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Biomedical subjects

A Wendel

Publications and source records attributed to A Wendel.

At least 109 records · Page 6Linked to original sources
PubMed1991

Topical liposome drugs to come: what the patent literature tells us. A review.

Drug-containing liposomes for topical use in dermatology have been devised during the last 10 years. Most recently the clinical superiority to a conventional gel of a topical glucocorticosteroid liposome preparation for eczema has been demonstrated. To get more insight from what may be expected from future liposome preparations for topical treatment, the pertinent patent literature has been reviewed.

Administration, Cutaneous↗
PubMed1990

Phospholipid hydroperoxide glutathione peroxidase in various mouse organs during selenium deficiency and repletion.

An assay for the determination of the newly discovered selenoenzyme, phospholipid hydroperoxide glutathione peroxidase (PH-GPx) in biological material is described. Dietary selenium deficiency and repletion was used as a tool in order to modify this enzyme activity in various mouse organs and to compare it to the activity of the 'classical' selenium-dependent glutathione peroxidase (GPx) (EC 1.11.1.9). A semipurified diet containing less than 12 ppb Se was used for depletion. Controls received this diet supplemented with 500 ppb Se in the form of Na2SeO3. The results showed that a rapid loss of GPx activity occurred in liver, kidney and lungs of selenium-deficient mice which reached undetectable levels within 130 days. In the heart, about 24% of control GPx activity was still present. In contrast, PH-GPx activity was more slowly depleted by Se deficiency and resulted in residual activities ranging from 30 to 70% in the different organs even after 250 days of depletion. In repletion experiments with a single application of 10 or 500 micrograms/kg Se, only the high dose restored either enzyme activity. The data demonstrate that the need for selenium of the two glutathione peroxidases is different. A markedly distinct organ distribution of both enzymes suggests that the heart may be the organ more sensitive to oxidative stress.

Animals↗
PubMed1990

In vivo evidence for protease-catalysed mechanism providing bioactive tumor necrosis factor alpha.

Mice pretreated by intravenous injection of 42 mg/kg of the serine protease inhibitor alpha 1-antitrypsin prior to a hepatotoxic dose of D-galactosamine/lipopolysaccharide (GalN/LPS) were fully protected against hepatitis. Pretreatment with alpha 1-antitrypsin with doses up to 300 mg/kg at different times failed to protect galactosamine sensitized animals against tumor necrosis factor alpha (TNF alpha)-induced hepatitis. No bioactive TNF alpha was detectable in serum of mice protected against GalN/LPS-induced hepatitis by pretreatment with alpha 1-antitrypsin. In contrast, abundant amounts of TNF were found in sera of GalN/LPS-treated control animals. It is concluded that a serine protease sensitive to alpha 1-antitrypsin provides bioactive TNF alpha by proteolytic cleavage of a TNF alpha precursor.

Alanine Transaminase↗
PubMed1990

Leukocyte alterations do not account for hepatitis induced by endotoxin or TNF alpha in galactosamine-sensitized mice.

