Phospholipid-dependent changes in membrane permeability induced by staphylococcal δ-lysin and bee venom melittin

1985 ◽  
Vol 63 (1) ◽  
pp. 1-6 ◽  
Author(s):  
M. Bhakoo ◽  
T. H. Birkbeck ◽  
J. H. Freer
Keyword(s):  
Dose Response ◽  
Mode Of Action ◽  
Response Curve ◽  
Atp Release ◽  
Cell Types ◽  
Bee Venom ◽  
Degree Of Saturation ◽  
Large Unilamellar Vesicles ◽  
Concentration Sensitivity ◽  
Lytic Peptides

The effect of purified staphylococcal δ-lysin and bee venom melittin on the permeability of large unilamellar vesicles (liposomes) composed of structurally defined lipids was investigated by following release of sequestered ATP using a bioluminescent assay. ATP release was linearly related to the logarithm of the peptide concentration. Sensitivity to the lytic peptides, as measured by the release of ATP and the slope of the dose–response curve, depended on the chain length and the degree of saturation of the hydrocarbon substituents of the phospholipid in the vesicles. Neither the sign of the surface charge nor the presence of sterol had any significant effect on the sensitivity of liposomes to peptide-induced lysis. Release of ATP and haemoglobin from intact sheep and cod erythrocytes was also determined after their exposure to δ-lysin and melittin. Both cell types showed similar degrees of sensitivity to each lytic peptide when ATP release was followed, but the release of haemoglobin from sheep erythrocytes by δ-lysin was much less than from cod erythrocytes. The implications of these results on the mode of action of the two agents are discussed.

A true threshold dose in chemical carcinogenesis cannot be defined for a population, irrespective of the mode of action

2000 ◽  
Vol 19 (10) ◽  
pp. 566-568 ◽  
Author(s):  
W K Lutz
Keyword(s):  
Cancer Incidence ◽  
Dose Response ◽  
Mode Of Action ◽  
Response Curve ◽  
Low Dose ◽  
Chemical Carcinogenesis ◽  
Threshold Dose ◽  
Tumor Incidence ◽  
True Threshold ◽  
Individual Threshold

Strongly sigmoidal (S-shaped) dose-cancer incidence relationships are often observed in animal bioassays for carcinogenicity. If a genotoxic contribution is not plausible, an epigenetic mode of carcinogen action is proposed and a thresholded low dose-response suggested. In a strictsense, a threshold implies a no-yes situation, i.e., no effect up to the threshold dose and an effect above the threshold dose. A convincing explanation ofthe discontinuity ofthe gradient of the dose-response curve at the threshold dose is not available to me. However, the existence of a threshold is accepted for an individual. The threshold dose is the dose required for the manifestation of the tumor in an individual exactly at the end of a defined period of observation (for instance, 2 years in an animal bioassay, 75 years in humans). Because of genetic and lifestyle-dependent susceptibility differences, each animal or human has his individual threshold dose. For a group, no single threshold dose can be defined, irrespective of the mode of carcinogen action. Furthermore, in view of the stochastic elements in the process of carcinogenesis, the exact threshold dose can only be defined after tumor incidence and cannot be predicted.

Factor VII Clotting Assay: Influence of Different Thromboplastins and Factor VII-Deficient Plasmas

1991 ◽  
Vol 65 (02) ◽  
pp. 160-164 ◽  
Author(s):  
Marina Poggio ◽  
Armando Tripodi ◽  
Guglielmo Mariani ◽  
Pier Mannuccio Mannucci ◽  
Keyword(s):  
Heart Disease ◽  
Ischemic Heart Disease ◽  
Dose Response ◽  
Response Curve ◽  
Ischemic Heart ◽  
Factor Vii ◽  
Response Curves ◽  
Assay Sensitivity ◽  
Clinical Laboratories ◽  
Coagulant Activity

