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Biomedical subjects

S B Christensen

Publications and source records attributed to S B Christensen.

At least 55 records · Page 3Linked to original sources
PubMed1995

The antileishmanial agent licochalcone A interferes with the function of parasite mitochondria.

Our previous studies have shown that licochalcone A, an oxygenated chalcone, has antileishmanial (M. Chen, S.B. Christensen, J. Blom, E. Lemmich, L. Nadelmann, K. Fich, T.G. Theander, and A. Kharazmi, Antimicrob, Agents Chemother. 37:2550-2556, 1993; M. Chen, S.B. Christensen, T.G. Theander, and A. Khrazmi, Antimicrob. Agents Chemother. 38:1339-1344, 1994) and antimalarial (M. Chen, T.G. Theander, S.B. Christensen, L. Hviid, L. Zhai, and A. Kaharazmi, Antimicrob. Agents Chemother. 38:1470-1475, 1994) activities. We have observed that licochalcone A alters the ultrastructure of the mitochondria of Leishmania promastigotes (Chen et al., Antimicrob. Agents Chemother. 37:2550-2556, 1993). The present study was designed to examine this observation further and investigate the mechanism of action of antileishmanial activity of licochalcone A. Electron microscopic studies showed that licochalcone A altered the ultrastructure of Leishmania major promastigote and amastigote mitochondria in a concentration-dependent manner without damaging the organelles of macrophages or the phagocytic function of these cells. Studies on the function of the parasite mitochondria showed that licochalcone A inhibited the respiration of the parasite by the parasites. Moreover, licochalcone A inhibited the activity of the parasite mitochondrial dehydrogenase. The inhibition of the activity of the parasite mitochondrial enzyme correlated well with the changes in the ultrastructure of the mitochondria shown by electron microscopy. These findings demonstrate that licochalcone A alters the ultrastructure and function of the mitochondria of Leishmania parasites.

Animals↗
PubMed1995

The ability of phosphodiesterase IV inhibitors to suppress superoxide production in guinea pig eosinophils is correlated with inhibition of phosphodiesterase IV catalytic activity.

Elevation of cyclic AMP (cAMP) content inhibits eosinophil function. Because phosphodiesterase IV (PDE IV) appears to be the major PDE isozyme present in eosinophils, inhibitors of this isozyme should suppress eosinophil activation. Previous studies on PDE IV have revealed that this enzyme possesses both cAMP catalytic activity that is inhibitable by rolipram, a prototypical PDE IV inhibitor, and a high-affinity binding site for rolipram. The function of this high-affinity rolipram binding site relative to the inhibitory action of compounds is not clear because the rank order potency of PDE IV inhibitors for competing with [3H]-rolipram binding is distinct from that for inhibiting cAMP hydrolysis. Consequently, the present experiments were carried out to fulfill the following objectives: 1) to determine whether PDE IV inhibitors suppress eosinophil function and, if so, 2) to establish a correlation between this functional activity and inhibition of PDE IV catalytic activity or interaction with the high-affinity rolipram binding site. Various PDE inhibitors produced approximately 60% maximal inhibition of formylmethionine-leucine-phenylalanine-induced superoxide anion production, so that IC30 concentrations were used as a basis to compare the potency of various PDE inhibitors. Selective PDE IV inhibitors were the most potent compounds tested. PDE inhibitors selective for other isozymes were devoid of activity or considerably less potent.(ABSTRACT TRUNCATED AT 250 WORDS)

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed1995

Inhibitors of phosphodiesterase IV (PDE IV) increase acid secretion in rabbit isolated gastric glands: correlation between function and interaction with a high-affinity rolipram binding site.

