Influence of microbial flora on xylose absorption in rats and mice

The absence of a microbial flora produced a twofold increase in the absorption of d-xylose in germfree mice as determined by the everted sac technique. The existence of a similar increase was confirmed in germfree rats by using one in vitro and two in vivo techniques. Monocontamination of germfree mice with pure cultures of microorganisms also produced changes in xylose absorption. Studies on water, Na+, and K+ absorption in germfree mice indicated that the flora produces no significant change in the absorption of Na+ or in the movement of water and K+.

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Presence and Possible Origin of ɛ(γ-Glutamyl)Lysine Isodipeptide in Human Plasma

Thrombosis and Haemostasis ◽

10.1055/s-0038-1648380 ◽

1992 ◽

Vol 67 (01) ◽

pp. 060-062 ◽

Cited By ~ 9

Author(s):

J Harsfalvi ◽

E Tarcsa ◽

M Udvardy ◽

G Zajka ◽

T Szarvas ◽

...

Keyword(s):

Human Plasma ◽

Fibrinolytic Therapy ◽

Normal Human Plasma ◽

Normal Human ◽

Hplc Technique ◽

Significant Change

Summaryɛ(γ-glutamyl)lysine isodipeptide has been detected in normal human plasma by a sensitive HPLC technique in a concentration of 1.9-3.6 μmol/1. Incubation of in vitro clotted plasma at 37° C for 12 h resulted in an increased amount of isodipeptide, and there was no further significant change when streptokinase was also present. Increased in vivo isodipeptide concentrations were also observed in hypercoagulable states and during fibrinolytic therapy.

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Contamination of erythropoietin by endotoxin: in vivo and in vitro effects on murine erythropoiesis

Blood ◽

10.1182/blood.v54.1.146.146 ◽

1979 ◽

Vol 54 (1) ◽

pp. 146-158 ◽

Cited By ~ 8

Author(s):

KS Zuckerman ◽

PJ Quesenberry ◽

J Levin ◽

R Sullivan

Keyword(s):

Significant Inhibition ◽

Erythropoietic Activity ◽

Limulus Amebocyte Lysate ◽

Endogenous Erythropoietin ◽

Significant Change ◽

In Vitro Effects ◽

Stimulation Of

Abstract Endotoxin was detected in all erythropoietin preparations tested and was removed from four lots, without loss of erythropoietic activity, by adsorption with limulus amebocyte lysate. Comparison of adsorbed (endotoxin-depleted) and nonadsorbed (endotoxin-containing) erythropoietin preparations demonstrated significant inhibition of CFU- e and BFU-e in vitro by nonadsorbed erythropoietin at concentrations higher than 0.25 U/ml and 2.0 U/ml, respectively. CFU-e and BFU-e were inhibited significantly by readdition in vitro of 10(-5)-10(-3) mug of endotoxin per unit of limulus-adsorbed erythropoietin. Administration of saline or 6 U of nonadsorbed or adsorbed erythropoietin twice a day for 4 days of CF1 mice resulted in reticulocyte counts of 2.1%, 9.9%, and 15.9%, respectively. Nonadsorbed erythropoietin resulted in a 29% decrease in erythropoiesis, a 42% decrease in CFU-e, and a 16% increase in granulopoiesis in the marrow, whereas adsorbed erythropoietin caused a 28% increase in erythropoiesis, no significant change in CFU-e and a 19% decrease in granulopoiesis in the marrow. Both preparations resulted in marked increases in splenic erythropoiesis and granulopoiesis. The effects of adsorbed erythropoietin are similar to those produced following stimulation of hematopoiesis by endogenous erythropoietin. Hemopoietic changes induced by nonadsorbed erythropoietin in vivo and in vitro are affected substantially by contamination of the erythropoietin preparations with endotoxin.

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A Validated HPLC-PDA-HRMS Method to Investigate the Biological Stability and Metabolism of Antiparasitic Triterpenic Esters

Molecules ◽

10.3390/molecules26237154 ◽

2021 ◽

Vol 26 (23) ◽

pp. 7154

Author(s):

Laura Schioppa ◽

Fanta Fall ◽

Sergio Ortiz ◽

Jacques H. Poupaert ◽

Joelle Quetin-Leclercq

Keyword(s):