Subtoxic doses of endotoxin (salmonella abortus equi lipopolysaccharide, LPS) (5 micrograms/kg i.p.) or tumor necrosis factor alpha (TNF alpha) (15 micrograms/kg i.v.) induced fulminant hepatitis within 8 hr, when mice had been sensitized by a subtoxic dose of D-galactosamine (700 mg/kg i.p.). LPS-treatment led to the release of TNF into the circulation, independently of the presence of D-galactosamine. The TNF-dependent development of hepatitis was accompanied by a severe lymphopenia and neutrophilia as assessed by leukocyte differential count. The total leukocyte count was not significantly affected. Lymphopenia and neutrophilia were induced by LPS or TNF alpha alone; however, the differential count was not influenced by D-galactosamine. A quantity of 260 micrograms/kg phorbol myristate acetate (PMA) i.p. or 5 micrograms/kg platelet activating factor (PAF) i.v. or 3.3 mg/kg N-formyl-methionyl-leucyl-phenylalanine methylester (FMLP) i.v. or 167 mg/kg zymosan i.v. also caused lymphopenia and neutrophilia in mice. However, none of these agents induced the production of systemic TNF and therefore failed to induce hepatitis in D-galactosamine-sensitized mice. In LPS-insensitive C3H/HeJ mice administration of LPS produced neither differential count changes nor hepatitis while both events were observed when TNF alpha was given. This shows that TNF alpha alone gives rise to lymphopenia/neutrophilia as well as hepatitis independent of LPS. When the action of TNF alpha was blocked by anti TNF alpha antiserum pretreatment of LPS-sensitive mice, the animals were protected against LPS-induced hepatitis. However, lymphopenia and neutrophilia still occurred to a similar extent. The involvement of a putative additional mediator of LPS-induced leukocyte alterations was checked. The findings suggest that this mediator, if present, is different from IL-1, IL-2, eicosanoids or superoxide. We conclude from our findings that changes in leukocyte numbers and composition following D-galactosamine LPS or D-galactosamine/TNF alpha administration is an epiphenomenon rather than a causal event of leukocyte stimulation in the process of inducing a fulminant hepatitis in mice.

Animals↗
PubMed1990

Glutathione enhancement in various mouse organs and protection by glutathione isopropyl ester against liver injury.

Intraperitoneal administration of glutathione isopropyl ester to fasted, male NMRI mice dose dependently increased the glutathione concentration in various organs. Administration of 1 g/kg glutathione isopropyl ester led to the following increases: liver 166%; lung 164%; heart 121% after 4 hr; and brain 133% after 6 hr. Spleen, kidney, muscle, serum and blood cell glutathione were not affected by the treatment. Pretreatment with glutathione isopropyl ester was found to protect against paracetamol- or allyl alcohol-induced liver damage. Following treatment with the ester a significant correlation between protection against liver damage and enhancement of liver glutathione content was obtained. The dose dependence of this protection was studied.

1-Propanol↗
PubMed1990

Studies on the hepatotoxicity of galactosamine/endotoxin or galactosamine/TNF in the perfused mouse liver.

Livers of male albino NMRI mice were perfused in situ at a flow rate of 3 ml/min/g liver in a non-recirculation system. The organs remained intact for at least 3 hr as assessed by release of lactate dehydrogenase (LDH) into the perfusate and by constant O2 consumption. The infusion of the following agents did not cause significant enzyme release or microscopically visible organ injuries: galactosamine (1.8 mg/ml), endotoxin (1 microgram/ml), murine recombinant tumor necrosis factor alpha (0.3 micrograms/ml/g) or combinations of them. In contrast, in vivo pretreatment of the animals with 700 mg/kg galactosamine + 5 micrograms/kg endotoxin, or 700 mg/kg galactosamine + 15 micrograms/kg tumor necrosis factor alpha (TNF) led to a massive LDH release into the perfusate. Infusion of uridine (0.67 mg/ml/g) into perfused livers from animals in vivo pretreated with either galactosamine/endotoxin or galactosamine/TNF, prevented LDH release and histologically visible liver injury. We conclude from these findings that in vivo pretreatment of the animals resulted in latent and reversible damage of the liver induced by extrahepatic factors which are prevented by intrahepatic events sensitive to uridine.

Animals↗
PubMed1990

Hepatic uptake and antihepatotoxic properties of vitamin E and liposomes in the mouse.

