Search Results (21)

Skin aging is primarily driven by oxidative stress, mitochondrial dysfunction, and cell cycle dysregulation. This study investigated the anti-senescence effects of fermented porcine placenta (FPP) and its dipeptides, leucine–glycine (LG) and proline–hydroxyproline (PH), in human epidermal keratinocytes (HEKs), using nicotinamide mononucleotide (NMN) as a reference for nicotinamide adenine dinucleotide (NAD⁺)-related pathways. FPP suppressed senescence-associated β-galactosidase (SA-β-gal) activity and Cyclin-dependent kinase inhibitor 2A (p16) expression while enhancing adenosine triphosphate (ATP) production and sirtuin 1 (SIRT1)–peroxisome proliferator-activated receptor-gamma coactivator 1α (PGC-1α) signaling. LG and PH exhibited distinct actions: LG improved redox balance by increasing the NAD⁺/NADH ratio and NAD(P)H quinone oxidoreductase 1 (NQO1) activity, whereas PH modulated cell cycle regulators and upregulated sirtuin 3 (SIRT3) expression. Although both peptides contributed to FPP’s effects, their combination did not fully replicate its overall activity, suggesting synergistic roles of multiple bioactive constituents. These findings highlight FPP as a multifactorial modulator of keratinocyte senescence, acting via mitochondrial and redox-related mechanisms. Full article

Mono(2-ethylhexyl) phthalate (MEHP), a bioactive metabolite of di(2-ethylhexyl) phthalate (DEHP), has been detected in the placenta and urine of pregnant women and is linked to adverse pregnancy outcomes. However, its effects on mitochondrial homeostasis in trophoblast cells remain incompletely understood. This study examined the impact of MEHP (0.5–200 µM) on mitochondrial function, dynamics, and biogenesis in human HTR-8/SVneo trophoblast cells. MEHP (≥5 µM) reduced MTT conversion without compromising membrane integrity, suggesting early metabolic or redox imbalance. A dose-dependent loss of mitochondrial membrane potential was observed, with increased reactive oxygen species (ROS) generation only at 200 µM. MEHP modulated the expression of mitochondrial dynamics genes, with a more pronounced mitofusin 1 (MFN1) induction at low doses and increased mitochondrial DNA content, suggesting a compensatory response to mild stress. Conversely, high doses more strongly induced fission and mitochondrial 1 (FIS1) expression, suggesting mitochondrial fragmentation. Both concentrations induced the expression of the mitochondrial biogenesis regulators peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC-1α) and nuclear factor erythroid 2–related factor 2 (Nrf2), while sirtuin 1 (SIRT1) expression and activity declined progressively with dose. These results demonstrate that MEHP disrupts mitochondrial homeostasis in trophoblast cells at concentrations spanning the estimated human exposure range. The dose-dependent effects, from adaptive responses to overt dysfunction, may help explain the associations between MEHP exposure and placental pathology observed in epidemiological studies. Full article

The central role of angiotensinogen in the control of blood pressure is revealed by a series of crystallographic structures, including complexes with renin. Specifically, the structures provide an understanding of the sequential molecular events that lead to the pre-eclamptic hypertensive crises of pregnancy. The release of the precursor vasopressor peptide from the amino-terminal tail of angiotensinogen appears to be modulated by a redox-sensitive disulphide bridge. Our findings indicate that the activation of the thiol-switch in the circulating maternal angiotensinogen occurs at the placental level in response to oxidative stress, exacerbated by placental insufficiency. We propose here that a contributory factor is the inherent redox stress accompanying the placental exchange of oxygenation between the haemoglobin of the mother (oxy-HbA) and the deoxygenated haemoglobin of the foetus (deoxy-HbF). Full article