Medicinal Plants ◽

Degradation Products ◽

Biological Stability ◽

Acidic Media ◽

Microsomal Metabolism ◽

Plasma Enzymes ◽

Absorption Studies ◽

H 30

Pentacyclic triterpenes (PTs) are commonly found in medicinal plants with well-known antiparasitic effects. Previous research on C-3 and C-27 triterpenic esters showed effective and selective in vitro antiparasitic activities and in vivo effectiveness by parenteral routes. The aim of this study was to determine triterpenic esters’ stability in different biological-like media and the main microsomal degradation products. An HPLC-PDA method was developed and validated to simultaneously analyze and quantify bioactive triterpenic esters in methanol (LOQ: 2.5 and 1.25–100 µg/mL) and plasma (LOQ: 5–125 µg/mL). Overall, both triterpenic esters showed a stable profile in aqueous and buffered solutions as well as in entire plasma, suggesting gaining access to the ester function is difficult for plasma enzymes. Conversely, after 1 h, 30% esters degradation in acidic media was observed with potential different hydrolysis mechanisms. C-3 (15 and 150 µM) and C-27 esters (150 µM) showed a relatively low hepatic microsomal metabolism (<23%) after 1 h, which was significantly higher in the lowest concentration of C-27 esters (15 µM) (>40% degradation). Metabolic HPLC-PDA-HRMS studies suggested hydrolysis, hydroxylation, dehydration, O-methylation, hydroxylation and/or the reduction of hydrolyzed derivatives, depending on the concentration and the position of the ester link. Further permeability and absorption studies are required to better define triterpenic esters pharmacokinetic and specific formulations designed to increase their oral bioavailability.

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Ketoprofen Suppository Dosage Forms: In Vitro Release and in Vivo Absorption Studies in Rabbits

Drug Development and Industrial Pharmacy ◽

10.1081/ddc-100102166 ◽

1999 ◽

Vol 25 (2) ◽

pp. 241-245 ◽

Cited By ~ 9

Author(s):

A. Babar ◽

T. Bellete ◽

F. M. Plakogiannis

Keyword(s):

In Vitro Release ◽

Dosage Forms ◽

Absorption Studies ◽

In Vivo Absorption ◽

Vitro Release

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Interaction between vascular endothelial cells and vascular intimal spindle-shaped cells in vitro

Journal of Cell Science ◽

10.1242/jcs.60.1.89 ◽

1983 ◽

Vol 60 (1) ◽

pp. 89-102

Author(s):

D de Bono ◽

C. Green

Keyword(s):

Extracellular Matrix ◽

Endothelial Cells ◽

Vascular Endothelial Cells ◽

Three Dimensional ◽

Vascular Endothelial ◽

Pure Cultures ◽

Species Specific ◽

Endothelial Growth Factor

The interactions between human or bovine vascular endothelial cells and fibroblast-like vascular intimal spindle-shaped cells have been studied in vitro, using species-specific antibodies to identify the different components in mixed cultures. Pure cultures of endothelial cells grow as uniform, nonoverlapping monolayers, but this growth pattern is lost after the addition of spindle cells, probably because the extracellular matrix secreted by the latter causes the endothelial cells to modify the way they are attached to the substrate. The result is a network of tubular aggregates of endothelial cells in a three-dimensional ‘polylayer’ of spindle-shaped cells. On the other hand, endothelial cells added to growth-inhibited cultures of spindle-shaped cells will grow in sheets over the surface of the culture. Human endothelial cells grown in contact with spindle-shaped cells have a reduced requirement for a brain-derived endothelial growth factor. The interactions of endothelial cells and other connective tissue cells in vitro may be relevant to the mechanisms of endothelial growth and blood vessel formation in vivo, and emphasize the potential importance of extracellular matrix in controlling endothelial cell behaviour.

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Effect of hypophysectomy on calcium transport by rat duodenum.

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.1977.232.2.e229 ◽

1977 ◽

Vol 232 (2) ◽

pp. E229

Author(s):

E L Krawitt ◽

A S Kunin ◽

H W Sampson ◽

B F Bacon

Keyword(s):

Calcium Transport ◽

Calcium Absorption ◽

Plasma Flux ◽

Perfusion Technique ◽

Intestinal Length ◽

Absorption Studies ◽

Luminal Perfusion ◽

Rat Duodenum

To examine the effect of hypophysectomy on intestinal calcium absorption, studies were performed on immature rats 7, 14, and 21 days after hypophysectomy. Duodenal calcium transport was measured in vitro utilizing everted gut sacs and in vivo by a luminal perfusion technique. Hypophysectomy produced no differences in the ability of everted gut sacs to transport calcium. Similarly, when in vivo transport data were expressed on the basis of intestinal length, no significant differences were noted. However, when transport data were expressed on the basis of mucosal weight, increases in absorption and lumen-to-plasma fluxes were apparent in hypophysectomized animals. No differences were seen in plasma-to-lumen fluxes. The results indicate that when the transport data are corrected for mass of intestinal mucosa, the duodenum from hypophysectomized animals absorbs calcium more avidly due to an increase in lumen-to-plasma flux.

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Influence of taurocholate, taurochenodeoxycholate, and taurodehydrocholate on sulfobromophthalein transport into bile.

