Eukaryotic response to hypothermia in relation to integrated stress responses

Adjirackor, Naki A; Harvey, K.E.; Harvey, Simon C.

doi:10.1007/s12192-020-01135-8

Cited by 11 publications

(8 citation statements)

References 124 publications

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“…Understanding how environmental stimuli cause cells within mammalian models to alter their functions in order to adapt to fluctuating culture environments could provide novel solutions to these issues. Stress is one of the best-studied of these stimuli and directly induces mechanisms that alter the expression of relevant genes, affect epigenetic changes and metabolism, and influence growth and proliferation (Adjirackor, Harvey, and Harvey 2020;Pakos-Zebrucka et al 2016;Wengrod and Gardner 2015). Here, P19 embryonic carcinoma cells were used to develop an assay that could detect fluctuating levels of pyruvate, glutamine and calcium lactate in culture media.…”

Section: Discussionmentioning

confidence: 99%

The development of a novel pluripotent cell-based assay for human IVF media quality control

Adjirackor,

Beckitt,

Harvey

et al. 2024

Preprint

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Quality control systems for assays and assay components are crucial to achieving optimum standards in healthcare. In human IVF, the mouse embryo assay is commonly used to assess the quality of media and instruments. Despite its popularity, there are some well-known issues with the assay, including insensitivity to sub-optimal conditions, ethical issues due to animal use and variation in end-point interpretation between operators. Here, we detail the development of a P19 embryonic carcinoma cell-based assay with the potential to be an alternative method for quality control testing of human IVF media, and we use this assay to test varying levels of the critical energy sources pyruvate, glutamine and calcium lactate in human blastocyst media. Trademark features of the mammalian cold stress response were also incorporated as potential tools for increasing assay sensitivity. Assessed by resorufin fluorescence, P19 cells responded to changes in pyruvate and glutamine in the presence of cold stress and the mTOR inhibitor rapamycin but demonstrated natural sensitivity to calcium lactate concentrations. In addition to increasing cell sensitivity, cold stress enhanced cell growth, whilst rapamycin treatment further amplified the effects of cold stress. The assay described is robust, suitable for detecting sub-optimal culture conditions and indicates the extent to which different energy substrates affect cell growth and proliferation.

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Section: Discussionmentioning

confidence: 99%

The development of a novel pluripotent cell-based assay for human IVF media quality control

Adjirackor,

Beckitt,

Harvey

et al. 2024

Preprint

View full text Add to dashboard Cite

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“…Another option is that the a2-AR-induced hypothermia contributes to GBZ therapeutic effect. Hypothermia elicits a cold-shock response that involves the coordinated cellular adaptation of transcription, translation, metabolism, cell cycle, and the cytoskeleton 56,57 and includes suppression of the ATF4-regulated CHOP protein. 58 Possibly, GBZ-induced hypothermia attenuates the enhanced expression of the ATF4 transcriptome in VWM mouse brain.…”

Section: Discussionmentioning

confidence: 99%

Guanabenz ameliorates disease in vanishing white matter mice in contrast to sephin1

Witkamp

Oudejans

Hu‐A‐Ng

et al. 2022

Ann Clin Transl Neurol

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Objective: Vanishing white matter (VWM) is a leukodystrophy, characterized by stress-sensitive neurological deterioration and premature death. It is currently without curative treatment. It is caused by bi-allelic pathogenic variants in the genes encoding eukaryotic initiation factor 2B (eIF2B). eIF2B is essential for the regulation of the integrated stress response (ISR), a physiological response to cellular stress. Preclinical studies on VWM mouse models revealed that deregulated ISR is key in the pathophysiology of VWM and an effective treatment target. Guanabenz, an a2-adrenergic agonist, attenuates the ISR and has beneficial effects on VWM neuropathology. The current study aimed at elucidating guanabenz's disease-modifying potential and mechanism of action in VWM mice. Sephin1, an ISR-modulating guanabenz analog without a2adrenergic agonistic properties, was included to separate effects on the ISR from a2-adrenergic effects. Methods: Wild-type and VWM mice were subjected to placebo, guanabenz or sephin1 treatments. Effects on clinical signs, neuropathology, and ISR deregulation were determined. Guanabenz's and sephin1's ISR-modifying effects were tested in cultured cells that expressed or lacked the a2-adrenergic receptor. Results: Guanabenz improved clinical signs, neuropathological hallmarks, and ISR regulation in VWM mice, but sephin1 did not. Guanabenz's effects on the ISR in VWM mice were not replicated in cell cultures and the contribution of a2-adrenergic effects on the deregulated ISR could therefore not be assessed. Interpretation: Guanabenz proved itself as a viable treatment option for VWM. The exact mechanism through which guanabenz exerts its ameliorating impact on VWM requires further studies. Sephin1 is not simply a guanabenz replacement without a2-adrenergic effects.

