Search Results (529)

Maternal undernutrition (MUN) causes severe metabolic disruption in the offspring of mammals. Here we determined the role of histone modification in hepatic gene expression in late-gestation fetuses of nutritionally restricted cows, an established model using low-nutrition (LN) and high-nutrition (HN) conditions. The chromatin immunoprecipitation sequencing results show that genes with an altered trimethylation of histone 3 lysine 4 (H3K4me3) are associated with cortisol synthesis and secretion, the PPAR signaling pathway, and aldosterone synthesis and secretion. Genes with the H3K27me3 alteration were associated with glutamatergic synapse and gastric acid secretion. Compared to HN fetuses, promoter H3K4me3 levels in LN fetuses were higher in GDF15, IRF2BP2, PPP1R3B, and QRFPR but lower in ANGPTL4 and APOA5. Intriguingly, genes with the greatest expression changes (>1.5-fold) exhibited the anticipated up-/downregulation from elevated or reduced H3K4me3 levels; however, a significant relationship was not observed between promoter CpG methylation or H3K27me3 and the gene set with the greatest expression changes. Furthermore, the stress response genes EIF2A, ATF4, DDIT3, and TRIB3 were upregulated in the MUN fetal liver, suggesting activation by upregulated GDF15. Thus, H3K4me3 likely plays a crucial role in MUN-induced physiological adaptation, altering the hepatic gene expression responsible for the integrated stress response and systemic energy metabolism, especially circulating lipoprotein lipase regulation. Full article

Recurrent pregnancy loss (RPL) is defined as the occurrence of two or more pregnancy losses before 20 weeks of gestation. RPL is a common medical condition among reproductive-age women, with approximately 23 million cases reported annually worldwide. Up to 5% of pregnant women may experience two or more consecutive pregnancy losses. Previous studies have investigated risk factors for RPL, including maternal age, uterine pathology, genetic anomalies, infectious agents, endocrine disorders, thrombophilia, and immune dysfunction. However, RPL is a disease caused by a complex interaction of genetic factors, environmental factors (e.g., diet, lifestyle, and stress), epigenetic factors, and the immune system. In addition, due to the lack of research on genetics research related to RPL, the etiology remains unclear in up to 50% of cases. Platelets play a critical role in pregnancy maintenance. This study examined the associations of platelet receptor and ligand gene variants, including integrin subunit beta 3 (ITGB3) rs2317676 A > G, rs3809865 A > T; fibrinogen gamma chain (FGG) rs1049636 T > C, rs2066865 T > C; glycoprotein 1b subunit alpha (GP1BA) rs2243093 T > C, rs6065 C > T; platelet endothelial cell adhesion molecule 1 (PECAM1) rs2812 C > T; and platelet endothelial aggregation receptor 1 (PEAR1) rs822442 C > A, rs12137505 G > A, with RPL prevalence. In total, 389 RPL patients and 375 healthy controls (all Korean women) were enrolled. Genotyping of each single nucleotide polymorphism was performed using polymerase chain reaction–restriction fragment length polymorphism and the TaqMan genotyping assay. All samples were collected with approval from the Institutional Review Board at Bundang CHA Medical Center. The ITGB3 rs3809865 A > T genotype was strongly associated with RPL prevalence (pregnancy loss [PL] ≥ 2: adjusted odds ratio [AOR] = 2.505, 95% confidence interval [CI] = 1.262–4.969, p = 0.009; PL ≥ 3: AOR = 3.255, 95% CI = 1.551–6.830, p = 0.002; PL ≥ 4: AOR = 3.613, 95% CI = 1.403–9.307, p = 0.008). The FGG rs1049636 T > C polymorphism was associated with a decreased risk in women who had three or more pregnancy losses (PL ≥ 3: AOR = 0.673, 95% CI = 0.460–0.987, p = 0.043; PL ≥ 4: AOR = 0.556, 95% CI = 0.310–0.997, p = 0.049). These findings indicate significant associations of the ITGB3 rs3809865 A > T and FGG rs1049636 T > C polymorphisms with RPL, suggesting that platelet function influences RPL in Korean women. Full article