Intravenous administration of soybean phosphatidylcholine liposomes containing different amounts of tocopherol acetate leads to a dose and time dependent increase of mouse liver tocopherol content, which was not observed when the preparation was given orally. When benzo[a]pyrene pretreated mice intoxicated with 400 mg/kg AAP were pretreated 2 h before with 1 g/kg phosphatidylcholine liposomes containing 4 mg/kg vitamin E acetate, these animals were protected against liver damage. Vitamin E alone or liposomes lacking vitamin E showed no protection. In an inflammatory liver disease model, i.e. fulminant hepatitis induced by intraperitoneal administration of 700 mg/kg galactosamine and 1 microgram/kg lipopolysaccharide phosphatidylcholine liposomes protected at a dose of 1 g/kg i.v. In this case, however, the protection was not due to the presence of vitamin E. These findings demonstrate the usefulness of phosphatidylcholine for liver protection and show that the protective spectrum is improved when they contain vitamin E. The data suggest that phosphatidylcholine is an excellent carrier for delivery of vitamin E to the liver.

Acetaminophen↗
PubMed1989

Alterations in the protein-synthesis, -degradation and/or -secretion rates in hepatic subcellular fractions of selenium-deficient mice.

Single mouse livers were subfractionated by differential centrifugation and isopycnic centrifugation on sucrose or metrizamide gradients and separated into subcellular compartments. The fractionation procedure was highly reproducible and yielded essentially similar results in different preparations of livers from selenium-adequate (Se+) and selenium-deficient (Se-) mice that were fed on a Torula-yeast-based diet containing less than 10 parts per 10(9) of selenium for at least 16 weeks. Mice of both dietary groups were injected intraperitoneally with 370 kBq of L-[U-14C]leucine, and 48 h later 1.85 MBq of L-[4,5-3H]leucine was injected intraportally. After another 1 h, the livers were removed and subjected to subcellular fractionation. Incorporation of the 3H label into proteins of the subcellular fractions was taken as a measure of relative protein-synthesis rate. The ratio of the 3H to the 14C protein-bound label of the same fractions was used as an estimate of relative protein-degradation and/or -secretion rate. The results showed a statistically significant 180% increase in protein-synthesis rate in the endoplasmic reticulum and a 80% increase in relative protein-degradation and/or -secretion rate in the same compartment. A significant decrease in the 3H/14C ratio, by 40 and 30% respectively, was observed in the Golgi fraction and in liver homogenate. The observed changes suggest a highly regulated hepatic response to selenium deficiency.

Animals↗
PubMed1989

Subcellular distribution of selenium in deficient mouse liver.

Selenium (Se)-deficient mice were labelled in vivo with single pulses of [75Se]selenite, and the intrahepatic distribution of the trace element was studied by subcellular fractionation. At 1 h after intraperitoneal injection of 3.3 or 10 micrograms of Se/kg body weight, 15% of the respective doses were found in the liver. Accumulation in the subcellular fractions followed the order: Golgi vesicular much greater than lysosomal greater than cytosolic = microsomal greater than mitochondrial, peroxisomal, nuclear and plasma-membrane fraction. At a dose of 3.3 micrograms/kg, more than 90% of the hepatic Se was protein-bound. When cross-contamination was accounted for, the following specific Se contents of the subcellular compartments were extrapolated: Golgi apparatus, 7.50 pmol/mg; cytosol, 0.90 pmol/mg; endoplasmic reticulum, 0.80 pmol/mg; mitochondria, 0.49 pmol/mg; nuclei, lysosomes, peroxisomes and plasma membrane, less than 0.4 pmol/mg. At 10 micrograms/kg, a roughly 2-3-fold increase in Se content of all fractions was found without major changes in the intrahepatic distribution pattern. An extraordinary rise in the cytosolic fraction was due to an apparently non-protein-bound Se pool. At 24 h after dosing, total hepatic Se had decreased to 6% of the initial dose and had become predominantly protein-bound. The 60% decrease in hepatic Se was reflected in a similar fall in the subcellular levels of the trace element. The Golgi apparatus still had the highest specific Se content, although accumulation was 5 times less than that after 1 h. The cytosolic pool accounted for 50% of the hepatic Se at both labelling times. After 1 h the Golgi apparatus was, with 19%, the second largest intrahepatic pool, followed by the endoplasmic reticulum with 16%. The high affinity and fast response of the Golgi apparatus to Se supplementation of deficient mice is interpreted in terms of a predominant function of this cell compartment in the processing and the export of Se-proteins from the liver.

