Mode of action classification of chemicals using multi-concentration time-dependent cellular response profiles

Xi, Zhankun; Khare, Swanand; Cheung, Aaron; Huang, Biao; Pan, Tianhong; Zhang, Weiping; Ibrahim, Fadi; Jin, Can; Gabos, Stephan

doi:10.1016/j.compbiolchem.2013.12.004

Cited by 13 publications

(13 citation statements)

References 29 publications

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“…More detailed descriptor functions that also capture the earlier part of impedance curves may be conceived in order to obtain compound signatures that reflect a specific mode of action. While such an application of single-frequency impedance spectroscopy has been reported for eukaryotic cells 69, 70 , the current work suggests that it is also viable for biofilm-forming bacteria. A diagnostic utility for clinical purposes may be derived following miniaturization of the assays to a low-cost chip format, as demonstrated for other applications of impedance microbiology.…”

Section: Discussionmentioning

confidence: 78%

Use of Single-Frequency Impedance Spectroscopy to Characterize the Growth Dynamics of Biofilm Formation in Pseudomonas aeruginosa

Duuren

Müsken

Karge

et al. 2017

Sci Rep

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Impedance spectroscopy has been applied in prokaryotic and eukaryotic cytometry as a label-free method for the investigation of adherent cells. In this paper, its use for characterizing the growth dynamics of P. aeruginosa biofilms is described and compared to crystal violet staining and confocal microscopy. The method allows monitoring the growth of biofilm-forming P. aeruginosa in a continuous and label-free manner over a period of 72 h in a 96 well plate format. Impedance curves obtained for P. aeruginosa PA14 wild type and mutant strains with a transposon insertion in pqsA and pelA genes exhibited distinct phases. We propose that the slope of the declining curve following a maximum at ca. 35–40 h is a measure of biofilm formation. Transplant experiments with P. aeruginosa biofilms and paraffin suggest that the impedance also reflects pellicle formation at the liquid-air interface, a barely considered contributor to impedance. Finally, the impairment of biofilm formation upon treatment of cultures with L-arginine and with ciprofloxacin, tobramycin and meropenem was studied by single frequency impedance spectroscopy. We suggest that these findings qualify impedance spectroscopy as an additional technique to characterize biofilm formation and its modulation by small molecule drugs.

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Section: Discussionmentioning

confidence: 78%

Use of Single-Frequency Impedance Spectroscopy to Characterize the Growth Dynamics of Biofilm Formation in Pseudomonas aeruginosa

Duuren

Müsken

Karge

et al. 2017

Sci Rep

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“…One example of this approach is the identification of novel kinase inhibitors based on their cytotoxicity profiles in 102 cancer cell lines by comparing the similarity of their profiles to known kinase inhibitors [9]. In addition to the pattern of cytotoxicity across cell lines, the kinetics of cytotoxicity can vary greatly for different groups of chemicals [10–12]; for example, immediate cellular changes can be seen for chemicals acting on ion channels, while a delayed cytotoxic response occurs for chemicals that act on cell cycle processes. However, it has also been shown that many chemicals with different pharmacological effects can display similar kinetics for cytotoxicity, implying that they share some underlying common mechanisms leading to cell death, despite their seemingly unrelated pharmacological functions [10].…”

Section: Introductionmentioning

confidence: 99%

Real-time cell toxicity profiling of Tox21 10K compounds reveals cytotoxicity dependent toxicity pathway linkage

et al. 2017

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Cytotoxicity is a commonly used in vitro endpoint for evaluating chemical toxicity. In support of the U.S. Tox21 screening program, the cytotoxicity of ~10K chemicals was interrogated at 0, 8, 16, 24, 32, & 40 hours of exposure in a concentration dependent fashion in two cell lines (HEK293, HepG2) using two multiplexed, real-time assay technologies. One technology measures the metabolic activity of cells (i.e., cell viability, glo) while the other evaluates cell membrane integrity (i.e., cell death, flor). Using glo technology, more actives and greater temporal variations were seen in HEK293 cells, while results for the flor technology were more similar across the two cell types. Chemicals were grouped into classes based on their cytotoxicity kinetics profiles and these classes were evaluated for their associations with activity in the Tox21 nuclear receptor and stress response pathway assays. Some pathways, such as the activation of H2AX, were associated with the fast-responding cytotoxicity classes, while others, such as activation of TP53, were associated with the slow-responding cytotoxicity classes. By clustering pathways based on their degree of association to the different cytotoxicity kinetics labels, we identified clusters of pathways where active chemicals presented similar kinetics of cytotoxicity. Such linkages could be due to shared underlying biological processes between pathways, for example, activation of H2AX and heat shock factor. Others involving nuclear receptor activity are likely due to shared chemical structures rather than pathway level interactions. Based on the linkage between androgen receptor antagonism and Nrf2 activity, we surmise that a subclass of androgen receptor antagonists cause cytotoxicity via oxidative stress that is associated with Nrf2 activation. In summary, the real-time cytotoxicity screen provides informative chemical cytotoxicity kinetics data related to their cytotoxicity mechanisms, and with our analysis, it is possible to formulate mechanism-based hypotheses on the cytotoxic properties of the tested chemicals.

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“…Thus, by Theorem 4.5, X(t) = 1/Y (t) is ergodic and its stationary measure µ 1 is the reciprocal of the measure ν 1 , so with respect to the Lebesgue measure has density p(x) = p 1 (1/x)/x 2 given in equation (26). Notice that we also have…”

Section: The Solution Of the Linear Equation Is Given Bymentioning

confidence: 89%

“…Cell-based in vitro assays [27] are efficient methods to study the effect of industrial chemicals on environment or human health. Our work is based on the cytotoxicity profiling project carried by Alberta Centre for Toxicology in which initially 63 chemicals were investigated using the xCELLigence Real-Time Cell Analysis High Troughput (RTCA HT) Assay [26]. We consider a mathematical model represented by stochastic differential equations to study cytotoxicity, i.e.…”

mentioning

confidence: 99%

“…The microelectrode electronic impedance value was converted by a software to Cell Index (n), which closely reflects not only cell growth and cell death, but also cell morphology. The time-dependent concentration response curves (TCRCs) for each test substance in each cell line were generated [26] and based on these curves the toxicants in the present study were divided in 10 groups [30]. In Fig.…”

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confidence: 99%

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Stochastic dynamics and survival analysis of a cell population model with random perturbations

Antón

Yong

2018

Mathematical Biosciences &Amp; Engineering

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We consider a model based on the logistic equation and linear kinetics to study the effect of toxicants with various initial concentrations on a cell population. To account for parameter uncertainties, in our model the coefficients of the linear and the quadratic terms of the logistic equation are affected by noise. We show that the stochastic model has a unique positive solution and we find conditions for extinction and persistence of the cell population. In case of persistence we find the stationary distribution. The analytical results are confirmed by Monte Carlo simulations.

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Mode of action classification of chemicals using multi-concentration time-dependent cellular response profiles

Cited by 13 publications

References 29 publications

Use of Single-Frequency Impedance Spectroscopy to Characterize the Growth Dynamics of Biofilm Formation in Pseudomonas aeruginosa

Use of Single-Frequency Impedance Spectroscopy to Characterize the Growth Dynamics of Biofilm Formation in Pseudomonas aeruginosa

Real-time cell toxicity profiling of Tox21 10K compounds reveals cytotoxicity dependent toxicity pathway linkage

Stochastic dynamics and survival analysis of a cell population model with random perturbations

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