scholarly journals Binding and Functional Studies with the Growth Hormone Receptor Antagonist, B2036-PEG (Pegvisomant), Reveal Effects of Pegylation and Evidence That It Binds to a Receptor Dimer1

2001 ◽  
Vol 86 (4) ◽  
pp. 1716-1723 ◽  
Author(s):  
R. J. M. Ross ◽  
K. C. Leung ◽  
M. Maamra ◽  
W. Bennett ◽  
N. Doyle ◽  
...  
Keyword(s):  
Receptor Antagonist ◽  
Growth Hormone Receptor ◽  
Membrane Binding ◽  
Membrane Receptor ◽  
High Concentration ◽  
Receptor Dimerization ◽  
Functional Studies ◽  
High Concentrations ◽  
The Impact ◽  
Receptor Dimer

GH actions are dependent on receptor dimerization. The GH receptor antagonist, B2036-PEG, has been developed for treating acromegaly. B2036 has mutations in site 1 to enhance receptor binding and in site 2 to block receptor dimerization. Pegylation (B2036-PEG) increases half-life and lowers immunogenicity, but high concentrations are required to control insulin-like growth factor-I levels. We examined antagonist structure and function and the impact of pegylation on biological efficacy. Unpegylated B2036 had a 4.5-fold greater affinity for GH binding protein (GHBP) than GH but similar affinity for membrane receptor. Pegylation substantially reduced membrane binding affinity and receptor antagonism, as assessed by a transcription assay, by 39- and 20-fold, respectively. GHBP reduced antagonist activity of unpegylated B2036 but did not effect antagonism by B2036-PEG. B2036 down-regulated receptors, and membrane binding sites doubled in the presence of dimerization-blocking antibodies, suggesting that B2036 binds to a receptor dimer. It is concluded that the high concentration requirement of B2036-PEG for clinical efficacy relates to pegylation, which decreases binding to membrane receptor but has the advantages of reduced clearance, immunogenicity, and interactions with GHBP. Our studies suggest that B2036 binds to a receptor dimer and induces internalization but not signaling.

scholarly journals Photocrosslinking and photopatterning of magneto-optical nanocomposite sol–gel thin film under deep-UV irradiation

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
C. Bidaud ◽  
D. Berling ◽  
D. Jamon ◽  
E. Gamet ◽  
S. Neveu ◽  
...  
Keyword(s):  
Uv Irradiation ◽  
Cobalt Ferrite ◽  
Sol Gel ◽  
Optical Devices ◽  
High Concentration ◽  
Nanocomposite Thin Films ◽  
Deep Uv ◽  
High Concentrations ◽  
193 Nm ◽  
The Impact

AbstractThis paper is aimed at investigating the process of photocrosslinking under Deep-UV irradiation of nanocomposite thin films doped with cobalt ferrite magnetic nanoparticles (MNPs). This material is composed of a hybrid sol–gel matrix in which MNP can be introduced with high concentrations up to 20 vol%. Deep-UV (193 nm) is not only interesting for high-resolution patterning but we also show an efficient photopolymerization pathway even in the presence of high concentration of MNPs. In this study, we demonstrate that the photocrosslinking is based on the free radical polymerization of the methacrylate functions of the hybrid precursor. This process is initiated by Titanium-oxo clusters. The impact of the nanoparticles on the photopolymerization kinetic and photopatterning is investigated. We finally show that the photosensitive nanocomposite is suitable to obtain micropatterns with sub-micron resolution, with a simple and versatile process, which opens many opportunities for fabrication of miniaturized magneto-optical devices for photonic applications.

scholarly journals Biphasic Effect of Pirfenidone on Angiogenesis

2022 ◽  
Vol 12 ◽  
Author(s):  
Donghao Gan ◽  
Wenxiang Cheng ◽  
Liqing Ke ◽  
Antonia RuJia Sun ◽  
Qingyun Jia ◽  
...  
Keyword(s):  
Vascular Endothelial Cells ◽  
Tube Formation ◽  
Endothelial Cell Migration ◽  
High Concentration ◽  
Low Concentrations ◽  
Biphasic Effect ◽  
High Concentrations ◽  
And Migration ◽  
The Impact

