10 and pentoxifylline inhibit C-reactive protein-induced tissue factor gene expression in peripheral human blood monocytes.

Fibrin deposition is an integral feature of the inflammatory response. In response to C-reactive protein (CRP), an acute-phase reactant, blood monocytes synthesize and express tissue factor (TF), the main initiator of blood coagulation. We report the inhibitory effect of interleukin 10 (IL-10) and that of pentoxifylline, a methyl xanthine derivative, on monocyte expression of TF activity, TF protein and TF mRNA in response to CRP. These agents may be of use in diseases where a TF-induced prothrombotic state is detrimental.

C-Reactive Protein↗
PubMed1986

Mathematical modelling accounting for discrepancies between blood levels and pharmacodynamic effects of a drug. Application to the numerical optimization of tertatolol.

In this paper we propose a non-linear model for explaining the relation between doses, blood levels and pharmacodynamic effects. Several models are examined and a functional relation (without derivatives or integrals) is retained. From there the medical system is optimized by using optimal control methods. In practice, optimal doses and times are numerically determined for the drug tertatolol.

Adult↗
PubMed1989

Echinococcus multilocularis: a rare cestode of the domestic cat in France.

A cat living in the city of Annemasse (Haute-Savoie) was parasitized by a single minute specimen of the cestode E. multilocularis. The main characteristics of the parasite are described and illustrated. The cat has not previously been reported as one of the definitive hosts of this cestode in France. A potentially serious epidemiological problem is raised by the presence of an infected cat in an urban estate.

Animals↗
PubMed1990

Seasonality of two gill monogeneans from two freshwater fish from an oligotrophic lake in northeast Finland.

The seasonal occurrence of Dactylogyrus amphibothrium and Discocotyle sagittata from the gills of ruffe (Gymnocephalus cernuus) and whitefish (Coregonus acronius), respectively was studied in Lake Yli-Kitka, a large oligotrophic lake in Northeast Finland. The lake, located near the Arctic Circle, is ice-covered for 7-8 months of the year. The prevalence of D. amphibothrium infection was 70.7% and remained high throughout all size-classes of fish. The length distribution and developmental stages of the worms indicated two generations per year. The overwintering generation produces a summer generation which lives for only a few weeks and matures in July. Discocotyle sagittata has only one generation yearly. Its worms mature and produce eggs in July-August and recruitment of the new generation starts in the autumn. The prevalence of D. sagittata infection varied between 40% (in January) and 6.7% (in September); smaller fish were more heavily infected than larger fish.

Animals↗
PubMed1991

Dactylogyrids on the gills of roach in central Finland: features of infection and species composition.

Monogenean parasites were examined from the gills of 660 roach (Rutilus rutilus) in four interconnected lakes in Central Finland between February and November 1986 and in three of the same lakes between February and December 1988. One of the lakes is eutrophic and polluted due to a paper and pulp mill, one is oligotrophic and in a natural state, and the other two lakes are eutrophic. The prevalence of Dactylogyrus infection was always high. Differences between the lakes and the years were observed in the intensity of infection, which was significantly higher in the polluted lake. The intensity was also higher in older fish. Nine Dactylogyrus species were found, and of these D. crucifer and D. nanus were numerically dominant in all of the lakes studied, especially in the oligotrophic lake. In 1986 D. fallax, D. similis and D. suecicus constituted significant proportions of the fauna in the polluted lake. D. micracanthus was most common in the eutrophic lakes. In 1988 the species composition in the polluted lake was most similar to that in the eutrophic lake.

Animals↗
PubMed1996

Pro-thrombotic effects of a folic acid deficient diet in rat platelets and macrophages related to elevated homocysteine and decreased n-3 polyunsaturated fatty acids.

Folic acid deficiency represents a vitamin deficiency that may be due either to an inadequacy of the dietary supply or to an increased requirement. It leads to a number of abnormalities including hematological, neurological and cardiovascular disorders. In this study, we investigated whether folic acid deficiency would influence platelet and macrophage activities. For 6 weeks, rats were fed a test diet containing a low amount of folic acid (250 mu g/kg) by comparison with a control diet (750 mu g/kg). We found 40 and 32 percent reductions (P < 0.05) of plasma and erythrocyte folates, respectively in the tested group. Peritoneal macrophages of the folic acid deficient animals exhibited greater (20 x) tissue factor (TF) activity than in the controls. We also found that folate depletion significantly enhanced the thrombin- and ADP-induced platelet aggregation (+64 and + 13 percent, respectively). Moreover, the results of incubations with radiolabeled arachidonic acid indicated that platelets of folic acid deficient animals incorporated more labeling than controls did. When stimulated with thrombin, the mobilization of arachidonate from platelet phospholipids and its subsequent formation of cyclooxygenase and lipoxygenase metabolites were enhanced in the deficient animals. In particular, thromboxane biosynthesis was markedly increased. The analysis of the plasma fatty acid composition showed a decrease in the plasma unsaturation index related to a marked fall of long chain (n-3) fatty acids which was also observed in platelets. These data suggested the occurrence of an oxidative stress in folic acid deficient animals which was confirmed by increases in plasma lipid peroxidation products (more than +20 percent) and an enhanced susceptibility of erythrocytes to free radicals (+23 percent). Altogether these data suggested that folic acid deficiency altered the circulating and cellular fatty acid composition and thus influenced the balance of the platelet eicosanoid synthesis. In addition, total homocysteine and glutathione concentrations were highly increased in plasma from folate-depleted rats. From these results, we conclude that folate deficiency can potentiate the coagulation pathway mediated by the macrophage TF as well as the platelet activation process. It is suggested that these dysfunctions might be related to the loss of (n-3) polyunsaturated fatty acids. The latter could result from an increased lipid peroxidation triggered by the folic acid deficiency-induced hyperhomocysteinemia.

Animals↗