Prenatal hypoxia, often accompanied by maternal glucocorticoid stress, can predispose offspring to neurological disorders in adulthood. If placental ischemia (PI) primarily reduces fetal oxygen supply, the maternal hypoxia (MH) model also elicits a pronounced fetal glucocorticoid exposure. Here, we compared MH and PI in rats to distinguish their unique and overlapping effects on embryonic and newborn brain development. We analyzed glucocorticoid transport into the developing brain, glucocorticoid receptor (GR) expression, and GR-dependent transcription, along with key enzymes regulating glucocorticoid metabolism in maternal (MP) and fetal placentas (FP) and in the brain. Additionally, we examined hypoxia-inducible factor 1-alpha (HIF1α) and its downstream genes, as well as glycolysis and the pentose phosphate pathway, both associated with the transport of substrates essential for glucocorticoid synthesis and degradation. Both MH and PI induced HIF1-dependent metabolic alterations, enhancing glycolysis and transiently disrupting redox homeostasis. However, only MH caused a maternal glucocorticoid surge that altered early fetal brain glucocorticoid responsiveness. Over time, these differences may lead to distinct long-term outcomes in neuronal structure and function. This work clarifies the individual contributions of hypoxic and glucocorticoid stresses to fetal brain development, suggesting that combining the MH and PI models could provide valuable insights for future investigations into the mechanisms underlying developmental brain pathologies, including non-heritable psychoneurological and neurodegenerative disorders. Full article

Oxidative stress (OS) and apoptosis are critical factors in placental development and function. Their interplay influences trophoblast proliferation, differentiation, and invasion, as well as vascular development. An imbalance between these processes can lead to pregnancy-related disorders such as preeclampsia, intrauterine growth restriction, and even spontaneous abortion. Our study seeks to elucidate the associations between preventive antioxidant/protective OS response factors—glutathione (GSH), MutT Homolog 1 (MTH1), and apoptotic regulation modulators—tumor protein p53 and B-cell lymphoma (Bcl-2) transcripts, in the context of spontaneous abortion (30 samples) versus elective termination of pregnancy (20 samples), using immunohistochemistry (IHC) to determine their proteomic expression in chorionic villi within abortive fetal placenta tissue samples. Herein, comparative statistical analyses revealed that both OS response factors, GSH and MTH1, were significantly under-expressed in spontaneous abortion cases as compared to elective. Conversely, for apoptotic regulators, p53 expression was significantly higher in spontaneous abortion cases, whereas Bcl-2 expression was significantly lower in spontaneous abortion cases. These findings suggest that a strong pro-apoptotic signal is prevalent within spontaneous abortion samples, alongside reduced anti-apoptotic protection, depleted antioxidant defenses and compromised oxidative DNA damage prevention/repair, as compared to elective abortion controls. Herein, our hypothesis that OS and apoptosis are closely linked processes contributing to placental dysfunction and spontaneous abortion was thus seemingly corroborated. Our results further highlight the importance of maintaining redox homeostasis and apoptotic regulation for a successful pregnancy. Understanding the mechanisms underlying this interplay is essential for developing potential therapies to manage OS, promote placentation, and avoid unwanted apoptosis, ultimately improving pregnancy outcomes. Antioxidant supplementation, modulation of p53 activity, and the enhancement of DNA repair mechanisms may represent potential approaches to mitigate OS and apoptosis in the placenta. Further research is needed to explore these strategies and their efficacy in preventing spontaneous abortion. Full article

Background: Obesity during pregnancy is related to adverse maternal and neonatal outcomes. Factors involved in these outcomes may include increased maternal insulin resistance, inflammation, oxidative stress, and nutrient mishandling. The placenta is the primary determinant of fetal outcomes, and its function can be impacted by maternal obesity. The aim of this study on mice was to determine the effect of obesity on maternal lipid handling, inflammatory and redox state, and placental oxidative stress, inflammatory signaling, and gene expression relative to female and male fetal growth. Methods: Female mice were fed control or obesogenic high-fat/high-sugar diet (HFHS) from 9 weeks prior to, and during, pregnancy. On day 18.5 of pregnancy, maternal plasma, and liver, placenta, and fetal serum were collected to examine the immune and redox states. The placental labyrinth zone (Lz) was dissected for RNA-sequencing analysis of gene expression changes. Results: the HFHS diet induced, in the dams, hepatic steatosis, oxidative stress (reduced catalase, elevated protein oxidation) and the activation of pro-inflammatory pathways (p38-MAPK), along with imbalanced circulating cytokine concentrations (increased IL-6 and decreased IL-5 and IL-17A). HFHS fetuses were asymmetrically growth-restricted, showing sex-specific changes in circulating cytokines (GM-CSF, TNF-α, IL-6 and IFN-γ). The morphology of the placenta Lz was modified by an HFHS diet, in association with sex-specific alterations in the expression of genes and proteins implicated in oxidative stress, inflammation, and stress signaling. Placental gene expression changes were comparable to that seen in models of intrauterine inflammation and were related to a transcriptional network involving transcription factors, LYL1 and PLAG1. Conclusion: This study shows that fetal growth restriction with maternal obesity is related to elevated oxidative stress, inflammatory pathways, and sex-specific placental changes. Our data are important, given the marked consequences and the rising rates of obesity worldwide. Full article

