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Heritable renal cancer syndromes (RCS) are associated with numerous chromosomal alterations including inactivating mutations in von Hippel-Lindau (VHL) gene. Here we identify a novel aspect of the phenotype in VHL-deficient human renal cells. We call it reductive stress as it is characterised by increased NADH/NAD + ratio that is associated with impaired cellular respiration, impaired CAC activity, upregulation of reductive carboxylation of glutamine and accumulation of lipid droplets in VHL-deficient cells. Reductive stress was mitigated by glucose depletion and supplementation with pyruvate or resazurin, a redox-reactive agent. This study demonstrates for the first time that reductive stress is a part of the phenotype associated with VHL-deficiency in renal cells and indicates that the reversal of reductive stress can augment respiratory activity and CAC activity, suggesting a strategy for altering the metabolic profile of VHL-deficient tumours., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Ischemia reperfusion injury is common in transplantation. Previous studies have shown that cooling can protect against hypoxic injury. To date, the protective effects of hypothermia have been largely associated with metabolic suppression. Since kidney transplantation is one of the most common organ transplant surgeries, we used human-derived renal proximal tubular cells (HKC8 cell line) as a model of normal renal cells. We performed a temperature titration curve from 37 °C to 22 °C and evaluated cellular respiration and molecular mechanisms that can counteract the build-up of reducing equivalents in hypoxic conditions. We show that the protective effects of hypothermia are likely to stem both from metabolic suppression (inhibitory component) and augmentation of stress tolerance (activating component), with the highest overlap between activating and suppressing mechanisms emerging in the window of mild hypothermia (32 °C). Hypothermia decreased hypoxia-induced rise in the extracellular lactate:pyruvate ratio, increased ATP/ADP ratio and mitochondrial content, normalized lipid content, and improved the recovery of respiration after anoxia. Importantly, it was observed that in contrast to mild hypothermia, moderate and deep hypothermia interfere with HIF1 (hypoxia inducible factor 1)-dependent HRE (hypoxia response element) induction in hypoxia. This work also demonstrates that hypothermia alleviates reductive stress, a conceptually novel and largely overlooked phenomenon at the root of ischemia reperfusion injury.

The successful implantation of the embryo into a receptive endometrium is essential for the establishment of a viable pregnancy while recurrent implantation failure (RIF) is a real challenge in assisted reproduction. The maternal innate immune system, specifically the Toll-like receptors (TLRs), are involved in maintaining immunity in the female reproductive tract (FRT) required for fertility. In this study, we aimed to investigate the importance of innate immunity-related gene expression in the regulation of human fertility and as a prediction of potential outcome of in vitro fertilization - embryo transfer (IVF-ET), thus, we assessed the gene expression levels of TLR signalling molecules using quantitative real-time PCR between endometrial biopsies of healthy fertile women, and the patients experiencing RIF. Interestingly, our results showed that, TRIB2 and TLR9 genes were differentially expressed between the endometrial biopsies of healthy women and those with RIF. However, comparing expression levels of same genes between pre-receptive and receptive healthy endometrial biopsies showed different genes (ICAM1, NFKBIA, VCAM1, LIF, VEGFB, TLR5) had significantly altered expression, suggesting their involvement in endometrial receptivity. Thus, further investigations will enable us to better understand the role of these genes in the biology of FRT and as a possible target for the improvement of infertility treatments and/or development of non-hormonal contraception., Competing Interests: Declaration of Competing Interest The authors report no declarations of interest., (Copyright © 2021. Published by Elsevier B.V.)

Sex role reversal is not uncommon in the animal kingdom but is taken to the extreme by the Syngnathidae, in which male pregnancy is one of the most astonishing idiosyncrasies. However, critical and time-dependent environmental effects on developing embryos, such as those extensively studied in mammalian pregnancy, have not been investigated in the male pregnancy context. Here, we tested the hypothesis that seahorse pregnancy is subject to 'critical windows' of environmental sensitivity by feeding male long-snouted seahorses ( Hippocampus reidi ) a diet deficient in polyunsaturated fatty acids during specific periods before and during pregnancy. Despite embryos being nourished principally by maternally supplied yolk, we found that offspring morphology, fatty acid composition and gene expression profiles were influenced by paternal diet in a manner that depended critically on the timing of manipulation. Specifically, reception of a diet deficient in polyunsaturated fatty acids in the days preceding pregnancy resulted in smaller newborn offspring, while the same diet administered towards the end of pregnancy resulted in substantial alterations to newborn gene expression and elongation of the snout at 10 days old. Although paternal diet did not affect 10 day survival, the observed morphological alterations in some cases could have important fitness consequences in the face of natural selective pressures such as predation and food availability. Our results demonstrate that, under male pregnancy, fine-scale temporal variation in parental diet quality and subsequent critical window effects should not be overlooked as determinants of developing offspring fitness., Competing Interests: Competing interestsThe authors declare no competing or financial interests., (© 2020. Published by The Company of Biologists Ltd.)