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.1979.236.1.e10 ◽

1979 ◽

Vol 236 (1) ◽

pp. E10

Author(s):

S Binet ◽

Y Delage ◽

S Erlinger

Keyword(s):

Bile Salts ◽

Mixed Micelle ◽

Mixed Micelles ◽

Important Determinant ◽

Micelle Formation ◽

Similar Increase ◽

Mixed Micelle Formation ◽

Series Of Experiments

To test the hypothesis that incorporation of sulfobromophthalein (BSP) into mixed micelles could account for the increase in its biliary transport maximum (Tmax) by bile salts, we have compared in hamsters the influence on BSP Tmax of taurocholate and taurochenodeoxycholate (two micelle-forming physiological bile salts) to that of taurodehydrocholate, a bile salt which, in vitro, does not form micelles. In a first series of experiments, it was observed that taurocholate and taurochenodeoxycholate increased the secretion of phospholipid (40 and 53%, respectively), and cholesterol (50 and 110%, respectively), whereas taurodehydrocholate decreased the secretion of phospholipid (-31%) and cholesterol (-43%). This result suggests that, in vivo, taurodehydrocholate or its metabolites do not form mixed micelles. In a second series of experiments, it was seen that the three bile salts induced a similar increase in BSP Tmax (63% with taurocholate, 52% with taurochenodeoxycholate, and 51% with taurodehydrocholate). These results provide circumstantial evidence for the hypothesis that mixed micelle formation is not an important determinant of maximal BSP secretion into bile.

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Interleukin-6 Depletion Selectively Improves Hepatic Insulin Action in Obesity

Endocrinology ◽

10.1210/en.2004-1468 ◽

2005 ◽

Vol 146 (8) ◽

pp. 3417-3427 ◽

Cited By ~ 172

Author(s):

Peter J. Klover ◽

Alicia H. Clementi ◽

Robert A. Mooney

Keyword(s):

Insulin Resistance ◽

Adipose Tissue ◽

Insulin Receptor ◽

Endogenous Glucose Production ◽

Hepatic Insulin Resistance ◽

Stat3 Phosphorylation ◽

Insulin Dependent ◽

Significant Change

Abstract Obesity and insulin resistance are considered chronic inflammatory states, in part because circulating IL-6 is elevated. Exogenous IL-6 can induce hepatic insulin resistance in vitro and in vivo. The importance of endogenous IL-6, however, to insulin resistance of obesity is unresolved. To test the hypothesis that IL-6 contributes to the inflammation and insulin resistance of obesity, IL-6 was depleted in Lepob mice by injection of IL-6-neutralizing antibody. In untreated Lepob mice, signal transducer and activator of transcription-3 (STAT3) activation was increased compared with that in lean controls, consistent with an inflammatory state. With IL-6 depletion, activation of STAT3 in liver and adipose tissue and expression of haptoglobin were reduced. Expression of the IL-6-dependent, hepatic acute phase protein fibrinogen was also decreased. Using the hyperinsulinemic-euglycemic clamp technique, insulin-dependent suppression of endogenous glucose production was 89% in IL-6-depleted Lepob mice, in contrast to only 32% in Lepob controls, indicating a marked increase in hepatic insulin sensitivity. A significant change in glucose uptake in skeletal muscle after IL-6 neutralization was not observed. In a direct comparison of hepatic insulin signaling in Lepob mice treated with anti-IL-6 vs. IgG-treated controls, insulin-dependent insulin receptor autophosphorylation and activation of Akt (pSer473) were increased by nearly 50% with IL-6 depletion. In adipose tissue, insulin receptor signaling showed no significant change despite major reductions in STAT3 phosphorylation and haptoglobin expression. In diet-induced obese mice, depletion of IL-6 improved insulin responsiveness in 2-h insulin tolerance tests. In conclusion, these results indicate that IL-6 plays an important and selective role in hepatic insulin resistance of obesity.

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Rat Urinary Bladder Carcinogenesis by Dual-Acting PPARα+γAgonists

PPAR Research ◽

10.1155/2008/103167 ◽

2008 ◽

Vol 2008 ◽

pp. 1-14 ◽

Cited By ~ 30

Author(s):

Martin B. Oleksiewicz ◽

Jennifer Southgate ◽

Lars Iversen ◽

Frederikke L. Egerod

Keyword(s):

Urinary Bladder ◽

Mode Of Action ◽

Carcinogenic Effect ◽

Attrition Rates ◽

Rat Urinary Bladder ◽

Mediated Effects ◽

Kidney Pelvis ◽

Rats And Mice

Despite clinical promise, dual-acting activators of PPARαandγ(here termed PPARα+γagonists) have experienced high attrition rates in preclinical and early clinical development, due to toxicity. In some cases, discontinuation was due to carcinogenic effect in the rat urothelium, the epithelial layer lining the urinary bladder, ureters, and kidney pelvis. Chronic pharmacological activation of PPARαis invariably associated with cancer in rats and mice. Chronic pharmacological activation of PPARγcan in some cases also cause cancer in rats and mice. Urothelial cells coexpress PPARαas well as PPARγ, making it plausible that the urothelial carcinogenicity of PPARα+γagonists may be caused by receptor-mediated effects (exaggerated pharmacology). Based on previously published mode of action data for the PPARα+γagonist ragaglitazar, and the available literature about the role of PPARαandγin rodent carcinogenesis, we propose a mode of action hypothesis for the carcinogenic effect of PPARα+γagonists in the rat urothelium, which combines receptor-mediated and off-target cytotoxic effects. The proposed mode of action hypothesis is being explored in our laboratories, towards understanding the human relevance of the rat cancer findings, and developing rapid in vitro or short-term in vivo screening approaches to faciliate development of new dual-acting PPAR agonist compounds.

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