Trophoblast differentiation is a crucial process in the formation of the placenta where cytotrophoblasts (CTs) differentiate and fuse to form the syncytiotrophoblast (ST). The bioactive components of cannabis, such as Δ⁹-THC, are known to disrupt trophoblast differentiation and fusion, as well as mitochondrial dynamics and respiration. However, less is known about the impact of cannabidiol (CBD) on trophoblast differentiation. Due to the central role of mitochondria in stem cell differentiation, we evaluated the impact of CBD on trophoblast mitochondrial function and differentiation. Using BeWo b30 cells, we observed decreased levels of mRNA for markers of syncytialization (GCM1, ERVW1, hCG) following 20 µM CBD treatment during differentiation. In CTs, CBD elevated transcript levels for the mitochondrial and cellular stress markers HSP60 and HSP70, respectively. Furthermore, CBD treatment also increased the lipid peroxidation and oxidative damage marker 4-hydroxynonenal. Mitochondrial membrane potential, basal respiration and ATP production were diminished with the 20 µM CBD treatment in both sub-lineages. mRNA levels for endocannabinoid system (ECS) components (FAAH, NAPEPLD, TRPV1, CB1, CB2, PPARγ) were altered differentially by CBD in CTs and STs. Overall, we demonstrate that CBD impairs trophoblast differentiation and fusion, as well as mitochondrial bioenergetics and redox homeostasis. Full article

This study aims to investigate the impact of dietary supplementation with selenium yeast (SeY) and glycerol monolaurate (GML) on the transfer of antioxidative capacity between the mother and fetus during pregnancy and its underlying mechanisms. A total of 160 sows with similar body weight and parity of 3–6 parity sows were randomly and uniformly allocated to four groups (n = 40) as follows: CON group, SeY group, GML group, and SG (SeY + GML) group. Animal feeding started from the 85th day of gestation and continued to the day of delivery. The supplementation of SeY and GML resulted in increased placental weight and reduced lipopolysaccharide (LPS) levels in sow plasma, placental tissues, and piglet plasma. Furthermore, the redox balance and inflammatory markers exhibited significant improvements in the plasma of sows fed with either SeY or GML, as well as in their offspring. Moreover, the addition of SeY and GML activated the Nrf2 signaling pathway, while downregulating the expression of pro-inflammatory genes and proteins associated with inflammatory pathways (MAPK and NF-κB). Vascular angiogenesis and nutrient transportation (amino acids, fatty acids, and glucose) were upregulated, whereas apoptosis signaling pathways within the placenta were downregulated with the supplementation of SeY and GML. The integrity of the intestinal and placental barriers significantly improved, as indicated by the increased expression of ZO-1, occludin, and claudin-1, along with reduced levels of DLA and DAO with dietary treatment. Moreover, supplementation of SeY and GML increased the abundance of Christensenellaceae_R-7_group, Clostridium_sensus_stricto_1, and Bacteroidota, while decreasing levels of gut microbiota metabolites LPS and trimethylamine N-oxide. Correlation analysis demonstrated a significant negative relationship between plasma LPS levels and placental weight, oxidative stress, and inflammation. In summary, dietary supplementation of SeY and GML enhanced the transfer of antioxidative capacity between maternal-fetal during pregnancy via gut–placenta axis through modulating sow microbiota composition. Full article