Background: Medication adherence can be divided into primary and secondary adherence. Primary medication non-adherence (PMN) occurs when a patient does not obtain medicine with their initial prescription. Secondary non-adherence measures prescription refills among patients who previously filled their first prescription. While secondary non-adherence has been studied thoroughly, PMN has been assessed less extensively, due to lack of available data. Estonian ePrescription system might prove a valuable tool for this., Objectives: The aim of this study was to evaluate PMN and the interval between prescribing and dispensing of medicines using the Estonian ePrescriptions database to establish its potential use for this purpose and for other qualitative drug utilization research measures. Osteoporosis medicines were used as an example., Methods: The Estonian Prescription Centre was used to evaluate if patients purchase medicines after initial prescription of osteoporosis medicine. Prescriptions from 2012 to 2015 of all patients over 18 were included. PMN was defined as the first prescription not being dispensed before it expired (60 days). The rate of PMN was calculated., Results: Estonian ePrescription System enabled fast evaluation of PMN of osteoporosis patients based on data about prescribing, dispensing and time intervals in-between. Of patients who started osteoporosis treatment 13.1% were primary non-adherent. Of primary non-adherent patients 42% still started treatment at some point during the study. Of patients who did purchase their first prescription 80.4% did so within a week and 95% within 25 days., Conclusion: The Estonian ePrescription system is a useful tool for monitoring PMN. The PMN of osteoporosis medicines was identified as lower than previously reported. More similar type of studies about other groups of medicines would be needed to understand the pattern of PMN and give valuable information to healthcare specialists about how to increase initiation of treatment., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Osteoporosis medicines reduce osteoporotic fractures. There is a very strong negative correlation between the consumption of medicines and the price of an average daily dose indicating that affordability is a key factor that could increase consumption of antiosteoporotic medicines and, through that, reduce fractures., Purpose: Osteoporosis is a major cause of morbidity and mortality in the modern world. Our study aims to describe the trends in incidence of hip fractures in relation to drug utilization patterns and the average price of antiosteoporotic medicines in Estonia., Methods: Data on hip fractures was obtained from the medical claims database of Estonian Health Insurance Fund (EHIF). Consumption and price data was obtained from the Estonian State Agency of Medicines (SAM).Consumption is presented using WHO defined daily doses methodology, and the prices reflect the average wholesale price of medicines., Results: From 2004 to 2010 there was a non-significant increasing trend in standardized hip fracture incidence in Estonia, but from 2010 to 2015, the trend turned to a significant decrease of 4.5% per year. The consumption of osteoporosis medication increased significantly from 2004 to 2009 by yearly average of 41.2%. After 2009, the consumption levelled. On contrast, the average price of one daily dose of osteoporosis medication decreased significantly from 2004 to 2009 by 16.9% per year and the decrease also levelled after 2009. This gives a very strong negative correlation of -0.93 (p < 0.001) between the consumption of antiosteoporotic medication and the average price of a daily dose of medication during the study period., Conclusions: The statistically significant decline of standardized incidence of hip fractures from 2010 onward could at least in part be the result of the high increase in consumption of antiosteoporotic medicines which in turn is strongly negatively correlated with the average price of osteoporosis medicines.

Toll-like receptors (TLRs) are major players of the innate immune system. Once activated, they trigger a signalling cascade that leads to NF-κB translocation from the cytoplasm to the nucleus. Single cell analysis shows that NF-κB signalling dynamics are a critical determinant of transcriptional regulation. Moreover, the outcome of innate immune response is also affected by the cross-talk between TLRs and estrogen signalling. Here, we characterized the dynamics of TLR5 signalling, responsible for the recognition of flagellated bacteria, and those changes induced by estradiol in its signalling at the single cell level. TLR5 activation in MCF7 cells induced a single and sustained NF-κB translocation into the nucleus that resulted in high NF-κB transcription activity. The overall magnitude of NF-κB transcription activity was not influenced by the duration of the stimulus. No significant changes are observed in the dynamics of NF-κB translocation to the nucleus when MCF7 cells are incubated with estradiol. However, estradiol significantly decreased NF-κB transcriptional activity while increasing TLR5-mediated AP-1 transcription. The effect of estradiol on transcriptional activity was dependent on the estrogen receptor activated. This fine tuning seems to occur mainly in the nucleus at the transcription level rather than affecting the translocation of the NF-κB transcription factor.

Definition of the periconception period is not an exact science and is probably somewhat arbitrary. One can define it as spanning the period from the final stages of gamete maturation until formation of the embryo and the stages of embryonic development and implantation. Hence, the periconception period includes periods when spermatozoa are in the female reproductive tract, oocytes are matured and ovulated into the oviduct, fertilization occurs and the embryo undergoes development. By definition the implantation process and the early stages of placenta formation are also regarded as a part of the periconception period. In this article we highlight a few of the major advances which have transformed this topic over the last two decades. It is now clear that the fitness and wellbeing of developing mammalian embryos, including the human, are highly dependent on the health status, diet and habits of both parents especially in the months and weeks that precede the formation of oocytes and spermatozoa.

Stress represents an unavoidable aspect of human life, and pathologies associated with dysregulation of stress mechanisms - particularly psychiatric disorders - represent a significant global health problem. While it has long been observed that levels of stress experienced in the periconception period may greatly affect the offspring's risk of psychiatric disorders, the mechanisms underlying these associations are not yet comprehensively understood. In order to address this question, this chapter will take a 'top-down' approach, by first defining stress and associated concepts, before exploring the mechanistic basis of the stress response in the form of the hypothalamic-pituitary-adrenal (HPA) axis, and how dysregulation of the HPA axis can impede our mental and physical health, primarily via imbalances in glucocorticoids (GCs) and their corresponding receptors (GRs) in the brain. The current extent of knowledge pertaining to the impact of stress on developmental programming and epigenetic inheritance is then extensively discussed, including the role of chromatin remodelling associated with specific HPA axis-related genes and the possible role of regulatory RNAs as messengers of environmental stress both in the intrauterine environment and across the germ line. Furthering our understanding of the role of stress on embryonic development is crucial if we are to increase our predictive power of disease risk and devise-effective treatments and intervention strategies.