A homotropic two-state model and auto-antagonism

Bindslev, Niels

doi:10.1186/1471-2210-4-11

Cited by 21 publications

(6 citation statements)

References 64 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Such an auto-inhibition dose-response curve may indicate a receptive unit with two binding sites or two separate receptors for IPP of which an inhibitory site or receptor has the lowest association constant. The IPP auto-inhibitory relationship in figure 7 was analyzed with a homotropic two-state model, HOTSM [25] . Since the spontaneous activity in absence of IPP is almost zero and because data are limited, we used a simplified form of HOTSM with spontaneous activity equal to zero ( L = 0).…”

Section: Resultsmentioning

confidence: 99%

“…HOTSM is an auto-regulatory reaction scheme with spontaneous activity, Fig. 10 [25] . Table 2 lists fitted values for HOTSM parameters A s , A m and c for the IPP bell-shaped response in our study.…”

Section: Discussionmentioning

confidence: 99%

“…Bell-shaped dose-response curves for IPP were analyzed by a simplified version of the homotropic two-state model, HOTSM, without spontaneous activity (parameter L = 0) [25] .…”

Section: Methodsmentioning

confidence: 99%

See 2 more Smart Citations

Synergistic Effects of Ethanol and Isopentenyl Pyrophosphate on Expansion of γδ T Cells in Synovial Fluid from Patients with Arthritis

et al. 2014

Self Cite

View full text Add to dashboard Cite

Low to moderate ethanol consumption has been associated with protective effects in autoimmune diseases such as rheumatoid arthritis, RA. An expansion of γδ T cells induced by isopentenyl pyrophosphate, IPP, likewise seems to have a protective role in arthritis. The aim of this project was to test the hypothesis that low doses of ethanol can enhance IPP-induced expansion of synovial fluid γδ T cells from patients with arthritis and may thereby potentially account for the beneficial effects of ethanol on symptoms of the arthritic process. Thus, mononuclear cells from synovial fluid (SF) from 15 patients with arthritis and from peripheral blood (PB) from 15 healthy donors were stimulated with low concentrations of ethanol and IPP for 7 days in vitro. IPP in combination with ethanol 0.015%, 2.5 mM, equivalent to the decrease per hour in blood ethanol concentration due to metabolism, gave a significantly higher fractional expansion of SF γδ T cells compared with IPP alone after 7 days (ratio 10.1+/−4.0, p<0.0008, n = 12) in patients with arthritis. Similar results were obtained for PB γδ T cells from healthy controls (ratio 2.0+/−0.4, p<0.011, n = 15). The augmented expansion of γδ T cells in SF is explained by a higher proliferation (p = 0.0034, n = 11) and an increased survival (p<0.005, n = 11) in SF cultures stimulated with IPP plus ethanol compared to IPP alone. The synergistic effects of IPP and ethanol indicate a possible allosteric effect of ethanol. Similar effects could be seen when stimulating PB with ethanol in presence of risedronate, which has the ability to increase endogenous levels of IPP. We conclude that expansion of γδ T cells by combinatorial drug effects, possibly in fixed-dose combination, FDC, of ethanol in the presence of IPP might give a protective role in diseases such as arthritis.

show abstract

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Synergistic Effects of Ethanol and Isopentenyl Pyrophosphate on Expansion of γδ T Cells in Synovial Fluid from Patients with Arthritis

et al. 2014

Self Cite

View full text Add to dashboard Cite

show abstract

“…Second, the pathway analysis is limited by the quality of annotation [30] . Third, not all dose responses fit a single sigmoidal model [51] . The clustering analysis we apply for quality control occasionally reveals treatments in which groups of transcripts show sigmoidal induction at low doses but have sigmoidal down-regulation at high doses or vice versa ( Text S1 ), presumably due to action on a second, counteractive target or process.…”

Section: Discussionmentioning

confidence: 99%

Transcriptional Profiling of the Dose Response: A More Powerful Approach for Characterizing Drug Activities