SummaryBeing a putative predictor of ischemic heart disease, the measurement of factor VII (FVTI) coagulant activity will be presumably requested to clinical laboratories with increasing frequency. To assess the influence on FVII assays of different thromboplastins and FVII-deficient plasmas we compared performances of all possible combinations of 5 thromboplastins and 6 deficient plasmas. The reproducibility of the clotting times of the dose-response curves for human and rabbit thromboplastins were acceptable (CV lower than 7%), whereas bovine thromboplastin had a higher CV. Reproducibility was very similar for all deficient plasmas when they were used in combination with a given thromboplastin. Responsiveness of the dose-response curve did not depend on the deficient plasma but rather on the thromboplastin: one rabbit thromboplastin was the least responsive, the bovine thromboplastin the most responsive, the human and the remaining two rabbit thromboplastins had intermediate responsiveness. Assay sensitivity to cold-activated FVII varied according to the thromboplastin: the bovine thromboplastin was the most sensitive, the human thromboplastin the least sensitive, of the three rabbit thromboplastins two were relatively sensitive, one was almost insensitive. In conclusion, our results indicate that thromboplastin rather than deficient plasma is the crucial factor in the standardization of FVII assay.

OVARIAN ASCORBIC ACID DEPLETION TEST FOR LUTEINIZING HORMONE

1967 ◽  
Vol 56 (4) ◽  
pp. 619-625 ◽  
Author(s):  
Hans Jacob Koed ◽  
Christian Hamburger
Keyword(s):  
Ascorbic Acid ◽  
Luteinizing Hormone ◽  
Dose Response ◽  
Response Curve ◽  
Dose Response Curve ◽  
Human Origin ◽  
Response Curves ◽  
Significant Difference ◽  
The Mean ◽  
Different Levels

ABSTRACT Comparison of the dose-response curves for LH of ovine origin (NIH-LH-S8) and of human origin (IRP-HMG-2) using the OAAD test showed a small, though statistically significant difference, the dose-response curve for LH of human origin being a little flatter. Two standard curves for ovine LH obtained with 14 months' interval, were parallel but at different levels of ovarian ascorbic acid. When the mean ascorbic acid depletions were calculated as percentages of the control levels, the two curves for NIH-LH-S8 were identical. The use of standards of human origin in the OAAD test for LH activity of human preparations is recommended.

HYPERTROPHIC ADRENALS AND THEIR RESPONSE TO STRESS AFTER LESIONS IN THE MEDIAN EMINENCE OF TOTALLY HYPOPHYSECTOMIZED PIGEONS

1961 ◽  
Vol 37 (4) ◽  
pp. 565-576 ◽  
Author(s):  
Richard A. Miller
Keyword(s):  
Dose Response ◽  
Median Eminence ◽  
Response Curve ◽  
Liver Parenchyma ◽  
Dose Response Curve ◽  
Pars Distalis ◽  
Adrenal Enlargement ◽  
Response To Stress ◽  
Lethal Doses ◽  
Chromaffin Tissue

ABSTRACT Four per cent formaldehyde, insulin, or epinephrine in oil was injected for 5 days into pigeons subjected to varying degrees of hypophysectomy alone or together with large lesions in the median eminence and hypothalamus. Adrenals atrophied after the removal of the pars distalis alone or together with the neurohypophysis in untreated pigeons but showed markedly hypertrophic interrenal tissue (cortex in mammals) after treatment with formaldehyde or insulin. The slope of the dose-response curve was similar in operated and unoperated pigeons. The accumulation of bile in the liver parenchyma, which may occur after removal of the pars distalis, is an endogenous stress which was associated regularly with adrenal hypertrophy. After very large lesions of the median eminence and ventral hypothalamus in addition to total hypophysectomy, adrenals hypertrophied rather than atrophied, and the response to formaldehyde paralleled that in intact and »hypohysectomized« pigeons. Interrenal tissue was stimulated regularly; chromaffin tissue was partially degranulated, sometimes showed hyperplasia with colchicine, but only occasionally appeared hypertrophied. Epinephrine in nearly lethal doses caused only minimal adrenal enlargement. After adrenal denervation followed by hypophysectomy, the adrenals were still stimulated by formaldehyde. It appears that the interrenal tissue of the pigeon responds to a humoral stimulus not of hypophyseal origin in the absence of the hypophyseal-hypothalamic system.