In this report, we describe the ability of selective inhibitors of phosphodiesterase (PDE) isozymes to increase aminopyrine accumulation in rabbit isolated gastric glands. Aminopyrine accumulation in the presence of histamine was increased by the nonselective PDE inhibitor isobutylmethylxanthine (EC50 = 4.8 microM) and by two selective PDE IV inhibitors, rolipram and Ro 20-1724 (EC50 = 0.013 and 0.07 microM, respectively) but not by selective PDE III inhibitors (siguazodan and SK&F 94120) or by a selective PDE V inhibitor (zaprinast). These results suggest that PDE IV is an important regulator of acid secretion in response to histamine. One of the more fascinating properties of PDE IV is the expression of a high-affinity binding site for [3H]-rolipram in addition to cAMP catalytic activity. Although agents that inhibit PDE IV catalytic activity also appear to bind to the high-affinity rolipram-binding site, the rank-order potencies of compounds for these two effects are poorly correlated. Also, certain pharmacological actions of PDE IV inhibitors appear to be related to an interaction with this binding site. In this study, we observed that the ability of PDE IV inhibitors to enhance acid secretion was not associated with their ability to inhibit PDE IV catalytic activity but did show a strong correlation with their ability to compete for [3H]-rolipram binding. Furthermore, we were able to detect [3H]-rolipram binding sites in gastric glands that had characteristics similar to those of the [3H]-rolipram binding sites in rat brain microsomes and human recombinant PDE IV.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed1994

Molluscicidal saponins from a Zimbabwean strain of Phytolacca dodecandra.

Three new monodesmosidic saponins, all glycosides of 2 beta-hydroxyoleanolic acid, were isolated from an aqueous extract of a Zimbabwean strain of Phytolacca dodecandra. Their structures were, mainly by spectroscopic methods (LSIMS, 1H NMR, COSY, NOESY, TOCSY, J-resolved 1H NMR, 13C NMR, HETCOR), established as 3-O-[2',4'-di-O-(beta-D-glucopyranosyl)-beta-D-glucopyranosyl]2 beta-hydroxyoleanolic acid, 3-O-[O-alpha-L-rhamnopyranosyl-(1-->2)-O-[beta-D-galactopyranosyl- (1-->3)]-beta-D-glucopyranosyl]2 beta-hydroxyoleanolic acid and 3-O-[3'-O-(beta-D-galactopyranosyl)-beta-D-glucopyranosyl]2 beta-hydroxyoleanolic acid. Two of the saponins were submitted to a preliminary screening for molluscicidal activity against the schistosomiasis transmitting snail Biomphalaria glabrata and showed, respectively, strong and weak activity. In addition, four saponins previously reported from other strains of Phytolacca dodecandra were identified.

Animals↗
PubMed1994

An antileishmanial chalcone from Chinese licorice roots.

A bioassay guided fractionation of an extract of Chinese licorice roots led to the isolation of (E)-1-[2,4-dihydroxy-3-(3-methyl-2-butenyl)phenyl]-3-[4- hydroxy-3-(3-methyl-2-butenyl]phenyl-2-propen-1-one, which in vitro showed potent antileishmanial activity. In addition, the novel chalcone (E)-1-[2,4-dihydroxy-3-(3-methyl-2- butenyl)phenyl]-3-(2,2-dimethyl-8-hydroxy-2H-benzopyran-6-yl)-2-prope n-1-one was isolated from the roots. The latter compound only showed antileishmanial activity at high concentrations.

Animals↗
PubMed1994

Antileishmanial activity of licochalcone A in mice infected with Leishmania major and in hamsters infected with Leishmania donovani.

This study was designed to examine the antileishmanial activity of the oxygenated chalcone licochalcone A in mice and hamsters infected with Leishmania parasites. Intraperitoneal administration of licochalcone A at doses of 2.5 and 5 mg/kg of body weight per day completely prevented lesion development in BALB/c mice infected with Leishmania major. Treatment of hamsters infected with L. donovani with intraperitoneal administration of licochalcone A at a dose of 20 mg/kg of body weight per day for 6 consecutive days resulted in a > 96% reduction of parasite load in the liver and the spleen compared with values for untreated control animals. The [3H]thymidine uptake by the parasites isolated from the treated hamsters was only about 1% of that observed in parasites isolated from the controls. Oral administration of licochalcone A at concentrations of 5 to 150 mg/kg of body weight per day for 6 consecutive days resulted in > 65 and 85% reductions of L. donovani parasite loads in the liver and the spleen, respectively, compared with those of untreated control hamsters. These data clearly demonstrate that licochalcone A is a promising lead for the development of a new drug against leishmaniases.

