Phyto-oestrogens affect fertilisation and embryo development in vitro in sheep

Phyto-oestrogens such as isoflavones are natural compounds that can profoundly affect reproductive function. In the present study, we tested whether including isoflavone compounds (genistein, biochanin A, formononetin) in the maturation medium would affect the outcomes for ovine oocytes in vitro. Each isoflavone compound was evaluated at five concentrations (0, 2.5, 5, 10, 25µgmL-1) and the entire protocol was repeated four times. Cumulus-oocyte complexes were randomly allocated to the treatments, then fertilised and cultured in vitro. Compared with control (0µgmL-1), the lower concentrations of isoflavone (2.5, 5 and 10µgmL-1) had no detectable effect on the rates of cleavage or embryo development, or on embryo total cell counts (TCC). However, the highest concentration (25µgmL-1) of all three isoflavones exerted a variety of effects (P<0.05): genistein decreased cleavage rate, blastocyst rate and blastocyst efficiency (blastocysts produced per 100 oocytes); biochanin A decreased cleavage rate and blastocyst efficiency; and formononetin decreased blastocyst rate and blastocyst efficiency. Biochanin A (25µgmL-1) reduced embryo TCC specifically at the hatched blastocyst stage (P<0.05). We conclude that the presence of isoflavones at 25µgmL-1 during IVM decreases the cleavage rate and inhibits blastocyst hatching

Impact of periconceptional and preimplantation undernutrition on factors regulating myogenesis and protein synthesis in muscle of singleton and twin fetal sheep.

In this study, we determined the effect of maternal undernutrition in the periconceptional (PCUN: ~80 days before to 6 days after conception) and preimplantation (PIUN: 0-6 days after conception) periods on the mRNA and protein abundance of key factors regulating myogenesis and protein synthesis, and on the relationship between the abundance of these factors and specific microRNA expression in the quadriceps muscle of singleton and twin fetal sheep at 135-138 days of gestation. PCUN and PIUN resulted in a decrease in the protein abundance of MYF5, a factor which determines the myogenic lineage, in singletons and twins. Interestingly, there was a concomitant increase in insulin-like growth factor-1 mRNA expression, a decrease in the protein abundance of the myogenic inhibitor, myostatin (MSTN), and an increase in the mRNA and protein abundance of the MSTN inhibitor, follistatin (FST), in the PCUN and PIUN groups in both singletons and twins. These promyogenic changes may compensate for the decrease in MYF5 protein abundance evoked by early embryonic undernutrition. PCUN and PIUN also increased the protein abundance of phosphorylated eukaryotic translation initiation factor binding protein 1 (EIF4EBP1; T70 and S65) in fetal muscle in singletons and twins. There was a significant inverse relationship between the expression of miR-30a-5p, miR-30d-5p, miR-27b-3p, miR106b-5p, and miR-376b and the protein abundance of mechanistic target of rapamycin (MTOR), FST, or MYF5 in singletons or twins. In particular, the expression of miR-30a-5p was increased and MYF5 protein abundance was decreased, in PCUN and PIUN twins supporting the conclusion that the impact of PCUN and PIUN is predominantly on the embryo

Metabolic subtypes of patients with NAFLD exhibit distinctive cardiovascular risk profiles

Background and Aims We previously identified subsets of patients with NAFLD with different metabolic phenotypes. Here we align metabolomic signatures with cardiovascular disease (CVD) and genetic risk factors. Approach and Results We analyzed serum metabolome from 1154 individuals with biopsy-proven NAFLD, and from four mouse models of NAFLD with impaired VLDL-triglyceride (TG) secretion, and one with normal VLDL-TG secretion. We identified three metabolic subtypes: A (47%), B (27%), and C (26%). Subtype A phenocopied the metabolome of mice with impaired VLDL-TG secretion; subtype C phenocopied the metabolome of mice with normal VLDL-TG; and subtype B showed an intermediate signature. The percent of patients with NASH and fibrosis was comparable among subtypes, although subtypes B and C exhibited higher liver enzymes. Serum VLDL-TG levels and secretion rate were lower among subtype A compared with subtypes B and C. Subtype A VLDL-TG and VLDL-apolipoprotein B concentrations were independent of steatosis, whereas subtypes B and C showed an association with these parameters. Serum TG, cholesterol, VLDL, small dense LDL5,6, and remnant lipoprotein cholesterol were lower among subtype A compared with subtypes B and C. The 10-year high risk of CVD, measured with the Framingham risk score, and the frequency of patatin-like phospholipase domain-containing protein 3 NAFLD risk allele were lower in subtype A. Conclusions Metabolomic signatures identify three NAFLD subgroups, independent of histological disease severity. These signatures align with known CVD and genetic risk factors, with subtype A exhibiting a lower CVD risk profile. This may account for the variation in hepatic versus cardiovascular outcomes, offering clinically relevant risk stratification.National Institutes of Health (R01DK123763, R01DK119437, HL151328, P30DK52574, P30DK56341, and UL1TR002345); Ministerio de Economía y Competitividad de España (SAF2017-88041-R); Ministerio de Economía y Competitividad de España for the Severo Ochoa Excellence Accreditation (SEV-2016-0644); CIBERehd (Biomedical Research Center in Hepatic and Digestive Diseases) and Netherlands Organization for Applied Scientific Research Program (PMC13 and PMC15); Spanish Carlos III Health Institute (PI15/01132 and PI18/01075); Miguel Servet Program (CON14/00129 and CPII19/00008); Fondo Europeo de Desarrollo Regional, CIBERehd, Department of Industry of the Basque Country (Elkartek: KK-2020/00008); La Caixa Scientific Foundation (HR17-00601); Liver Investigation: Testing Marker Utility in Steatohepatitis consortium funded by the Innovative Medicines Initiative Program of the European Union (777377), which receives support from the European Union’s Horizon 2020 research and innovation programme and EFPIA; Newcastle NIHR Biomedical Research Center; Czech Ministry of Health (RVO-VFN64165/2020); Fondo Nacional De Ciencia y Tecnología de Chile (1191145); and the Comisión Nacional de Investigación, Ciencia y Tecnología (AFB170005, CARE Chile UC); Agencia Nacional de Investigación y Desarrollo (ANID ACE 210009); European Union's Horizon 2020 Research and Innovation Program (825510)