ANTI-OVULATORY ACTIVITY OF STEROIDS ADMINISTERED BY GAVAGE IN THE ADULT OESTRUS RABBIT

1963 ◽  
Vol 42 (2_Suppl) ◽  
pp. S17-S30
Author(s):  
Fred A. Kind ◽  
Ralph I. Dorfman
Keyword(s):  
Dose Response ◽  
Active Compound ◽  
Subcutaneous Injection ◽  
Response Curve ◽  
Parent Compound ◽  
Dose Response Curve ◽  
Relative Potency ◽  
Reference Standard ◽  
Highly Active ◽  
Dose Levels

ABSTRACT Thirty-seven steroids have been studied as orally effective inhibitors of ovulation in the mated oestrus rabbit. Norethisterone served as the reference standard and a dose response curve was established between the 0.31 and 1.25 mg dose levels. Nine highly active anti-ovulatory compounds are described listed in a decreasing order of potency with norethisterone having the arbitrary value of one: 6-chloro-Δ6-dehydro-17α-acetoxyprogesterone (35), 6α-methyl-Δ1-dehydro-17α-acetoxyprogesterone (≥ 10), 6-fluoro-Δ6-dehydro-17α-acetoxyprogesterone(9), 6-methyl-Δ6-dehydro-17α-acetoxyprogesterone (5), Δ6-dehydro-17α-acetoxyprogesterone (≥ 3), 6α-methyl-17α-acetoxyprogesterone (2.6), 6-chloro-Δ1,6-bisdehydro-17α-acetoxyprogesterone (≥ 2), 2-hydroxymethyl-17α-methyl-17β-hydroxyandrostan-3-one (≥ 2), and 6α-fluoro-16α-methyl-17α-acetoxyprogesterone (≥ 1.25). The anti-ovulatory activity of a compound was not related necessarily to the progestational activity of a compound nor to the anti-gonadotrophic activity as measured in parabiotic rats. 6-Chloro-Δ60dehydro-17-acetoxyprogesterone was as effective by gavage as previously shown by subcutaneous injection. 2-Hydroxymethyl-17α-methyl-17β-hydroxyandrostan-3-one was at least 2.5 times more active by gavage than by injection. While 17α-acetoxyprogesterone was a very weak anti-ovulatory steroid, modifications of the structure by addition of methyl or halogen at the 6α position with or without unsaturation greatly increased the activity. 6-Chloro-Δ6-dehydro-27α-acetoxyprogesterone was the most active compound in this series showing a relative potency of 3500 times that of the parent compound 17α-acetoxyprogesterone.

scholarly journals Predicting the in vivo developmental toxicity of benzo[a]pyrene (BaP) in rats by an in vitro–in silico approach

2021 ◽  
Author(s):  
Danlei Wang ◽  
Maartje H. Rietdijk ◽  
Lenny Kamelia ◽  
Peter J. Boogaard ◽  
Ivonne M. C. M. Rietjens
Keyword(s):  
Dose Response ◽  
In Silico ◽  
Response Curve ◽  
Developmental Toxicity ◽  
Toxicity Testing ◽  
Maximal Effect ◽  
Blood Concentrations ◽  
Reverse Dosimetry

AbstractDevelopmental toxicity testing is an animal-intensive endpoints in toxicity testing and calls for animal-free alternatives. Previous studies showed the applicability of an in vitro–in silico approach for predicting developmental toxicity of a range of compounds, based on data from the mouse embryonic stem cell test (EST) combined with physiologically based kinetic (PBK) modelling facilitated reverse dosimetry. In the current study, the use of this approach for predicting developmental toxicity of polycyclic aromatic hydrocarbons (PAHs) was evaluated, using benzo[a]pyrene (BaP) as a model compound. A rat PBK model of BaP was developed to simulate the kinetics of its main metabolite 3-hydroxybenzo[a]pyrene (3-OHBaP), shown previously to be responsible for the developmental toxicity of BaP. Comparison to in vivo kinetic data showed that the model adequately predicted BaP and 3-OHBaP blood concentrations in the rat. Using this PBK model and reverse dosimetry, a concentration–response curve for 3-OHBaP obtained in the EST was translated into an in vivo dose–response curve for developmental toxicity of BaP in rats upon single or repeated dose exposure. The predicted half maximal effect doses (ED50) amounted to 67 and 45 mg/kg bw being comparable to the ED50 derived from the in vivo dose–response data reported for BaP in the literature, of 29 mg/kg bw. The present study provides a proof of principle of applying this in vitro–in silico approach for evaluating developmental toxicity of BaP and may provide a promising strategy for predicting the developmental toxicity of related PAHs, without the need for extensive animal testing.