Background: Preeclampsia (PE) is a hypertensive disorder of pregnancy that is associated with substantial morbidity and mortality for the mother and fetus. Reduced nitric oxide bioavailability and oxidative stress contribute to the maternal and fetal pathophysiology of PE. In this study, we evaluated the efficacy of a novel dual-function nitric oxide donor/redox modulator, AKT-1005, in reducing PE symptoms in a mouse model of PE. Method: The potential therapeutic effect of AKT-1005 was tested in an animal model of Ad.sFlt-1-induced hypertension, proteinuria and glomerular endotheliosis, a model of PE. Pregnant Ad.sFlt-1-overexpressing CD1 mice were randomized into groups administered AKT-1005 (20 mg/kg) or a vehicle using a minipump on gd11 of pregnancy, and the impact on blood pressure and renal and placental damage were assessed. Results: In healthy female mice, ex vivo treatment of resistance vessels with AKT-1005 induced vasorelaxation, and 6 days of treatment in vivo did not significantly alter blood pressure with or without pregnancy. When given for 6 days during pregnancy along with Ad.sFlt-1-induced PE, AKT-1005 significantly increased plasma nitrate levels and reduced hypertension, renal endotheliosis and plasma cystatin C. In the placenta, AKT-1005 improved placental function, with reduced oxidative stress and increased endothelial angiogenesis, as measured by CD31 staining. As such, AKT-1005 treatment attenuated the Ad.sFlt-1-induced increase in placental and free plasma soluble endoglin expression. Conclusions: These data suggest that AKT-1005 significantly attenuates the sFlt-1-induced PE phenotypes by inhibiting oxidative stress, the anti-angiogenic response, and increasing NO bioavailability. Additional research is warranted to investigate the role of AKT-1005 as a novel therapeutic agent for vascular disorders such as preeclampsia. Full article

Background: Preeclampsia (PE) is a severe, life-threatening complication during pregnancy (~5–7%), and no causative treatment is available. Early aberrant spiral artery remodeling is associated with placental stress and the release of oxygen radicals and other reactive oxygen species (ROS) in the placenta. This precedes the production of anti-angiogenic factors, which ultimately leads to endothelial and trophoblast damage and the key features of PE. We tested whether a novel dual-function redox modulator—AKT-1005—can effectively reduce placental oxidative stress and alleviate PE symptoms in vitro. Method: Isolated human villous explants were exposed to hypoxia and assessed to determine whether improving cell-redox function with AKT-1005 diminished ROS production, mitochondrial stress, production of the transcription factor HIF1A, and downstream anti-angiogenic responses (i.e., sFLT1, sEng production). MitoTEMPO was used as a reference antioxidant. Results: In our villous explant assays, pretreatment with AKT-1005 reduced mitochondrial-derived ROS production, reduced HIF-1A, sFLT1, and sEng protein expression, while increasing VEGF in hypoxia-exposed villous trophoblast cells, with better efficiency than MitoTEMPO. In addition, AKT-1005 improved mitochondrial electron chain enzyme activity in the stressed explant culture. Conclusions: The redox modulator AKT-1005 has the potential to intervene with oxidative stress and can be efficacious for PE therapy. Future studies are underway to assess the in vivo efficacy of HMP. Full article

Preeclampsia (PE) is a pregnancy-specific syndrome affecting 5–7% of patients. There is no effective treatment available. Early abnormal placental development is associated with oxidative stress (OS) and a release of reactive oxygen species (ROS) in the placenta. This phenomenon leads to downstream signaling, Hypoxia Inducible Factor 1A (HIF1A) stabilization and transcription of the anti-angiogenic factors soluble fms-like tyrosine kinase 1 (sFLT1) and soluble endoglin (sEng), which are known to cause endothelial and trophoblast dysfunction and cardinal features of PE: hypertension, proteinuria and, in severe cases, eclampsia. We tested whether 3-(Hydroxymethyl)-1-oxy-2,2,5,5-tetramethylpyrrolidine (HMP)—a nitroxide-type antioxidant molecule—can reduce placental OS and mitigate PE symptoms in vitro. We induced OS in human trophoblast (HTR-8/SVneo) cells with hydrogen peroxide (H₂O₂) and assessed whether modulating cell redox function with HMP reduces cell injury, mitochondrial stress and HIF1A and sFLT1 production. Pre-treatment with HMP reduced mitochondrial-derived ROS production, restored LC3B expression and reduced HIF1A and sFLT1 expression in H₂O₂-exposed HTR-8/SVneo trophoblast cells. HMP improved the mitochondrial electron chain enzyme activity, indicating that a reduction in OS alleviates mitochondrial stress and also reduces anti-angiogenic responses. In reducing placental trophoblast OS, HMP presents a potential novel therapeutic approach for the treatment of PE. Future investigation is warranted regarding the in vivo use of HMP. Full article