Animals↗
PubMed1994

Licochalcone A, a new antimalarial agent, inhibits in vitro growth of the human malaria parasite Plasmodium falciparum and protects mice from P. yoelii infection.

Licochalcone A, isolated from Chinese licorice roots, inhibited the in vitro growth of both chloroquine-susceptible (3D7) and chloroquine-resistant (Dd2) Plasmodium falciparum strains in a [3H]hypoxanthine uptake assay. The growth inhibition of the chloroquine-resistant strain by licochalcone A was similar to that of the chloroquine-susceptible strain. To examine the activity of licochalcone A on the different asexual blood stages of the parasite, licochalcone A was added to highly synchronized cultures containing rings, trophozoites, and schizonts. The growth of the parasites at all stages was inhibited by licochalcone A. The in vivo activity of licochalcone A was tested in a mouse model of infection with P. yoelii. Licochalcone A administered either intraperitoneally or orally for 3 to 6 days protected the mice from the otherwise lethal P. yoelii infection. These results demonstrate that licochalcone A exhibits potent antimalarial activity and might be developed into a new antimalarial drug.

Animals↗
PubMed1993

Derivatives of thapsigargin as probes of its binding site on endoplasmic reticulum Ca2+ ATPase. Stereoselectivity and important functional groups.

The naturally occurring sesquiterpene lactone thapsigargin is a potent and selective inhibitor of SERCA ATPases, a family of Ca(2+)-pumping ATPases present in the endoplasmic reticulum of all mammalian cells. We have studied some of the molecular features of thapsigargin responsible for its inhibitory action towards these Ca2+ ATPases. A series of thapsigargin analogues were synthesised and their inhibitory potencies determined using the uptake of 45Ca2+ in bovine cerebellar microsomes as a sensitive marker of Ca2+ ATPase activity. An attenuation of the inhibitory potency relative to the parent compound was found ranging from slight to over 3 orders of magnitude. The inhibitory activity showed a very strong configuration dependence, a major contribution from the ester groups at C3 and C10, and an apparently minor contribution from the lactone ring substituents. The data are consistent with thapsigargin fitting to a sterically discriminating cleft involving the hydrophobic transmembrane region of the ATPase, and is compatible with available kinetic evidence of thapsigargin-mediated inhibition.

Animals↗
PubMed1993

The crystal structure, absolute configuration, and phosphodiesterase inhibitory activity of (+)-1-(4-bromobenzyl)-4-(3-(cyclopentyloxy)- 4-methoxyphenyl)-pyrrolidin-2-one.

Chiral HPLC resolution of the phosphodiesterase IV (PDE IV) inhibitor rolipram (1) provided (-)-1, and this enantiomer was converted into its 1-(4-bromobenzyl) derivative, (+)-2. X-ray structural analysis of (+)-2 established the absolute configuration as R, which provides the first direct evidence for a previously assumed assignment of configuration. The crystal structure of (+)-2 and the PDE inhibitory activity of both enantiomers of 2 are discussed in the context of a previously proposed topological model.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed1993

[Idiopathic scolioses].

The article summarizes the current theories on the aetiology, natural history, diagnosis and treatment of adolescent idiopathic scoliosis. Much remains unknown concerning the genesis of scoliosis. The current treatment with bracing or spinal fusion is effective.

Adolescent↗
PubMed1993

[Surgical management of idiopathic scoliosis using Harrington DTT instruments]].

