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Maternal undernutrition during the periconceptional period alters the transcriptomic profile of pig endometrium and embryos. Herein, we tested the hypothesis that restricted maternal consumption by females during the periconceptional period impairs the pattern of DNA methylation in both the endometrium and embryos during the peri-implantation period (Day 15-16 of gestation). Affected genes in restricted-diet-fed pig endometrium and embryos were identified using quantitative methylation-specific PCR and comprised those genes which are known to be important in reproductive, metabolic and epigenetic function, thereby exhibiting altered transcriptomic expression in endometrium and embryos of restricted-diet-fed gilts. Specifically, levels of DNA methylation of selected genes with altered expression in the endometrium included acid phosphatase type 2C (PPAP2C), salivary lipocalin (SAL1), endothelin receptor type B (EDNRB), regulator of G-protein signalling 12 (RGS12), type 4 17ß-hydroxysteroid dehydrogenase (HSD17B4), toll-like receptor 3 (TLR3), and adiponectin receptor 1 (ADIPOR1). In embryos, adiponectin receptor 2 (ADIPOR2), prostaglandin-endoperoxide synthase 2 (PTGS2), arachidonate 12-lipoxygenase (ALOX12), progestin and adipoQ receptor family member 7 (PAQR7), progesterone receptor membrane component 2 (PGRMC2), steroidogenic acute regulatory protein (STAR), and serpin family A member 1 (SERPINA1) were altered. Finally, 5 acid phosphatase tartrate resistant (ACP5), high mobility group box 2 (HMGB2), and DNA (cytosine-5)-methyltransferase 1 (DNMT1) were altered in both the endometrium and in embryos. In the endometrium, the methylation levels of ACP5 (regulation of endometrial-conceptus iron transport), RGS12 (protein-coupled receptor signalling), and TLR3 (immune response) were increased, while that of EDNRB (corpus luteum maintenance) was decreased. In embryos, the methylation levels of ADIPOR2 (metabolic homeostasis) and DNMT1 (DNA methylation maintenance) were increased. The levels of methylation in other studied endometrial and embryonic genes were unchanged. DNA methylation levels in both the peri-implantation pig endometrium and embryos may be altered in response to female nutritional restriction.

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Two main isoforms of heme oxygenase (HO-1 and HO-2), the main enzyme of heme metabolism, were identified in the pineal gland. This suggests possible interactions between the melatonin synthesis pathway and the HO system. The aim of this study was to investigate the participation of carbon monoxide (CO), an HO by-product, on the melatonin synthesis pathway. Tests were carried using primary cell cultures of porcine pineal glands. The tricarbonyldichlororuthenium (II) dimer (CORM-2) compound was used as a CO donor at concentrations of 1 and 3 µM, as low concentrations of CORM-2 affect the regulation of the melatonin synthesis pathway in pineal cells in vitro. In addition, the presence of Sn-protoporphyrin-IX, an HO inhibitor, changed the melatonin response of pineal cells. These results suggest the existence of an intermediate mechanism in the pineal gland, which is associated with HO activity, that is involved in the modulation of melatonin synthesis.

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Cardiac and extracardiac lipid metabolism is known to be significantly altered in the course of the heart failure with reduced ejection fraction (HF-REF), however the precise mechanisms are not fully elucidated. The aim of the study was to use of untargeted metabolomics to identify and validate changes in the blood metabolites profile, occurring as a result of HF-REF development. The analyses were performed first in the derivation set (36 chronic HF-REF patients and 19 controls without the disease) and repeated in validation cohort (31 chronic HF-REF patients and 20 controls). Independent analyses of both sets revealed statistically significant decline in intensities of phosphatidylcholine (PC): 34:4 and 36:5, lysophosphatidylcholine (lyso-PC): 14:0, 15:0, 18:0, 18:2, 20:3, lysophosphatidylethanolamine (lyso-PE): 18:1 and 18:2 in chronic HF-REF patients. More symptomatic patients and those with ischaemic etiology of HF-REF presented greater deficit in phospholipids (PLs) intensities. The decrease of identified PLs intensities (as compared to controls) correlated with decreased serum cholesterol level, impaired renal function, reduced exercise capacity, enhanced ventilatory response and metabolic parameters associated with altered fatty acids oxidation. In multiple regression analysis PLs deficit was significantly associated with age, carnitines serum intensity, renal function, uric acid, cholesterol level. In conclusion, HF-REF is associated with significant disturbances in phospholipids metabolism. Greater reduction in serum intensities of particular identified PLs is associated with older age, worse clinical condition, impaired oxidative muscle metabolism and enhanced catabolic status.