Pirfenidone (PFD), a synthetic arsenic compound, has been found to inhibit angiogenesis at high concentrations. However, the biphasic effects of different PFD concentrations on angiogenesis have not yet been elucidated, and the present study used an in vitro model to explore the mechanisms underlying this biphasic response. The effect of PFD on the initial angiogenesis of vascular endothelial cells was investigated through a Matrigel tube formation assay, and the impact of PFD on endothelial cell migration was evaluated through scratch and transwell migration experiments. Moreover, the expression of key migration cytokines, matrix metalloproteinase (MMP)-2 and MMP-9, was examined. Finally, the biphasic mechanism of PFD on angiogenesis was explored through cell signaling and apoptosis analyses. The results showed that 10–100 μM PFD has a significant and dose-dependent inhibitory effect on tube formation and migration, while 10 nM–1 μM PFD significantly promoted tube formation and migration, with 100 nM PFD having the strongest effect. Additionally, we found that a high concentration of PFD could significantly inhibit MMP-2 and MMP-9 expression, while low concentrations of PFD significantly promoted their expression. Finally, we found that high concentrations of PFD inhibited EA.hy926 cell tube formation by promoting apoptosis, while low concentrations of PFD promoted tube formation by increasing MMP-2 and MMP-9 protein expression predominantly via the EGFR/p-p38 pathway. Overall, PFD elicits a biphasic effect on angiogenesis through different mechanisms, could be used as a new potential drug for the treatment of vascular diseases.

scholarly journals Physiological and biochemical reactions of Hordeum vulgare seedlings to the action of silver nanoparticles

2015 ◽  
Vol 23 (2) ◽  
Author(s):  
N. O. Khromykh ◽  
L. V. Shupranova ◽  
Y. V. Lykholat ◽  
V. S. Bil’chuk ◽  
V. S. Fedenko ◽  
...  
Keyword(s):  
Hordeum Vulgare ◽  
Leaf Growth ◽  
Leaf Length ◽  
Fresh Weight ◽  
High Concentration ◽  
Hordeum Vulgare L ◽  
Antioxidant Defense Systems ◽  
High Concentrations ◽  
The Impact ◽  
Physiological And Biochemical

Morphometrical indexes, and spectrophotometrically measured protein and glutathione (GSH, GSSG) contents and activity of peroxidase (POD, EC 1.11.1.7), glutathione-reductase (GR, EC 1.6.4.2) and glutathione S-transferase (GST, EС 2.5.1.18) were examined in Hordeum vulgare L. seedlings after 0.01 and 0.1 mg/l AgNPs treatment during 24 h. We tested the hypothesis that the action of nanoparticles has a stressful effect on the physiological and biochemical processes of seedlings. Growth of roots was inhibited and fresh weight decreased by 29% and 21% under low and high concentrations respectively. Conversely, leaf growth was intensified, and leaf length (16% and 18%) and fresh weight (35% and 44%) increased at low and high concentrations respectively. POD activity in roots increased by 26% and 7%, and decreased in leaves to 57% and 81% of control at low and high concentrations respectively. GSH content changed insignificantly, but GSSG content increased in roots (2 and 2.5-fold) and in leaves (13% and 30%) at both AgNPs concentrations. GSH/GSSG-ratio decreased in roots (1.9 and 2.6-fold) and in leaves (1.1 and 1.3-fold) at low and high concentrations respectively. GR activity decreased at a concentration of 0.01 mg/l (7% in roots and 17% in leaves respectively) and increased at 0.1 mg/l (52% in roots and 6% in leaves). GST activity increased in leaves (52% and 78% at low and high concentrations) but decreased by 17% in roots under high concentration of nanosilver. Thus, the action of AgNPs on barley seedlings had a dose-dependent and organ-specific character. The various directions of changes in growth, metabolic processes and activity of antioxidant defense systems appear to be a stress response of barley seedlings to the impact of AgNPs, which underlines the necessity of detailed study of plant intracellular processes exposed to the action of nanomaterial. 

The Toxicity of Castor Beans and its Treatment with Doxycycline in Local Rabbits

2018 ◽  
Vol 9 (2) ◽  
Author(s):  
Nael Mohammed Sarheed ◽  
Osamah Faisal Kokas ◽  
Doaa Abd Alabas Muhammed Ridh
Keyword(s):  
Castor Bean ◽  
The Body ◽  
Control Group ◽  
High Concentration ◽  
Biochemical Tests ◽  
Doxycycline Treatment ◽  
High Concentrations ◽  
Physiological Tests ◽  
Animal House ◽  
Physiological And Biochemical