This study applies Computational Fluid Dynamics (CFD) and mathematical modeling to examine uterine and umbilical arterial blood flow during pregnancy, providing a more detailed understanding of hemodynamic changes across gestation. Statistical analysis of Doppler ultrasound data from a large cohort of more than 200 pregnant women (in the second and third trimesters) reveals significant increases in the umbilical arterial peak systolic velocity ($PSV$) between the 22nd and 30th weeks, while uterine artery velocities remain relatively stable, suggesting adaptations in vascular resistance during pregnancy. By combining the Navier–Stokes equations with Doppler ultrasound-derived inlet velocity profiles, we quantify several key fluid dynamics parameters, including time-averaged wall shear stress ($TAWSS$), oscillatory shear index ($OSI$), relative residence time ($RRT$), Reynolds number ($Re$), and Dean number ($De$), evaluating laminar flow stability in the uterine artery and secondary flow patterns in the umbilical artery. Since blood exhibits shear-dependent viscosity and complex rheological behavior, modeling it as a non-Newtonian fluid is essential to accurately capture pulsatile flow dynamics and wall shear stresses in these vessels. Unlike conventional imaging techniques, CFD offers enhanced visualization of blood flow characteristics such as streamlines, velocity distributions, and instantaneous particle motion, providing insights that are not easily captured by Doppler ultrasound alone. Specifically, CFD reveals secondary flow patterns in the umbilical artery, which interact with the primary flow, a phenomenon that is challenging to observe with ultrasound. These findings refine existing hemodynamic models, provide population-specific reference values for clinical assessments, and improve our understanding of the relationship between umbilical arterial flow dynamics and fetal growth restriction, with important implications for maternal and fetal health monitoring. Full article

Background and Objectives: The long-term renal and cardiovascular effects of neonatal acute kidney injury (AKI) in preterm infants remain unclear. This study investigated whether neonatal AKI leads to persistent subclinical kidney injury and blood pressure changes in school-aged children born preterm. Methods: In this prospective cohort, preterm-born children (≤35 weeks’ gestation) with (n = 19) and without (n = 38) neonatal AKI were evaluated at 7–12 years. A term-born control group (n = 44) was included for biomarker comparison. Assessments included perinatal data, anthropometry, office and ambulatory blood pressure monitoring (ABPM), and renal ultrasonography. Kidney function was evaluated using serum creatinine (sCr), cystatin C, and estimated glomerular filtration rate (eGFR). Tubular injury was assessed using urinary kidney injury molecule-1/Cr (KIM-1/Cr), neutrophil gelatinase-associated lipocalin/Cr (NGAL/Cr), and trefoil factor 3/Cr (TFF3/Cr) ratios, as well as serum TFF3. Results: Conventional kidney function markers were similar among groups. However, the AKI group had higher serum cystatin C, lower cystatin C–based eGFR, and elevated urinary KIM-1/Cr and NGAL/Cr compared to no-AKI and term controls. Serum TFF3 was also higher in the AKI group. ABPM revealed higher nocturnal systolic blood pressure and blood pressure load in the AKI group. Kidney size did not differ between preterm subgroups. Conclusions: Neonatal AKI in preterm infants is associated with subtle alterations and potential renal stress or injury at school age, detectable only with sensitive biomarkers and ABPM. Further prospective studies are needed to validate these biomarkers and determine their role in predicting long-term outcomes in preterm infants with neonatal AKI. Full article