Animals↗
PubMed1989

Tumor necrosis factor is a terminal mediator in galactosamine/endotoxin-induced hepatitis in mice.

Intravenous injection of murine recombinant tumor necrosis factor alpha(TNF-alpha) to male NMRI albino mice in doses greater than 4 micrograms/kg (specific activity 4 x 10(7) U/mg) resulted in a fulminant hepatitis when animals had been sensitized 1 hr before by intraperitoneal administration of 700 mg/kg galactosamine. Liver injury was assessed by measurement of serum transaminases as well as sorbitol dehydrogenase activity 8 hr after administration of TNF-alpha. Pretreatment with either galactosamine or 40 micrograms/kg TNF-alpha alone did not cause hepatitis. Pretreatment of galactosamine/TNF-alpha-injured mice with 800 mg/kg uridine or with 6 mg/kg calmidazolium fully protected the animals, while administration of either verapamil or nifedipine (100 mg/kg, respectively) had no significant effect. The following inhibitors of generation or action of leukotriene D4, which were previously shown to block galactosamine/endotoxin-induced hepatitis in mice, failed to protect against galactosamine/TNF-alpha-induced intoxication: 200 micrograms/kg dexamethasone, 174 mg/kg BW 755 C or 13 x 10 mg/kg FPL 55712. In addition, unlike in the galactosamine/endotoxin model no prevention was achieved by pretreatment of galactosamine/TNF-alpha-injured animals with the following substances blocking the development of an ischemia/reperfusion syndrome: 2 x 100 mg/kg allopurinol, 3.3 x 10(4) U/kg superoxide dismutase, 10(6) U/kg catalase or 10 micrograms/kg iloprost. We conclude from our results that tumor necrosis factor alpha is likely to act as a final mediator of endotoxin action in a sequence of events which includes formation of leukotriene D4 and reactive oxygen species.

Allopurinol↗
PubMed1989

A possible role of plasma glutathione in glucose-mediated insulin secretion: in vitro and in vivo studies in rats.

In isolated rat pancreatic islets exogenous glutathione which is not able to penetrate into cells, augmented glucose (11.1 mmol/l)-mediated insulin release. In the presence of a non-stimulatory glucose concentration (2.8 mmol/l) glutathione had no effect. The half-maximal synergistic action of glutathione on insulin secretion was observed at approximately 8.0 mumol/l. This concentration of glutathione is similar to that found in the plasma of non-fasted anaesthetised rats (6.5 mumol/l). Oral ingestion of glucose increased the arterial plasma glutathione in rats. Our data provide for the first time indirect evidence for a modulating effect of plasma glutathione in postprandial glucose-mediated insulin secretion which appears to be located at the extracellular site of islet cells.

Animals↗
PubMed1988

Choleresis and increased biliary efflux of glutathione induced by phenolic antioxidants in rats.