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“…Известно, что в ответ на холодовой стресс в организме развивается комплекс защитных реакций, связанных с экспрессией генов клеточного ответа [16], обеспечивающих включение в организме нескольких путей. К ним относятся активация выработки разобщающих окисление и фосфорилирование белков [17,18], а также HIF-1α-зависимое переключение обмена в условиях гипоксии на сукцинатные пути [19].…”

Section: Discussionunclassified

Pathophysiological mechanisms of adverse interactions of hypoxia and temperature factors in relation to physical working ability

Ким¹,

Шустов²,

Зайцева³

et al. 2022

Zhurnal «Patologicheskaia Fiziologiia I Eksperimental`naia Terapiia»

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Введение. Статья посвящена решению задачи количественной оценки взаимодействия двух неблагоприятных факторов - гипоксического и температурного, при их сочетанном действии на организм лабораторных животных. Исследовали эффекты нормобарической и гемической гипоксии, воздействия высоких и низких температур. цель работы - количественная оценка взаимодействия гипоксии и температурных факторов при их сочетанном действии на организм лабораторных животных. методика. Состояние нормобарической гипоксии моделировали с использованием мембранного гипоксикатора. Установка обеспечивала плавную регулировку концентрации кислорода от 2 до 10% в гипоксической газовой смеси. Гипертермию моделировали путем термостатического поддержания температуры воздуха +40 °С и влажности 30-60%. Гипотермия формировалась в условиях воздушного охлаждения (в холодовой камере при температуре воздуха 5±1 °С и влажности 75-80%). Для оценки функционального состояния проводили тестирование физической работоспособности методом вынужденного плавания с грузом 5% от массы тела в воде различной температуры. Оценка взаимодействия факторов проводилась методом двухфакторного дисперсионного анализа с тремя уровнями выраженности каждого фактора. результаты. Установлено, что гипоксический и тепловой фактор оказывают влияние независимо друг от друга, при превалировании воздействия гипоксии. Взаимодействие между факторами cинергидное умеренное по выраженности, протекает по типу дополняющего эффекта, и может служить основой развития синдрома взаимного отягощения. Воздушная гипотермия слабо влияет на переносимость гипоксического воздействия, влияние иммерсионной гипотермии проявляется более существенно. Заключение. Критическое ухудшение функционального состояния при действии гипоксии и экстремальных температурсопряжено с активацией гипоталамо-гипофизарно-надпочечниковой системы, интенсификацией катаболизма белков, жиров и углеводов, развитием вторичной тканевой гипоксии и формированием митохондриальных дисфункций. Наиболее вероятным механизмом развития синдрома взаимного отягощения при сочетанном воздействии гипоксии и гипертермии является нарушение генерации АТФ в процессе фосфорилирующего митохондриального окисления, который является общим звеном патогенеза различных экстремальных состояний. Introduction. The article focuses on quantitative assessment of the interaction of two unfavorable factors, hypoxia and temperature, during their combined effect on the body of laboratory animals. The effects of normobaric and hemic hypoxia and of high and low temperatures were studied. the aim of the study was to quantify the interaction between hypoxia and temperature factors during their combined effect on the body of laboratory animals.methods. Normobaric hypoxia was produced in a membrane hypoxicator. The oxygen concentration in the hypoxic gas mixture was smoothly adjustable from 2 to 10%. Hyperthermia was modeled by thermostatic maintenance of the air temperature at +40°C and the humidity at 30-60%. Hypothermia was produced in a cold chamber at the air temperature of 5±1°C and the air humidity of 75-80%. Physical performance was tested using forced swimming with a load of 5% of body weight at various water temperatures. The interaction of the factors was assessed by a two-factor analysis of variance for three levels of severity of each factor. results. The hypoxic and thermal factors exerted independent effects, with hypoxia effects prevailing. The factor interaction was synergistic, moderately severe, complementary, and could underlie the mutual aggravation syndrome. Air hypothermia had a slight effect on the tolerance to hypoxic exposure; the effect of immersion hypothermia was more pronounced.conclusion. The critical impairment of the functional state under the action of hypoxia and extreme temperature is associated with the activation of the hypothalamic-pituitary-adrenal system, intensification of protein, lipid and carbohydrate catabolism, development of secondary tissue hypoxia, and the formation of mitochondrial dysfunction. The most likely mechanism for the development of mutual aggravation syndrome under the combined action of hypoxia and hyperthermia is impairment of ATP generation in the process of phosphorylating mitochondrial oxidation, which is a common stage in the pathogenesis of various extreme conditions.

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Eukaryotic response to hypothermia in relation to integrated stress responses

Cited by 11 publications

References 124 publications

The development of a novel pluripotent cell-based assay for human IVF media quality control

The development of a novel pluripotent cell-based assay for human IVF media quality control

Guanabenz ameliorates disease in vanishing white matter mice in contrast to sephin1

Pathophysiological mechanisms of adverse interactions of hypoxia and temperature factors in relation to physical working ability

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