This study aimed to explore the effects of dietary supplementation with soy isoflavones (SI) in the later stages of pregnancy on the antioxidant capacity of sows and intestinal health of newborn piglets. Forty sows with similar body weights and parity (average of 1–2 parity) were randomly divided into two groups (n = 20): the control group and SI group (dose: 100 mg/kg of feed). Feeding was started on day 85 of gestation and continued until farrowing. SI supplementation significantly increased the antioxidant levels in the serum of the sows and newborn piglets, placental tissue, and the intestinal tract of the piglets. This observation was indicated by a decreased activity of the oxidative stress marker malondialdehyde (MDA); increased activity of antioxidant enzymes such as superoxide dismutase, glutathione peroxidase, and catalase; and enhanced total antioxidant capacity. The organ indices of the intestine and liver and the villus height/crypt depth of the jejunum of newborn piglets significantly increased. SI supplementation activated the Nrf2 signaling pathway in the jejunum of neonatal piglets and the expression of placental antioxidant proteins, and it downregulated the expression of the Bax and Caspase 3 apoptotic proteins in the placenta and neonatal piglets. Intestinal and placental barrier integrity was strengthened. For example, ZO-1, Occludin, and Claudin 1 exhibited elevated expression. In conclusion, dietary supplementation with SI enhanced the antioxidant capacity of sows and piglets and improved the health of the placenta and intestinal tract of newborn piglets. Full article

Background/Objectives: SIRT1 is a NAD⁺-dependent protein deacetylase regulating metabolic and stress response pathways. Genetic variations in the SIRT1 gene may contribute to the pathogenesis of type 2 diabetes mellitus (T2DM). This case–control study investigates the associations of two SIRT1 promoter polymorphisms, rs12778366 and rs3758391, in patients with type 2 diabetes mellitus (T2DM), gestational diabetes mellitus (GDM), preeclampsia, and healthy controls. Methods: This case–control study compared the genotypes between T2DM and pregnant and non-pregnant controls. We also compared genotypes between pregnant women with T2DM, GDM, preeclampsia, and healthy pregnant controls. Genomic DNA was extracted and analyzed using PCR-RFLP for the detection of rs12778366 and rs3758391 polymorphisms. Genotype frequencies were compared using chi-square tests, and odds ratios (ORs) with 95% confidence intervals (CIs) were calculated. Results: The study included 66 patients with T2DM, 36 with GDM, 12 with preeclampsia, and 81 pregnant and non-pregnant controls (33 pregnant controls). Although rs3758391 was more frequent in T2DM, the difference was not statistically significant between SIRT1 polymorphisms and T2DM. The CT genotype was more prevalent in T2DM (54.5%) compared to controls (33.4%); however, this difference was not significant. We finally found no significant association of the investigated SIRT1 polymorphisms with any of the conditions studied. In addition, the small sample size, especially for preeclampsia cases, limits the statistical power to detect significant associations. Conclusions: Although no significant association was observed between SIRT1 polymorphisms and diabetes, the findings of our study underscore the need for further studies examining SIRT1 polymorphisms in various ethnic groups, with a focus on leveraging these genetic variations in diabetes pathophysiology. Larger studies in the Greek population could also provide additional meaningful findings. Full article

MicroRNA-based regulatory mechanisms show disturbances related to oxidative stress (OS) interconnected with inflammation (IFM), as well as impairments associated with gestational diabetes (GDM). The aim of this study was to assess the diagnostic and prognostic significance of the OS/IFM-related microRNA in GDM by using peripheral blood mononuclear cells (PBMCs) and serum-derived extracellular vesicles (EVs) as biological samples. We selected the known OS/IFM-associated microRNAs miR-146a-5p, miR-155-5p, and miR-21-5p as candidates for our GDM biomarker analysis. Quantitative RT-PCR was employed for relative quantification of the selected microRNAs from paired samples of PBMCs and EVs derived from patients with GDM and healthy controls (n = 50 per group). The expression levels were analyzed for correlations with lipid and glycemic status indicators; metal ion-related parameters; serum thiol content; protein carbonyl and thiobarbituric acid-reactive substances’ (TBARS) levels; glutathione reductase (GR), Superoxide dismutase (SOD), and catalase (CAT) activity; and NRF2 expression. MiR-146a-5p and miR-21-5p were significantly upregulated in both PBMCs and EVs obtained from GDM patients. EVs-miR-21-5p showed a positive correlation with glycemic status in GDM patients, while miR-155-5p from PBMCs demonstrated correlation with iron-related parameters. The expression of selected microRNAs was found to correlate with NRF2 expression and SOD activity. The level of miR-146a-5p negatively correlated with neonatal anthropometric characteristics, while a higher level of PBMCs-miR-21-5p expression was determined in GDM patients with adverse pregnancy outcomes (p = 0.012). Our data demonstrate a disturbance of OS/IFM-microRNAs in GDM and illustrate their potential to serve as indicators of the associated OS-related changes, neonatal characteristics, and adverse pregnancy outcomes. Full article