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Female under-nutrition during early pregnancy may affect the physiological pattern of the transcriptomic profile in the endometrium. We aimed to determine if restricted diet applied to females during peri-conceptional period, that is, from the onset of the oestrus until day nine of pregnancy, alters transcriptomic profile in the endometrium during the peri-implantation period. The restricted diet gilts were fed forage, in which the dose of proteins and energy had been reduced by 30% compared to normal diet. Microarray analysis revealed that approximately 4% of transcripts, that is 1690 of 43803 probes from The Porcine (V2) Gene Expression Microarray 4 × 44 (Agilent Technologies, Santa Clara, CA, USA) were consistently altered (p ≤ .05) in the endometrium harvested from pigs fed restricted diet. In pigs fed restricted diet out of 1690 genes, 714 genes were upregulated and 976 genes were downregulated versus in pigs fed normal diet. From 1690 genes, 510 (30%) were genes with known biological functions in the KEGG database. The proportions of the differentially expressed transcripts were organized into six major categories and 39 subcategories containing 259 pathways associated with the differentially expressed genes. The largest amount of differentially expressed genes was involved in metabolism category. The most relevant genes were involved in gene ontology (GO) cellular component (CC) term. These findings suggest that females under-nutrition during peri-conceptional period may create changes in endometrial transcriptome during the peri-implantation period creating the potential changes in physiological functions of peri-implantation endometrium.

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The endometrium of pregnant and cyclic pigs is a source of oestrone (E1) and 17ß-oestradiol (E2). However, the roles of LH, FSH and prolactin (PRL) as regulators of endometrial steroidogenesis, and the presence of 17ß-hydroxysteroid dehydrogenase (17ß-HSD) in the porcine endometrium, remain unknown. Therefore, in the present study we examined 17ß-HSD expression and the effects of LH, FSH and PRL on E1 and E2 release in vitro in endometrial explants harvested from gravid pigs on Days 10-11 (embryo migration within the uterus), 12-13 (maternal recognition of pregnancy) and 15-16 (beginning of implantation) and compared them with results obtained in non-gravid pigs. The results show that: (1) endometrial 17ß-HSD activity was decreased on Days 15-16 in pregnant and cyclic pigs compared with the preceding days; (2) LH, FSH and PRL increased endometrial E1 secretion on Days 10-11 and 15-16 of pregnancy and on Days 12-13 and 15-16 of the oestrous cycle; and (3) LH, FSH and PRL increased endometrial E2 secretion on Days 15-16 of pregnancy and during the days studied in the oestrous cycle. In conclusion, data suggest that LH, FSH and PRL affect endometrial secretion of estrogens in pigs.

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Female undernutrition during early pregnancy may affect the physiological pattern of genomic DNA methylation. We hypothesised that in utero DNA methylation may be impaired in females fed a restrictive diet in early pregnancy. In this study we evaluated whether poor maternal nutritional status, induced by applying a restricted diet during the peri-conceptional period, may influence: (1) the potential for in utero DNA methylation, expressed as changes in the mRNA expression and protein abundance of methyltransferases: DNA methyltransferase 1 (DNMT1) and DNMT3a in the endometrium and the myometrium, (2) the intrauterine microenvironment, measured as oestradiol 17ß (E2) and progesterone (P4) concentrations in uterine flushings and (3) plasma concentration of E2 and P4 during the peri-implantation period. Our results indicate that maternal peri-conceptional undernutrition affects maintenance and de novo DNA methylation in the endometrium, de novo methylation in the myometrium and a results in a decrease in intrauterine E2 concentration during the peri-implantation period. The intrauterine concentration of P4 and plasma concentrations of E2 and P4 did not change. These findings suggest that undernutrition during the earliest period of pregnancy, and perhaps the pre-pregnancy period, may create changes in epigenetic mechanisms in the uterus and intrauterine milieu of E2 during the peri-implantation period.