We reviewed the clinical charts and roentgenogram of 111 patients operated with Harrington-DTT instrumentation for idiopathic adolescent scoliosis at Copenhagen University Hospital from 1983 to 1989. Male/female ratio was 1:9. Median age was 14.5 (11-21) years at the time of surgery. Median follow-up time was 4.0 (1-7) years. Of the 111 patients, complications were registered in fifteen. Seven were reoperated, four due to gliding of the upper hook, three due to fatigue fracture of the Harrington rod before union. We found no deep infections or persisting neurological damage.

Adolescent↗
PubMed1993

[Idiopathic scolioses treated with the Boston brace].

It is well known that Boston bracing may stop progression in many patients with minor curves. One hundred and thirty-eight patients were treated with the Boston brace for idiopathic scoliosis. Age was 14.1 +/- 1.6 years at the time of bracing, and the length of time spent in the brace was 2.6 +/- 1.0 years. The major curve at the time of bracing was 39 +/- 10 degrees, and 36 +/- 11 degrees at the time of follow-up in the patients who completed bracing. Thirty-six patients progressed, and were later fused. None of the patients with the apex of the curve between T11 and L1 required spinal fusion (p < 0.0001). No patients with curve magnitude on sidebending of less than 11 degrees needed spinal fusion. None of the patients who had a Harrington factor of less than five degrees per vertebra needed spinal fusion.

Adolescent↗
PubMed1993

Calcium entry in Xenopus oocytes: effects of inositol trisphosphate, thapsigargin and DMSO.

Agonist- and inositol 1,4,5-trisphosphate (InsP3)-evoked responses in Xenopus oocytes utilize calcium mobilized from cellular stores as well as from the medium. We studied the effect of the status of Ca stores on InsP3-induced Ca entry. Thapsigargin (TG) caused a net increase of 45Ca2+ efflux from oocytes in a time and dose dependent manner (31 and 54% of total label, at 30 and 60 min, respectively). Incubation with TG (60 min) resulted in a complete loss of the response to InsP3 implying that InsP3-sensitive Ca stores were depleted. Challenge with 1.8 mM Ca2+ resulted in a large depolarizing chloride current (1231 +/- 101 nA) which was not further potentiated by InsP3. This suggested that extensive depletion of cellular Ca stores is sufficient to induce maximal entry of extracellular Ca (Cao). Following the injection of InsP3, a much more limited loss of cellular Ca was sufficient to produce large Ca entry. Dimethyl sulfoxide (DMSO) alone, the vehicle used to dissolve TG, did not cause increase in either efflux of 45Ca2+, nor in the Cao-evoked Cl- current. It did, however, markedly potentiate this current following the injection of InsP3. DMSO moderately inhibited InsP3-induced 45Ca2+ efflux from oocytes. Hence, apparent potentiation of Ca entry can be observed without additional depletion of cellular Ca. We conclude that Ca entry may be induced via either stimulation with InsP3 and limited Ca depletion or depletion of a specific and, possibly small, cellular Ca store alone. The mechanism of DMSO potentiation is unknown, but may be important in view of the universal use of this solvent as vehicle.

Animals↗
PubMed1993

Licochalcone A, a novel antiparasitic agent with potent activity against human pathogenic protozoan species of Leishmania.

Licochalcone A, an oxygenated chalcone isolated from the roots of Chinese licorice plant, inhibited the growth of both Leishmania major and Leishmania donovani promastigotes and amastigotes. The structure of the licochalcone A was established by mass and nuclear magnetic resonance spectroscopies and by synthesis, and its purity was verified by high-pressure liquid chromatography. The 50% inhibition of growth of logarithmic- and stationary-phase promastigotes of L. major, as measured by [3H]thymidine uptake, were 4 and 2.5 micrograms/ml, respectively. The growth of L. major promastigotes was totally inhibited after a 20-h incubation period with licochalcone A at 5 micrograms/ml. At a concentration of 0.5 microgram/ml, licochalcone A markedly reduced the infection rate of human peripheral blood monocyte-derived macrophages and U937 cells with L. major promastigotes and exhibited a strong intracellular killing of the parasite. These data show that intracellular Leishmania amastigotes are more susceptible than promastigotes to licochalcone A. Results of studies on the site of action of licochalcone A indicate that the target organelle appears to be the parasite mitochondria. These findings demonstrate that licochalcone A in concentrations that are nontoxic to host cells exhibits a strong antileishmanial activity and that appropriate substituted chalcones might be a new class of antileishmanial drugs.

