The protective effects of creatine against glutamate cytotoxicity have been demonstrated in neuronal cells and animal models of neurodegenerative diseases. The mechanisms underlying creatine neuroprotection against glutamate-induced cell death are understood poorly. For the first time, we demonstrate a correlation between the protective effect of creatine and the modulation of Ras-mediated redox-dependent signaling pathways, which involve nuclear factor kappaB (NF-kappaB) and reactive oxygen species (ROS). In primary cerebrocortical cultures of mixed neurons and glia, creatine significantly reduced glutamate-induced cell death. The increase in cell survival was accompanied by increased generation of oxygen radicals and decreased levels of farnesylated Ras and IkappaB, an inhibitor of NF-kappaB. Non-farnesylated Ras and ROS-dependent activation of NF-kappaB have been shown to promote neuronal survival. Our data suggest that creatine may enhance survival signaling via activation of the Ras/NF-kappaB system. Possible mechanisms underlying the protective effect of creatine are discussed, including normalization of cellular GTP levels.
STUDY QUESTION
How did coronavirus disease 2019 (COVID-19) impact on medically assisted reproduction (MAR) services in Europe during the COVID-19 pandemic (March to May 2020)?
SUMMARY ANSWER
MAR services, and hence treatments for infertile couples, were stopped in most European countries for a mean of 7 weeks.
WHAT IS KNOWN ALREADY
With the outbreak of COVID-19 in Europe, non-urgent medical care was reduced by local authorities to preserve health resources and maintain social distancing. Furthermore, ESHRE and other societies recommended to postpone ART pregnancies as of 14 March 2020.
STUDY DESIGN, SIZE, DURATION
A structured questionnaire was distributed in April among the ESHRE Committee of National Representatives, followed by further information collection through email.
PARTICIPANTS/MATERIALS, SETTING, METHODS
The information was collected through the questionnaire and afterwards summarised and aligned with data from the European Centre for Disease Control on the number of COVID-19 cases per country.
MAIN RESULTS AND THE ROLE OF CHANCE
By aligning the data for each country with respective epidemiological data, we show a large variation in the time and the phase in the epidemic in the curve when MAR/ART treatments were suspended and restarted. Similarly, the duration of interruption varied. Fertility preservation treatments and patient supportive care for patients remained available during the pandemic.
LARGE SCALE DATA
N/A
LIMITATIONS, REASONS FOR CAUTION
Data collection was prone to misinterpretation of the questions and replies, and required further follow-up to check the accuracy. Some representatives reported that they, themselves, were not always aware of the situation throughout the country or reported difficulties with providing single generalised replies, for instance when there were regional differences within their country.
WIDER IMPLICATIONS OF THE FINDINGS
The current article provides a basis for further research of the different strategies developed in response to the COVID-19 crisis. Such conclusions will be invaluable for health authorities and healthcare professionals with respect to future similar situations.
STUDY FUNDING/COMPETING INTEREST(S)
There was no funding for the study, apart from technical support from ESHRE. The authors had no COI to disclose.
The effects of 3,5,3'-triiodo-l-thyronine (T3) and l-thyroxine (T4) on the integrin αvβ3 receptor of thyroid hormones (TH) were investigated in pheochromocytoma PC-12 cells. Differentiation was induced by treatment of PC-12 cells with fisetin and the levels of phosphorylated extracellular signal-regulated kinase (ERK) and Akt in cytoplasm, as well as the content of FoxO6 transcription factor in nuclei was analysed in undifferentiated and differentiated conditions. We have found that in undifferentiated PC-12 cells, tetraiodothyroacetic acid (TETRAC), a known inhibitor of binding of T4 and T3 to plasma membrane integrin αvβ3 receptor inhibits T4-dependent phosphorylation of ERK, whereas in differentiated PC-12 cells, TETRAC abolishes the effect of T3. In undifferentiated PC-12 cells, both TH increase the level of p-Akt, and this enhancement is not sensitive to TETRAC. In differentiated PC-12 cells, both TH increase the level of p-Akt; however, only T3-dependent activation of Akt is sensitive to the TETRAC. Furthermore, our results have shown that in differentiated PC-12 cells, the expression of FoxO6 was higher than in undifferentiated PC-12 cells, and this elevation has not changed under the action of TH. Only in undifferentiated PC-12 cells the T3-dependent expression of FoxO6 was sensitive to the TETRAC. We propose that PC-12 cells contain integrin αvβ3 receptor, which T3 and T3/T4 sites are differentially regulated by TH in undifferentiated and differentiated conditions.
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