The plant of castor is widely spread in the Iraqi land, and characterized with containing ricin toxin, which has a very serious effects, and because the seeds of this plant scattered in the agricultural soil and rivers water, which increases the exposure of humans and animals to these beans. Objective: This experiment was designed to study the effect of high concentration of castor bean powder in some physiological and biochemical parameters and changes in some tissues of the body, as well as trying to use doxycycline to reduce the effects of ingestion of these seeds. Materials and Methods: In the experiment, 24 local rabbits were raised and fed in the Animal House of the Faculty of Medicine / Al-Muthanna University, then divided into four groups and treated for three weeks (21 days), Control group: treated with normal saline solution (0.9) orally throughout the experiment, G1: was treated orally with a concentration of 25 mg / kg of castor bean powder daily during the experiment, G2 : orally treated 25 mg / kg of castor bean and 25 mg / kg of doxycycline, G3: orally treated 25 mg / kg of castor powder with 50 mg / kg of doxycycline daily throughout the trial period. Results: The results of the experiment showed significant changes (P less than 0.05) in all physiological and biochemical blood tests when compared with control group. There was a significant decrease in PCV, Hb, RBC, T.protein and body weights, while demonstrated a significant increase in WBC, Urea, Creatinine, ALT, AST and ALP, with distortions in liver and kidney of animals that treated with Castor beans. In contrast, the treatment with doxycycline and caster beans showed significant improvement reflected by a normal proportion in physiological tests and biochemical tests with improvement in the tissues when compared to control group. Conclusions: It can be concluded from this study that castor bean has high toxic and pathogenic effects that may be dangerous to the life of the organism. Therefore, it is advisable to be cautious of these pills and avoid exposure to them, also recommended to take high concentrations of doxycycline treatment when infected with castor bean poisoning.

The Effects of Shock Vancomycin Concentrations on the Formation of Heteroresistance in Staphylococcus aureus

2020 ◽  
Vol 65 (9-10) ◽  
pp. 3-7
Author(s):  
V. V. Gostev ◽  
Yu. V. Sopova ◽  
O. S. Kalinogorskaya ◽  
M. E. Velizhanina ◽  
I. V. Lazareva ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
In Vitro Selection ◽  
Methicillin Resistant Staphylococcus Aureus ◽  
High Concentration ◽  
Short Term ◽  
High Concentrations ◽  
Selection Of ◽  
Selection Of Resistance ◽  
Test Cultures

Glycopeptides are the basis of the treatment of infections caused by MRSA (Methicillin-Resistant Staphylococcus aureus). Previously, it was demonstrated that antibiotic tolerant phenotypes are formed during selection of resistance under the influence of high concentrations of antibiotics. The present study uses a similar in vitro selection model with vancomycin. Clinical isolates of MRSA belonging to genetic lines ST8 and ST239, as well as the MSSA (ATCC29213) strain, were included in the experiment. Test isolates were incubated for five hours in a medium with a high concentration of vancomycin (50 μg/ml). Test cultures were grown on the medium without antibiotic for 18 hours after each exposure. A total of ten exposure cycles were performed. Vancomycin was characterized by bacteriostatic action; the proportion of surviving cells after exposure was 70–100%. After selection, there was a slight increase in the MIC to vancomycin (MIC 2 μg/ml), teicoplanin (MIC 1.5–3 μg/ml) and daptomycin (MIC 0.25–2 μg/ml). According to the results of PAP analysis, all strains showed an increase in the area under curve depending on the concentration of vancomycin after selection, while a heteroresistant phenotype (with PAP/AUC 0.9) was detected in three isolates. All isolates showed walK mutations (T188S, D235N, E261V, V380I, and G223D). Exposure to short-term shock concentrations of vancomycin promotes the formation of heteroresistance in both MRSA and MSSA. Formation of VISA phenotypes is possible during therapy with vancomycin.

Chemical Composition and Metal Speciation in Porewaters from the Upper Qu’Appelle River Basin, Saskatchewan

1993 ◽  
Vol 28 (1) ◽  
pp. 83-110 ◽  
Author(s):  
Richard E. Farrell ◽  
Jae E. Yang ◽  
P. Ming Huang ◽  
Wen K. Liaw
Keyword(s):  
Amino Acids ◽  
Trace Metal ◽  
River Basin ◽  
Drainage Basin ◽  
Metal Speciation ◽  
Anthropogenic Activities ◽  
High Concentration ◽  
Metal Concentrations ◽  
Carbonate Equilibria ◽  
The Impact