Silva

Jin

et al. 2009

PLoS Comput Biol

View full text Add to dashboard Cite

The dose response curve is the gold standard for measuring the effect of a drug treatment, but is rarely used in genomic scale transcriptional profiling due to perceived obstacles of cost and analysis. One barrier to examining transcriptional dose responses is that existing methods for microarray data analysis can identify patterns, but provide no quantitative pharmacological information. We developed analytical methods that identify transcripts responsive to dose, calculate classical pharmacological parameters such as the EC50, and enable an in-depth analysis of coordinated dose-dependent treatment effects. The approach was applied to a transcriptional profiling study that evaluated four kinase inhibitors (imatinib, nilotinib, dasatinib and PD0325901) across a six-logarithm dose range, using 12 arrays per compound. The transcript responses proved a powerful means to characterize and compare the compounds: the distribution of EC50 values for the transcriptome was linked to specific targets, dose-dependent effects on cellular processes were identified using automated pathway analysis, and a connection was seen between EC50s in standard cellular assays and transcriptional EC50s. Our approach greatly enriches the information that can be obtained from standard transcriptional profiling technology. Moreover, these methods are automated, robust to non-optimized assays, and could be applied to other sources of quantitative data.

show abstract

“…Такое двухфазное поведение кривой зависимости активации рГЦ от дозы активатора, как полагают иссле-дователи, связано с наличием на ферменте двух сайтов (активаторного и ингибиторного) для взаимодействия с регулятором [52,53]. В настоящее время «колоколо-образный» механизм регуляции описан для белков раз-личных классов [54], и, вероятно, в ближайшем будущем рГЦ сможет пополнить их ряды.…”

Section: исследования влияния тф на функциональную активность ргц троunclassified

Soluble Guanylyl Cyclase (sGC) in Mechanisms of Hypotensive and Antiaggregatory Effects Induced by Teraphtal (TP, sodium salt 4,5-cardoxyphtalQcyanin-cobalt)

Ta¹,

Nv²,

Is³

et al. 2016

Клиническая онкогематология

View full text Add to dashboard Cite

Background & Aims. Many antitumor drugs produces not only the variety of therapeutic effects but also a broad spectrum of side effects, including acute hemodynamic dysfunctions (hypotension/hypertension, coagulation disorders). The aim of the paper is to investigate the role of soluble guanylyl cyclase (sGC) in mechanisms of hypotensive and antiaggregatory effects induced by teraphtal (TP) under experimental conditions in the clinic. Methods. The effect of different products on the basal activity of sGC isolated from platelets of human peripheral blood was assessed by the immunoenzyme method based on production of cyclic guanosine monophosphate (cGMP). The effect of TP on ADP-induced human platelet aggregation was evaluated by the turbidimetric Born method using an aggregometer. Results. In the presence of TP, the basal sGC activity increased by the average of 2.5-fold. The TP-induced dose-response curve of sGC activation displays a bell-shaped behavior with maximal stimulation effect achieved at a concentration of 1 μmol/L. TP does not affect the sGC activation induced by known sGC regulators, such as sodium nitroprusside (SNP) and YC-1. On the other hand, after preliminary incubation of sGC with TP, the ability of YC-1 to potentiate the enzyme stimulation induced by SNP decreased by about 33 %. In vitro tests demonstrated the ability of TP to inhibit the ADP-induced platelet aggregation and established the IC<sub>50</sub> value for TP (15 μmol/L). Conclusion. TP is a direct sGC activator and therefore is able to participate in regulation of the NO→sGC→cGMP signaling pathway that controls the basal vascular tone and aggregatory platelet properties. Taking into account the TP characteristics, the paper discusses the involvement of additional mechanisms in the development of hypotension and hemostatic disorders induced by the drug.

show abstract

A homotropic two-state model and auto-antagonism

Cited by 21 publications

References 64 publications

Synergistic Effects of Ethanol and Isopentenyl Pyrophosphate on Expansion of γδ T Cells in Synovial Fluid from Patients with Arthritis

Synergistic Effects of Ethanol and Isopentenyl Pyrophosphate on Expansion of γδ T Cells in Synovial Fluid from Patients with Arthritis

Transcriptional Profiling of the Dose Response: A More Powerful Approach for Characterizing Drug Activities

Soluble Guanylyl Cyclase (sGC) in Mechanisms of Hypotensive and Antiaggregatory Effects Induced by Teraphtal (TP, sodium salt 4,5-cardoxyphtalQcyanin-cobalt)

Contact Info

Product

Resources

About