Pre-eclampsia (PE) is a hypertensive pregnancy complication. Oxidative stress is hypothesized to contribute to the pathophysiology of PE. Both the hydrogen sulfide (H₂S) and oxytocin (OT) systems might play a role in the pathophysiology of PE, like their antioxidant and hypotensive effects. Thus, the role of the interaction of the OT and H₂S systems in the context of PE was further elucidated in the present clinical case–control study “NU-HOPE” (Nürnberg-Ulm: The role of H₂S and Oxytocin Receptor in Pre-Eclampsia; ethical approval by the Landesärztekammer Bayern, file number 19033, 29 August 2019), comparing uncomplicated pregnancies, early onset PE (ePE, onset < 34 weeks gestational age) and late onset PE (lPE, onset > 34 weeks gestational age). Routine clinical data, serum H₂S and homocysteine levels, and tissue protein expression, as well as nitrotyrosine formation, were determined. The main findings were (i) unchanged plasma sulfide levels, (ii) significantly elevated homocysteine levels in ePE, but not lPE, (iii) significantly elevated expression of H₂S enzymes and OT receptor in the placenta in lPE, and (iv) significantly elevated nitrotyrosine formation in the lPE myometrium. Taken together, these findings suggest a role for the interaction of the endogenous H₂S- and OT/OTR systems in the pathophysiology of pre-eclampsia, possibly linked to impaired antioxidant protection. Full article

Maternal obesity programs the fetus for increased risk of chronic disease development in early life and adulthood. We hypothesized that maternal nutrient excess leads to fetal inflammation and impairs offspring skeletal muscle mitochondrial biogenesis in non-human primates. At least 12 months before pregnancy, female baboons were fed a normal chow (CTR, 12% energy fat) or a maternal nutrient excess (MNE, 45% energy fat, and ad libitum fructose sodas) diet, with the latter to induce obesity. After 165 days of gestation (0.9 G), offspring baboons were delivered by cesarean section, and the soleus muscle was collected (CTR n = 16, MNE n = 5). At conception, MNE mothers presented increased body fat and weighed more than controls. The soleus muscle of MNE fetuses exhibited increased levels of stress signaling associated with inflammation (TLR4, TNFα, NF-kB p65, and p38), concomitant with reduced expression of key regulators of mitochondrial biogenesis, including PGC1α, both at the protein and transcript levels, as well as downregulation of PPARGC1B, PPARA, PPARB, CREB1, NOS3, SIRT1, SIRT3. Decreased transcript levels of NRF1 were observed alongside diminished mitochondrial DNA copy number, mitochondrial fusion elements (MFN1, MFN2), cytochrome C protein levels, and cytochrome C oxidase subunits I and II transcripts (cox1 and cox2). MNE coupled to MO-induced stress signaling in fetal baboon soleus muscle is associated with impaired mitochondrial biogenesis and lower mitochondrial content, resembling the changes observed in metabolic dysfunctions, such as diabetes. The observed fetal alterations may have important implications for postnatal development and metabolism, potentially increasing the risk of early-onset metabolic disorders and other non-communicable diseases. Full article