UNLABELLED: The mechanism by which high doses of the synthetic antioxidants butylated hydroxyanisole (BHA) and butylated hydroxytoluene (BHT) raise hepatic glutathione levels above physiological values was investigated in rats. A single dose of an antioxidant (200 mg/kg; p.o.) reduced the hepatic glutathione content by 17% (BHA) or 36% (BHT) after 5 h, but in contrast levels of 55% (BHA) or 34% (BHT) above controls (7.1 +/- 0.5 mumol GSH-equivalents/g liver wt) were measured 48 h after dosing. Both antioxidants increased basal bile flow (1.37 +/- 0.11 microliter/min per g liver wt) and biliary efflux of total glutathione, i.e. GSH and GSSG, (4.18 +/- 0.97 nmol GSH-eq./min per g) severalfold (up to 250%) over controls 24 h after in vivo antioxidant treatment. The sinusoidal efflux of reduced glutathione (14.9 +/- 2.2 nmol GSH-eq./min per g) was significantly reduced (BHA: 23%; BHT: 41%). The increased glutathione excretion into bile is likely to be independent of the induction of the choleresis. The secretion of bile salts was unaffected by BHA treatment and only temporarily reduced by BHT. CONCLUSION: phenolic antioxidants increase the hepatic turnover of glutathione by stimulating the biliary efflux of GSH. The resulting shift from a predominantly sinusoidal efflux of GSH in controls (hepato-renal circulation) to a predominantly biliary efflux of GSH in antioxidant-treated animals (entero-hepatic circulation) may lead to increased concentrations of cysteine, glycine and glutamic acid in the portal vein and consequently may stimulate the biosynthesis of GSH by enhanced substrate availability in the liver.

Animals↗
PubMed1988

Leukotriene-mediated liver injury.

The pathogenic mechanism of fulminant hepatitis induced by 700 mg/kg D-galactosamine plus 33 micrograms/kg endotoxin was investigated in male NMRI mice. The extent of liver injury was assessed by measurement of serum transaminases and sorbitol dehydrogenase activities 9 hr after intoxication, as well as by histopathological evaluation. When the hepatic glutathione content of galactosamine endotoxin-treated animals had been decreased by more than 90% following administration of 250 mg/kg phorone or 400 mg/kg diethyl maleate given three times, no signs of liver injury were observed. Since different agents interfering with the leukotriene synthesis pathway also prevented galactosamine/endotoxin-induced hepatitis, we suspected that a glutathione-derived peptidoleukotriene may be the pathogenic metabolite. In vivo inhibition of the catabolism of leukotriene C4 by administration of 50 mg/kg of the glutamyl transpeptidase inhibitor AT 125 (Acivicin) also protected the animals against liver injury. In order to elucidate which metabolite of leukotriene C4 was responsible for the observed hepatotoxicity we intravenously injected leukotrienes into animals that had received only galactosamine. Injection of 50 micrograms/kg leukotriene E4 1 hr after galactosamine had no effect. The same dose of leukotriene D4 led to a fulminant hepatitis which was prevented when the leukotriene D4 antagonist FPL 55712 had been given before. In contrast, lipoxygenase inhibitors or AT 125 did not protect against galactosamine + LTD4. Galactosamine/endotoxin-induced and galactosamine/leukotriene D4-induced hepatitis resulted in similarly localized histopathological changes, i.e. diffuse necrosis in the organ. We conclude from our results that galactosamine/endotoxin-induced hepatitis is mediated by a leukotriene D4-dependent mechanism.

Animals↗
PubMed1987

Evidence for the involvement of a reperfusion injury in galactosamine/endotoxin-induced hepatitis in mice.

Simultaneous intraperitoneal administration of 700 mg/kg galactosamine and 33 micrograms/kg Salmonella abortus equi endotoxin to male NMRI albino mice resulted in fulminant hepatitis as assessed after nine hours by measurement of serum transaminases as well as sorbitol dehydrogenase activities. Intraperitoneal pretreatment of animals with 2 X 100 mg/kg allopurinol, or intravenous pretreatment with 33 kU superoxide dismutase or 1 MU catalase fully prevented hepatitis. Administration of 10 micrograms/kg of the prostacyclin analogue iloprost antagonized liver injury when given simultaneously with galactosamine/endotoxin but did not protect when given 90 min later. Tocopherol or desferal pretreatment of the animals had no significant protective effect. Together with our recent finding that hepatic leukotriene D4 production is likely to be responsible for galactosamine/endotoxin-induced hepatitis we interpret these results as evidence for a leukotriene-induced hepatic ischemia followed by a reperfusion syndrome.

Allopurinol↗
PubMed1987

Alterations in the intermediary metabolism of selenium-deficient mice.