Mass-spectrometry-based metabolomics: limitations and recommendations for future progress with particular focus on nutrition research

Mass spectrometry (MS) techniques, because of their sensitivity and selectivity, have become methods of choice to characterize the human metabolome and MS-based metabolomics is increasingly used to characterize the complex metabolic effects of nutrients or foods. However progress is still hampered by many unsolved problems and most notably the lack of well established and standardized methods or procedures, and the difficulties still met in the identification of the metabolites influenced by a given nutritional intervention. The purpose of this paper is to review the main obstacles limiting progress and to make recommendations to overcome them. Propositions are made to improve the mode of collection and preparation of biological samples, the coverage and quality of mass spectrometry analyses, the extraction and exploitation of the raw data, the identification of the metabolites and the biological interpretation of the results

2017 HRS/EHRA/ECAS/APHRS/SOLAECE expert consensus statement on catheter and surgical ablation of atrial fibrillation: executive summary.

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Periconceptional undernutrition and being a twin each alter kidney development in the sheep fetus during early gestation

Adaptive growth responses of the embryo and fetus to nutritional restraint are important in ensuring early survival, but they are implicated in the programming of hypertension. It has been demonstrated that kidney growth and nephrogenesis are each regulated by intrarenal factors, including the insulin-like growth factors, glucocorticoids, and the renin-angiotensin system. Therefore, we have investigated the impact of periconceptional undernutrition (PCUN; from ∼6 wk before to 7 days after conception) in singleton (control, n = 18; PCUN, n = 16) and twin pregnancies (control, n = 6; PCUN, n = 5) on the renal mRNA expression of 11β- hydroxysteroid dehydrogensase type 1 and type 2 (11β-HSD-1 and -2), the glucocorticoid (GR), and mineralocorticoid receptors, angiotensinogen, angiotensin receptor type 1 (AT1R) and 2 (AT2R), IGF-1 and IGF-2, and IGF1R and IGF2R at ∼55 days gestation. There was no effect of PCUN or fetal number on fetal weight on relative kidney weight at approximately day 55 of gestation. There was an inverse relationship between the relative weight of the fetal kidney at approximately day 55 and maternal weight loss during the periconceptional period in fetuses exposed to PCUN. Exposure to PCUN resulted in a higher expression of IGF1 in the fetal kidney in singleton and twin pregnancies. Being a twin resulted in higher intrarenal expression of IGF-1 and IGF-2, GR, angiotensinogen, AT1R, and AT2R mRNA at 55 days gestation. Renal 11β-HSD-2 mRNA expression was higher in PCUN singletons, but not PCUN twins, compared with controls. Thus, there may be an adaptive response in the kidney to the early environment of a twin pregnancy, which precedes the fetal growth restriction that occurs later in pregnancy. The kidney of the twin fetus exposed to periconceptional undernutrition may also be less protected from the consequences of glucocorticoid exposure.

Impact of maternal periconceptional overnutrition on fat mass and expression of adipogenic and lipogenic genes in visceral and subcutaneous fat depots in the postnatal lamb

Women entering pregnancy with a high body weight and fat mass have babies who are at increased risk of becoming overweight or obese in later life. We investigated whether maternal overnutrition in the periconceptional period results in an increased fat mass and expression of adipogenic and lipogenic genes in offspring and whether dietary restriction can reverse these changes. Nonpregnant donor ewes (n = 23) were assigned to one of four groups: control-control fed at 100% maintenance energy requirements (MER) for at least 5 months, control-restricted fed 100% MER for 4 months and 70% MER for 1 month, high-high (HH) fed ad libitum (170–190% MER) for 5 months, or high-restricted (HR) fed ad libitum for 4 months and 70% MER for 1 month. Single embryos were transferred to nonobese recipient ewes, and lamb fat depots were weighed at 4 months. Peroxisome proliferator-activated receptor-{gamma}, glyceraldehyde-3-phosphate dehydrogenase, lipoprotein lipase, leptin, and adiponectin mRNA expression was measured in the lamb fat depots. Total fat mass was higher in female lambs in the HH but not HR group than controls. There was a relationship between donor ewe weight and total fat mass and G3PDH mRNA expression in perirenal fat in female lambs. There was no effect of periconceptional nutritional treatment on peroxisome proliferator-activated receptor-{gamma}, glyceraldehyde-3-phosphate dehydrogenase, lipoprotein lipase, leptin, and adiponectin mRNA expression in any fat depot. Thus, exposure to maternal overnutrition in the periconceptional period alone results in an increased body fat mass in the offspring and that a short period of dietary restriction can reverse this effect.