Preterm birth (PTB) refers to a labor before 37 gestational weeks. This is a major global contributor to neonatal morbidity and mortality. Although fetal sex is frequently treated as a confounding variable in PTB research, relatively few studies have conducted sex-stratified analyses to investigate how male and female fetuses may respond differently to various intrauterine exposures. This represents an underexplored area with important implications for understanding fetal sexual dimorphism-specific vulnerability to adverse pregnancy outcomes. Understanding the role of fetal sex differences in the pathophysiology of preterm birth (PTB) regarding processes such as inflammation, placental dysfunction, and oxidative stress is crucial. These delicate processes are tightly interrelated, but also independently contribute to pregnancy complications. Recognizing fetal sex as a biological variable for such processes is essential for improving mechanistic insight, providing refined predictive models. Full article

Salivary cortisol is widely used to assess stress and circadian rhythms, yet its control variables in neonates, particularly regarding postnatal age, remain poorly understood. To elucidate age-specific effects of clinical variables on cortisol levels, 91 neonates with a mean (standard deviation) gestational age of 34.2 (3.8) weeks and postnatal age of 38.3 (35.4) days were categorised into Early, Medium, and Late groups by quartiles (days 10 and 56). Interactions with postnatal age were evaluated by comparing Early-to-Medium or Early-to-Late differences in regression coefficients between independent variables and cortisol levels. In the whole cohort, maternal hypertensive disorders of pregnancy and morning sampling were associated with reduced cortisol levels (both p = 0.001). Mean regression coefficients (95% CI) between variables and cortisol levels were as follows: for postconceptional age, Early, −0.102 (−0.215, 0.010) and Late, 0.065 (−0.203, 0.332) (p = 0.035); for feeding duration, Early, 0.796 (−0.134, 1.727) and Late, −0.702 (−2.778, 1.376) (p = 0.010); for time elapsed since feeding, Early, −0.748 (−1.275, −0.221) and Late, −0.071 (−1.230, 1.088) (p = 0.036); and for blood lactate, Early, 0.086 (0.048 to 0.124), Medium, 0.022 (−0.063, 0.108), and Late, −0.018 (−0.106, 0.070) (p = 0.008 and <0.001 vs. Medium and Late, respectively). The influence of postconceptional age, oral feeding, and anaerobic metabolism on salivary cortisol levels was observed during the birth transition period but not beyond 10 days of life. Given the age-specific dependence of cortisol levels on clinical variables, including postconceptional age, feeding, and oxygen metabolism, caution is warranted when interpreting findings from studies on salivary cortisol in newborn infants. Full article

Cardiovascular diseases are a leading cause of mortality, driving the search for alternative preventive strategies. This study investigates the antioxidant effects, among others, of a mixture of four bioactive peptides (BPs) derived from dry-cured pork ham on endothelial cells from healthy (C-HUVECs) and gestational diabetes (GD-HUVECs) pregnancies, as well as human plasma, using an integrative omics approach. Human umbilical vein endothelial cells (HUVECs) were treated with 300 μM purified BP, followed by transcriptomic and proteomic analyses. The results revealed significant alterations in mitochondrial gene expression and downregulation of genes associated with inflammation and oxidative stress in healthy HUVECs. Furthermore, BP treatment modulated key signalling pathways, including Ras and MAPK, leading to changes in the phosphorylation of ERK, AKT, and NF-κB, suggesting potential cardioprotective effects. The effects of BP were compared to those of the antioxidant hydroxytyrosol, highlighting their relative efficacy in vascular protection. The proteomic analysis of human plasma demonstrated BP-induced modulation of lipid metabolism, inflammation, and oxidative stress with notable changes in proteins such as APOA1 and MMP-8. These natural compounds demonstrate significant preventive potential in vascular health, highlighting their promise as effective tools for reducing cardiovascular risk before the progression of the pathology. These findings emphasize the importance of integrative omics in understanding the mechanisms behind BP’s effects and suggest promising applications for nutraceuticals aimed at cardiovascular protection. Full article