Animals↗
PubMed1993

Axillary biopsy compared with dissection in the staging of lymph nodes in operable breast cancer. A randomised trial.

OBJECTIVE: To compare the accuracy of axillary dissection with that of axillary node biopsy for staging of lymph nodes in operable breast cancer. DESIGN: Randomised study. SETTING: District hospital, Oestersund, Sweden. SUBJECTS: 200 women with operable breast cancer who presented between 1985-87 and 1989-91. INTERVENTIONS: Women were randomised (n = 100 in each group) to have either axillary dissection (in which all fat tissue was removed from the axilla) or biopsy (in which the lower half of the axillary fat, together with obviously malignant nodes were removed for histopathological examination). MAIN OUTCOME MEASURES: Number of nodes harvested by each method, and number that contained metastases. RESULTS: Nodes that contained metastases were found in 43 of the patients in the dissection group and 46 of those who had undergone biopsy alone. The median (range) yield of nodes in the dissection group was 8.5 (0-16) and in the biopsy group 6 (0-14), p < 0.001. In only two patients (one in each group) were no nodes identified. Patients without histologically confirmed node metastases were followed up for a median of 30 months; one in the biopsy group had a metastatic node detected three months after operation. During the last 100 operations the surgeon was asked to assess clinically whether the patients had involved nodes or not; this had a sensitivity of 59% and a specificity of 89%. CONCLUSION: Axillary node dissection and biopsy give similar results in the staging of breast cancer. Perioperative clinical judgement is unsatisfactory.

Adult↗
PubMed1992

Toxicodynamics of tumour promoters of mouse skin. III. Specific binding of the tumour promoter thapsigargin as measured by the cold-acetone filter assay.

A method is described for measuring rapid, specific, and saturable binding of the skin irritant and tumour-promoting secretagogue thapsigargin (sesquiterpene lactone) to the microsomal fraction from mouse brain. Employing the tritium-labelled compound its apparent dissociation constant, Kd, and the maximal amount of binding Bmax are shown to be 9.8 nM and 1.9 pmol/mg protein respectively. Such a Kd for thapsigargin is similar to (a) its IC50 value for inhibiting Ca2+ uptake in the microsomal fraction from rat brain and (b) its EC50 values for inducing a rise in the cytoplasmic Ca2+ concentration of human platelets and histamine release from rat peritoneal mast cells. A positive correlation is found between the binding affinities of thapsigargin, thapsitranstagin, and trilobolide, their potencies as secretagogues and their lipophilicities. This correlation does not extend to the skin-irritant activities of the compounds thus emphasizing that their mechanism of action is unlike that of 12-O-tetradecanoylphorbol 13-acetate.

Animals↗
PubMed1992

The molluscicidal activity of coumarins from Ethulia conyzoides and of dicumarol.

The molluscicidal principles of Ethulia conyzoides were identified as ethuliacoumarin A (1) and isoethuliacoumarin A (2). Ethuliacoumarin A possessed an LC90 between 19 and 23.5 ppm depending on the age of the snail against Biomphalaria glabrata, and between 12 and 15 ppm against Bulinus truncatus. In addition, ethuliacoumarin A was found to be cercaricidal at 25 ppm and ovicidal. Ethuliacoumarin has the structural requirements considered essential for anticoagulant activity. Consequently the anticoagulant dicumarol (4) was tested and found to be molluscicidal in the range from 2.5 to 10 ppm. In contrast, the coumarin anticoagulant warfarin (3) did not show molluscicidal activity.

Animals↗