Male albino mice were pair-fed a torula yeast-based selenium-deficient (Se-) diet containing 10 ppb selenium for 4 months, while a control group (Se+) received a similar diet supplemented with 330 ppb selenium as Na2SeO3. In addition to previously observed modulations of drug-metabolizing enzymes (Reiter, R. and Wendel, A. (1985) Biochem. Pharmacol. 34, 2287-2290), an increase of 6-phosphogluconate dehydrogenase activity and succinate dehydrogenase activity in liver by about 60% was found. In vivo, an increased 14CO2 exhalation from a tracer dose of glucose either labeled in the C-1- or C-6 position was observed in selenium-deficient mice. However, no difference in the total CO2 exhalation of Se(-)- as compared to Se+-mice was detectable. In line with the assumption that Se(-)-mice have an increased glucose turnover, Se(-)-mice exhibited a greater glucose tolerance when treated with an oral glucose load of 2.5 mg glucose/kg body weight. Also, the Se(-)-mice had a lower blood glucose level as compared to Se+-controls (89 +/- 3 versus 110 +/- 12 mg glucose/100 ml blood). Further in vitro experiments with red blood cells from Se(-)-mice showed that erythrocytes did not contribute to an increased CO2 formation from glucose via the pentose phosphate shunt. No significant differences between Se(-)- and Se+-animals were found in the profile of urinary metabolites, including ketone bodies and nitrogen excretion. These findings suggest a hitherto unknown involvement of selenium in specific regulatory sites of intermediary metabolism.

Animals↗
PubMed1987

The role of acrolein in allyl alcohol-induced lipid peroxidation and liver cell damage in mice.

Male NMRI mice were fed a sucrose diet for 48 hr in order to reduce the hepatic glutathione content and to level off its diurnal variation. After administration of allyl alcohol (AA: 1.1 mmol/kg), hepatic glutathione (24.3 +/- 7.0 nmol GSH/mg protein) was almost totally lost within the first 15 min (less than 0.5 nmol GSH/mg protein). Subsequently, a massive lipid peroxidation was observed, i.e. the animals exhaled 414 +/- 186 nmol ethane/kg/hr compared to 0.9 +/- 0.8 of controls, and the hepatic TBA-reactive compounds had increased from 55 +/- 16 pmol/mg protein in controls to 317 +/- 163 after 1 hr. Concomitantly, a 40-45% loss of the polyunsaturated fatty acids (arachidonic and docosahexaenoic acid) in the liver lipids was observed. About 80% of the cytosolic alcohol dehydrogenase activity and about 50% of the microsomal P450-content were destroyed. In vivo-inhibition of alcohol dehydrogenase by pyrazole or induction of aldehyde dehydrogenase by phenobarbital abolished AA-induced liver damage as well as glutathione depletion and lipid peroxidation, while inhibition of aldehyde dehydrogenase by cyanamide made a subtoxic dose of AA (0.60 mmol/kg) highly toxic. These results strongly favour the importance of acrylic acid formation as an additional detoxification pathway. Enhanced hepatic levels of glutathione protected in vivo against the damaging effects of AA. Depletion of the liver glutathione content by phorone or diethylmaleate alone caused marginally enhanced lipid peroxidation (phorone) but not liver cell damage. Monooxygenase inhibitors (metyrapone, diethyldithiocarbamate, alpha-naphthoflavone) or an inducer (benz(a)pyrene) did not affect AA-induced toxicity. The ferric iron chelator desferoxaminemethanesulfonate prevented AA-induced lipid peroxidation and liver cell damage in vivo. In vitro, acrolein alone failed to initiate lipid peroxidation in soy bean phospholipid liposomes or in mouse liver microsomes. Thus, acrolein not only impairs the glutathione defense system but also directly destroys cellular proteins and evokes lipid peroxidation by an indirect iron-depending mechanism.

1-Propanol↗