Carbohydrate consumption during pregnancy represents an important source of energy; its consumption, however, can cause gestational diabetes mellitus (GDM), body weight gain, inflammation, increased glucose transport to the fetus, adiposity, and a risk of macrosomia. The objective was to research the impact of sucrose consumption during pregnancy on the metabolic, immune, and redox profile in female mice with GDM. A total of 24 female CD1 mice were used, divided into two groups: Control and GDM. Each group was subdivided into two subgroups: (a) Without sucrose and (b) With sucrose. The females were mated, and, once pregnancy was confirmed, GDM was induced by administering 230 mg/kg of streptozotocin subcutaneously. GDM was confirmed by glucose ≥ 200 mg/dL and the presence of polyphagia, polydipsia, and change in body weight. Metabolic, immune, and redox profile parameters were determined. Sucrose consumption groups increase HOMA-IR and the secretion of insulin, adiponectin, and leptin; it also increased the secretion of proinflammatory cytokines and the production of IgA and IgG antibodies, decreased the activity of the Glutathione Reductase enzyme, and increased the production of TBARS and AGE. High sucrose consumption increases the inflammatory response mediated mainly by CD8⁺ lymphocytes and the production of proinflammatory cytokines; it can trigger a compensatory humoral response and alter redox mechanisms, causing a state of Oxidant Stress. Full article

Gestational chronic hypoxia impacts prenatal development, leading to fetal growth restriction (FGR), defined as the fetus’s failure to reach its genetic growth potential. Postnatal hypoxia in the cerebral tissue can induce a redox imbalance and mitochondrial dysfunction, consequently increasing neuronal death. However, these data cannot necessarily be extrapolated to prenatal hypoxia. In this regard, this study aims to describe the effect of gestational hypoxia on redox balance and apoptosis cell death mechanisms in the prefrontal cortex of guinea pigs. Ten Guinea pig (Cavia porcellus) pregnant dams were utilized in this study; five gestated in normoxia (Nx; three newborn males, and two females) and five gestated under chronic hypobaric hypoxia (Hx; two newborn males, and three females). We monitored the pregnancies by ultrasound examinations from gestational days 20 to 65 (term ~ 70). At birth, pups were euthanized, and the fetal brain was collected for cellular redox measurement, mitochondrial enzyme expression, and apoptosis assay. Gestation under hypoxia induced an imbalance in the expression of anti- and pro-oxidant enzymes, resulting in increased oxidative stress. Additionally, a decrease in cytochrome I and III expression and neuronal density in the neonatal prefrontal cortex was observed. Finally, DNA fragmentation was increased by the TUNEL assay in the brain tissue of newborns gestated under chronic hypoxia. Our findings demonstrate the association of gestational hypoxia with oxidative stress and neuronal death in newborns, which may predispose to neuronal dysfunction in adulthood. Full article

In this study, thirty female dogs, aged one to five years and varying in weight, in the last week of gestation were evaluated. The animals were divided into two groups: GC, which comprised twenty-two bitches undergoing elective cesarean section, and GD, which consisted of eight dogs requiring therapeutic cesarean section as a treatment to dystocia. We found that cortisol levels in the amniotic fluid were significantly higher in pups delivered via elective cesareans (mean: 9.86 ng/mL) compared to those from therapeutic c-sections (mean: 4.11 ng/mL). This observation contrasted with previous studies that reported lower cortisol levels in elective procedures, suggesting complexities in the physiological responses to different delivery methods that warrant further investigation. Notably, our study observed no significant association between amniotic fluid meconium presence and other distress markers, indicating that meconium may be more closely associated with fetal maturation rather than distress (p > 0.05). Neonatal viability (Apgar score) revealed that 92.86% of the neonates from elective procedures demonstrated no distress shortly after delivery, contrasting with 56.25% in therapeutic c-section. Fetal distress can be a direct consequence of dystocia caused by various stressors, such as pain and hypoxia. These factors can impair the fetus’ ability to adapt to extrauterine life, often leading to lower Apgar scores. Notably, neonatal weight was directly related to fetal cortisol levels, while no significant associations were noted between the litter size or birth order and cortisol concentrations, irrespective of the delivery type. These findings underscore the need for ongoing investigation into the relationships between cesarean delivery types, maternal and neonatal stress markers, and resultant health outcomes, aiming to enhance care strategies for expectant canine mothers and their puppies. Full article