Abstract Porewater samples from the upper Qu’Appelle River basin in Saskatchewan, Canada, were analyzed to obtain metal, inorganic ligand and amino add profiles. These data were used to compute the aqueous speciation of the metals in each porewater using the computer program GEOCHEM-PC. The porewaters were classified as slightly to moderately saline. Metal concentrations reflected both the geology of the drainage basin and the impact of anthropogenic activities. Whereas K and Na were present almost entirely as the free aquo ions, carbonate equilibria dominated the speciation of Ca. Mg and Mn (the predominant metal ligand species were of the type MCO3 (s). MCO30. and MHCO3+). Trace metal concentrations were generally within the ranges reported for non-polluted freshwater systems. Whereas the speciation of the trace metals Cr(III) and Co(II) was dominated by carbonate equilibria, Hg(II)-, Zn(II)- and Fe(II)-speciation was dominated by hydroxy-metal complexes of the type M(OH)+ and M(OH)2°. The speciation of Fe(III) was dominated by Fe(OH)3 (s). In porewaters with high chloride concentrations (> 2 mM), however, significant amounts of Hg(II) were bound as HgCl20 and HgClOH0. The aqueous speciation of Al was dominated by Al(OH)4− and Al2Si2O4(OH)6 (s). Total concentrations of dissolved free amino acids varied from 15.21 to 25.17 umole L−1. The most important metal scavenging amino acids were histidine (due to high stability constants for the metal-histidine complexes) and tryptophan (due to its relatively high concentration in the porewaters. i.e., 5.96 to 7.73 umole L−1). Secondary concentrations of various trace metal-amino add complexes were computed for all the porewaters, but metal-amino acid complexes dominated the speciation of Cu(II) in all the porewaters and Ni(II) in two of the porewaters.

Growth responses of periphyton and chironomids exposed to biologically treated bleached kraft pulp mill effluent

1997 ◽  
Vol 35 (2-3) ◽  
pp. 339-345 ◽  
Author(s):  
M. G. Dubé ◽  
J. M. Culp
Keyword(s):  
Kraft Pulp ◽  
Pulp Mill ◽  
Pulp Mill Effluent ◽  
Growth Responses ◽  
High Concentration ◽  
Wood Extractives ◽  
Kraft Pulp Mill ◽  
Bleached Kraft Pulp ◽  
Low Levels ◽  
High Concentrations

Experiments were conducted in artificial streams to determine the effects of increasing concentrations of biologically treated bleached kraft pulp mill effluent (BKPME) on periphyton and chironomid growth in the Thompson River, British Columbia. Periphyton growth, as determined by increases in chlorophyll a, was significantly stimulated at all effluent concentrations tested (0.25%, 0.5%, 1.0%, 5.0% and, 10.0%). Chironomid growth (individual weight) was also significantly stimulated at low effluent concentrations (≤1.0%). At higher concentrations (5.0% and 10.0%), chironomid growth was inhibited relative to the 1.0% treatment streams. Increases in growth were attributed to the effects of nutrient and organic enrichment from BKPME. The effluent contained high concentrations of phosphorus and appears to be an important source of carbon for benthic insects grazing on the biofilm. In high concentration effluent streams, chironomid growth decreased despite low levels of typical pulp mill contaminants. This suggests that other compounds in the effluent, such as wood extractives, may be inhibiting chironomid growth. These results support findings of field monitoring studies conducted in the Thompson River where changes in periphyton and chironomid abundance occurred downstream of the bleached kraft pulp mill.

scholarly journals Spatial Analysis (Measurements at Heights of 10 m and 20 m above Ground Level) of the Concentrations of Particulate Matter (PM10, PM2.5, and PM1.0) and Gaseous Pollutants (H2S) on the University Campus: A Case Study

Atmosphere ◽  
2021 ◽  
Vol 12 (1) ◽  
pp. 62
Author(s):  
Robert Cichowicz ◽  
Maciej Dobrzański
Keyword(s):  
Spatial Distribution ◽  
Hydrogen Sulfide ◽  
Particulate Matter ◽  
Air Quality ◽  
Spatial Analysis ◽  
Ground Level ◽  
Leeward Side ◽  
High Concentration ◽  
Above Ground Level ◽  
High Concentrations

Spatial analysis of the distribution of particulate matter PM10, PM2.5, PM1.0, and hydrogen sulfide (H2S) gas pollution was performed in the area around a university library building. The reasons for the subject matter were reports related to the perceptible odor characteristic of hydrogen sulfide and a general poor assessment of air quality by employees and students. Due to the area of analysis, it was decided to perform measurements at two heights, 10 m and 20 m above ground level, using measuring equipment attached to a DJI Matrice 600 unmanned aerial vehicle (UAV). The aim of the measurements was air quality assessment and investigate the convergence of the theory of air flow around the building with the spatial distribution of air pollutants. Considerable differences of up to 63% were observed in the concentrations of pollutants measured around the building, especially between opposite sides, depending on the direction of the wind. To explain these differences, the theory of aerodynamics was applied to visualize the probable airflow in the direction of the wind. A strong convergence was observed between the aerodynamic model and the spatial distribution of pollutants. This was evidenced by the high concentrations of dust in the areas of strong turbulence at the edges of the building and on the leeward side. The accumulation of pollutants was also clearly noticeable in these locations. A high concentration of H2S was recorded around the library building on the side of the car park. On the other hand, the air turbulence around the building dispersed the gas pollution, causing the concentration of H2S to drop on the leeward side. It was confirmed that in some analyzed areas the permissible concentration of H2S was exceeded.

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