scholarly journals Enhancement of morphine-induced antinociception after electroconvulsive shock in mice

2021 ◽  
Vol 17 ◽  
pp. 174480692199262
Author(s):  
Ken Iwata ◽  
Yukio Takamatsu ◽  
Nagafumi Doi ◽  
Kazutaka Ikeda
Keyword(s):  
Dose Response ◽  
Response Curve ◽  
Antinociceptive Effect ◽  
Dose Response Curve ◽  
Expression Level ◽  
Morphine Injection ◽  
Hot Plate ◽  
Hot Plate Test ◽  
Plate Test ◽  
Pain Patients

Electroconvulsive therapy (ECT) has been applied for chronic pain for decades. The amounts of opioids to treat pain are sometimes reduced after a series of ECT. The effect of ECT on morphine-induced analgesia and its mechanism underlying the reduction of morphine requirement has yet to be clarified. Therefore, we administered electroconvulsive shocks (ECS) to mice and investigated the antinociceptive effect of morphine in a hot plate test. We examined the expression level of µ-opioid receptor in the thalami of mice 25 h after administration of ECS compared to the thalami of mice without ECS administration using western blotting. ECS disturbed the development of a decrease in the percentage of maximal possible effect (%MPE), which was observed 24 h after a morphine injection, when ECS was applied 25, 23, 21, and 12 h before the second administration of morphine. We also examined the effect of ECS on the dose-response curve of %MPE to morphine-antinociception. Twenty-five hours after ECS, the dose-response curve was shifted to the left, and the EC50 of morphine given to ECS-pretreated mice decreased by 30.1% compared to the mice that were not pretreated with ECS. We also found that the expression level of µ-opioid receptors was significantly increased after ECS administration. These results confirm previous clinical reports showing that ECT decreased the required dose of opioids in neuropathic pain patients and suggest the hypothesis that this effect of ECT works through the thalamus.

A receptor-antibody sandwich assay for teicoplanin.

1987 ◽  
Vol 33 (9) ◽  
pp. 1615-1618 ◽  
Author(s):  
A Corti ◽  
L Cavenaghi ◽  
E Giani ◽  
G Cassani
Keyword(s):  
Detection Limit ◽  
Dose Response ◽  
Response Curve ◽  
Synthetic Analog ◽  
Sandwich Complexes ◽  
Sandwich Assay ◽  
Receptor Antibody ◽  
Microtiter Plates ◽  
Analytical Recovery ◽  
Biological Target

Abstract We have developed a new method for quantifying teicoplanin in complex matrixes, a receptor-antibody sandwich assay (RASA). The method is based on bioselective adsorption of teicoplanin onto microtiter plates coated with albumin-epsilon-aminocaproyl-D-alanyl-D-alanine, a synthetic analog of its biological target, and reaction with anti-teicoplanin antibodies. The sandwich complexes are detected by incubation with peroxidase-labeled goat antibodies to rabbit IgGs and chromogenic reaction with o-phenylenediamine. The dose-response curve was linear for teicoplanin concentrations in the range from 0 to 0.15 mg/L. We used the assay to measure teicoplanin concentrations in various biological matrixes. Analytical recovery from serum was 99.5%, the interassay CV was 5.1%, and the detection limit was 30 micrograms/L (P less than 0.01). Mean analytical recoveries from other biological specimens were 98% from ascitic fluid, 100% from pleuric liquid, 104.8% from prostate homogenate, and 98.5% from bronchial expectorate.

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