Dataset Information

Modeling Direct and Indirect Action on Cell Survival After Photon Irradiation under Normoxia and Hypoxia.

ABSTRACT: The demand for personalized medicine in radiotherapy has been met by a surge of mechanistic models offering predictions of the biological effect of ionizing radiation under consideration of a growing number of parameters. We present an extension of our existing model of cell survival after photon irradiation to explicitly differentiate between the damage inflicted by the direct and indirect (radicals-mediated) action of ionizing radiation. Within our approach, we assume that the oxygenation status affects the indirect action. The effect of different concentrations of dimethyl sulfoxide (DMSO), an effective radical scavenger, has been simulated at different dose levels in normoxic and hypoxic conditions for various cell lines. Our model is found to accurately predict experimental data available in literature, validating the assumptions made in our approach. The presented extension adds further flexibility to our model and could act as basis for further developments of our model.

SUBMITTER: Liew H

PROVIDER: S-EPMC7278970 | biostudies-literature | 2020 May

REPOSITORIES: biostudies-literature

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Modeling Direct and Indirect Action on Cell Survival After Photon Irradiation under Normoxia and Hypoxia.

Liew Hans H Mein Stewart S Debus Jürgen J Dokic Ivana I Mairani Andrea A

International journal of molecular sciences 20200514 10

The demand for personalized medicine in radiotherapy has been met by a surge of mechanistic models offering predictions of the biological effect of ionizing radiation under consideration of a growing number of parameters. We present an extension of our existing model of cell survival after photon irradiation to explicitly differentiate between the damage inflicted by the direct and indirect (radicals-mediated) action of ionizing radiation. Within our approach, we assume that the oxygenation stat ...[more]

PMID: 32423018

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Project description:ObjectiveProinflammatory cytokine interleukin 17 (IL-17) is involved in ventricular remodeling, mainly of the left ventricle. This study was designed to explore the role of IL-17 played in the pathogenesis of right ventricular hypertrophy (RVH), aiming to provide a novel treatment target or diagnostic biomarker options for improving the care of RVH patients.MethodsC57BL/6 mice were maintained in 10% O2 chamber or room air for four weeks. Right ventricular hypertrophy index (RVHI), RV/body weight ratio, pulmonary arteriolar remodeling determined by percent media thickness (%MT), and the cardiomyocyte diameter of RV were evaluated. Mice were treated with exogenous recombinant mouse IL-17 (rmIL-17, 1 μg per dose twice a week) for four weeks. H9c2 cardiomyocytes were cultured and treated with IL-17 (10 ng/mL) and STAT3 inhibitor (10 ng/mL) either under normoxia (21% O2, 5% CO2, 74% N2) or under hypoxia (3% O2, 5% CO2, 92% N2). Cardiomyocyte viability was assessed by Cell counting kit 8 (CCK-8) assay. The mRNA level was detected by RT-PCR, where as the protein expression was measured by Western blot, immunohistochemistry, and immunofluorescent analyses.ResultsIn vivo experiments showed that IL-17 did not affect the pulmonary artery under normoxia, after treatment with rmIL-17, %MT was not changed, while RVHI and the RV/body weight ratio were increased, indicating that IL-17 directly induced right ventricular hypertrophy. In a time-course study, the mice were exposed to hypoxia for 0, 1, 2, 3, 4 weeks, respectively. We found that the expression of IL-17 was gradually upregulated in RV tissue in a time-dependent manner after one week of hypoxia exposure, especially at the third and fourth week. Cardiomyocyte hypertrophy and apoptosis were observed after the exposure of the mice to hypoxia for four weeks, rmIL-17 further aggravated the hypoxia-induced cardiomyocyte hypertrophy and apoptosis. The expression of p-STAT3 in the IL-17-deficient mice was lower than in the wild-type mice. In vitro, IL-17 inhibited cardiomyocyte viability and induced cardiomyocyte apoptosis via STAT3 under both normoxic and hypoxic conditions.ConclusionsThese findings support a role for IL-17 as a mediator in the pathogenesis RVH, which might be considered as a potential novel anti-inflammation therapeutic strategy or diagnostic biomarker for RVH.

Project description:ATP synthase inhibitory factor subunit 1 (IF1) is an inhibitory subunit of mitochondrial ATP synthase, playing a crucial role in regulating mitochondrial respiration and energetics. It is well-established that IF1 interacts with the F1 sector of ATP synthase to inhibit the reversal rotation and, thus, ATP hydrolysis. Recent evidence supports that IF1 also inhibits forward rotation or the ATP synthesis activity. Adding to the complexity, IF1 may also facilitate mitophagy and cristae formation. The implications of these complex actions of IF1 for cellular function remain obscure. In the present study, we found that IF1 expression was markedly upregulated in hypoxic MEFs relative to normoxic MEFs. We investigate how IF1 affects cellular growth and function in cultured mouse embryonic fibroblasts derived from mouse lines with systemic IF1 overexpression and knockout under normoxia and hypoxia. Cell survival and proliferation analyses revealed that IF1 overexpression exerted limited effects on cellular viability but substantially increased proliferation under normoxia, whereas it facilitated both cellular viability and proliferation under hypoxia. The absence of IF1 may have a pro-survival effect but not a proliferative one in both normoxia and hypoxia. Cellular bioenergetic analyses revealed that IF1 suppressed cellular respiration when subjected to normoxia and was even more pronounced when subjected to hypoxia with increased mitochondrial ATP production. In contrast, IF1 knockout MEFs showed markedly increased cellular respiration under both normoxia and hypoxia with little change in mitochondrial ATP. Glycolytic stress assay revealed that IF1 overexpression modestly increased glycolysis in normoxia and hypoxia. Interestingly, the absence of IF1 in MEFs led to substantial increases in glycolysis. Therefore, we conclude that IF1 mainly inhibits cellular respiration and enhances cellular glycolysis to preserve mitochondrial ATP. On the other hand, IF1 deletion can significantly facilitate cellular respiration and glycolysis without leading to mitochondrial ATP deficit.

Dataset Information

Modeling Direct and Indirect Action on Cell Survival After Photon Irradiation under Normoxia and Hypoxia.

Publications

Modeling Direct and Indirect Action on Cell Survival After Photon Irradiation under Normoxia and Hypoxia.

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