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INTRODUCTION: Atrial fibrillation (AF) is the most common arrhythmia and is associated with significant morbidity and mortality. The impact of matrix metalloproteinases (MMPs) on structural atrial remodeling and sustainment of AF in patients with persistent and permanent AF is unresolved. OBJECTIVES: The aim was to evaluate MMP-9 and its tissue inhibitor-1 (TIMP-1) as markers of atrial remodeling in patients with persistent AF (PAF) who underwent electrical cardioversion (ECV) and in patients with permanent AF (continuous AF, CAF). PATIENTS AND METHODS: Plasma levels of MMP-9 and TIMP-1, clinical findings, and echocardiographic parameters were evaluated in 39 patients with AF and in 14 controls with sinus rhythm. RESULTS: The concentrations of MMP-9 were significantly higher in patients with PAF and CAF compared to controls. There was a significant increase of MMP-9 after ECV in the persistent AF group. The values of TIMP-1 were not significantly different between the groups. In patients with AF, MMP-9 levels were positively related to posterior wall thickness of the LV (r=0.356, P=0.049) and body mass index (r=0.367, P=0.046). CONCLUSION: Elevated levels of MMP-9 were related to the occurrence and maintenance of AF. This suggests that MMP-9 can be a marker of atrial remodeling in patients with AF. Regulation of the extracellular collagen matrix might be a potential therapeutic target in AF.

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PURPOSE: Methylenetetrahydrofolate reductase (MTHFR) is an enzyme involved in endothelial nitric oxide synthase (eNOS) coupling and homocysteine metabolism. The rs1801133 polymorphism of the MTHFR gene affects risk of coronary artery disease. We assessed its influence on 5-year survival of patients with ST-elevation acute myocardial infarction (STEMI). MATERIAL/METHODS: The study group comprised consecutive patients with STEMI. Genotyping was performed with a TaqMan SNP Genotyping Assay using the ABI 7500 Real Time PCR System (Applied Biosystems). The analyzed end-point was all-cause 5-year survival. RESULTS: The study group comprised 637 patients (mean age 62.3 ± 11.9 years; 25.1% females, n=160; 5-year mortality 16.3%, n=104). The percentages of TT, CT and CC genotypes were: 10.8 (n=69), 39.7 (n=253) and 49.45 (n=315), respectively. No significant differences in clinical characteristics were identified between the genotypes (p>0.05 for all parameters). Eleven (15.9%) TT homozygotes, 40 (15.8%) heterozygotes and 53 (16.8%) CC homozygotes died during follow up (p=0.99 log-rank test). TT homozygotes presented only weak and insignificant tendency towards higher mortality rates in subgroups of patients ≤75 years old (15.6 vs. 11.54%, p=0.35) or with intermediate risk according to the GRACE risk score (13.3% vs. 8.76%, p=0.42). CONCLUSIONS: The rs1801133 polymorphism did not show significant association with 5-year survival.

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PURPOSE: To assess low-grade, systemic inflammation and antioxidant status as additional factors contributing to pathophysiology of essential arterial hypertension (HTN) and compare them with traditional risk factors, like abnormal lipids profile, considering their potential diagnostic usefulness. MATERIAL AND METHODS: Serum high-sensitivity C-reactive protein (hs-CRP) concentrations and total antioxidant status (TAS) were measured in 143 subjects - 71 patients with diagnosed HTN and in 72 healthy controls. RESULTS: In hypertensive patients, as compared to healthy control group, the median hs-CRP concentration was higher (2.0 mg/L, 25%; 75% quartile range: 0.1; 27.1 vs 0.4 mg/L, 25%; 75% quartile range: 0.0; 4.6, respectively, p<0.001) and TAS concentration lower (1.4 mmol/L, 25%; 75% quartile range: 1.0; 2.1 vs 1.5 mmol/L, 25%; 75% quartile range: 0.5; 1.8, respectively, p=0.048). Hypertensives had higher low-density lipoprotein cholesterol concentration (LDL-C) as well as triglycerides concentration (TG) and lower high-density lipoprotein cholesterol concentration (HDL-C). Higher diagnostic sensitivity was found for hs-CRP (87%) and for TAS (89%). According to the global linear regression analysis, age, gender, hs-CRP, TAS and HDL-C were the only parameters influencing the occurrence of HTN. ROC analysis identified hs-CRP, HDL-C and TG as statistically significant to diagnose HTN (0.839; 0.816 and 0.855, respectively). Moreover, in ROC analysis there were no differences in hs-CRP and TAS in females and males. CONCLUSIONS: These results indicate that low-grade, systemic inflammation measured by hs-CRP as well as antioxidant status assessed by TAS, in the presence of traditional risk factors, are significant factors contributing to pathophysiology and diagnosis of essential arterial hypertension.

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The proportion of non-parenchyma (non-gas exchanging tissue) varies with postnatal age and with the distance from the hilum of the lung. We have sampled 11 lungs varying in volume from 24.7 ml to 1308 ml and found that the mid-sagittal slice, or a combination of the two central slices in a lung producing four slices, adequately represents the amount of non-parenchyma and of air in bronchi and bronchioles in the entire lung.

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