Pre-eclampsia (PE) is a hypertensive disorder of pregnancy and has been associated with placental growth restriction. The pre-eclamptic placenta releases free radicals to maternal circulation, thus increasing oxidative stress. An impaired redox state leads to reduction in circulating nitric oxide (NO) levels and activation of extracellular matrix metalloproteinases (MMPs). However, activation of MMPs induced by oxidative stress is still unclear in PE. Antioxidant effects have been demonstrated with the use of pravastatin. Therefore, we hypothesized that pravastatin protects against oxidative stress-induced activation of MMPs in a rat model of PE. The animals were divided into four groups: normotensive pregnant rats (Norm-Preg); pregnant rats treated with pravastatin (Norm-Preg + Prava); hypertensive pregnant rats (HTN-Preg); and hypertensive pregnant rats treated with pravastatin (HTN-Preg + Prava). The deoxycorticosterone acetate (DOCA) and sodium chloride (DOCA-salt) model was used to induce hypertension in pregnancy. Blood pressure, and fetal and placental parameters were recorded. The gelatinolytic activity of MMPs, NO metabolites and lipid peroxide levels were also determined. Endothelium function was also examined. Pravastatin attenuated maternal hypertension, prevented placental weight loss, increased NO metabolites, inhibited increases in lipid peroxide levels, and reduced the activity of MMP-2, and these effects were observed along with enhanced endothelium-derived NO-dependent vasodilation. The present results provide evidence that pravastatin protects against activation of MMP-2 induced by oxidative stress in pre-eclamptic rats. These findings may also involve improvement in endothelial function related to NO and antihypertensive effects of pravastatin, thus suggesting pravastatin as a therapeutic intervention for PE. Full article

The chemical element selenium (Se) is a nonmetal that is in trace amounts indispensable for normal cellular functioning. During pregnancy, a low Se status can increase the risk of oxidative stress. However, elevated concentrations of Se in the body can also cause oxidative stress. This study aimed to compare the effects of BSA-stabilized Se nanoparticles (SeNPs, Se⁰) (BSA-bovine serum albumin) and inorganic sodium selenite (NaSe, Se⁺⁴) supplementation on the histological structure of the placenta, oxidative stress parameters and the total placental Se concentration of Wistar rats during pregnancy. Pregnant females were randomized into four groups: (i) intact controls; (ii) controls that were dosed by daily oral gavage with 8.6% bovine serum albumin (BSA) and 0.125 M vit C; (iii) the SeNP group that was administered 0.5 mg of SeNPs stabilized with 8.6% BSA and 0.125 M vit C/kg bw/day by oral gavage dosing; (iv) the NaSe group, gavage dosed with 0.5 mg Na₂SeO₃/kg bw/day. The treatment of pregnant females started on gestational day one, lasted until day 20, and on day 21 of gestation, the fetuses with the placenta were removed from the uterus. Our findings show that the mode of action of equivalent concentrations of Se in SeNPs and NaSe depended on its redox state and chemical structure. Administration of SeNPs (Se⁰) increased fetal lethality and induced changes in the antioxidative defense parameters in the placenta. The accumulation of Se in the placenta was highest in SeNP-treated animals. All obtained data indicate an increased bioavailability of Se in its organic nano form and Se⁰ redox state in comparison to its inorganic sodium selenite form and Se⁺⁴ redox state. Full article

Oxidative stress is associated with a myriad of diseases including pregnancy pathologies with long-term cardiovascular repercussions for both the mother and baby. Aberrant redox signalling coupled with deficient antioxidant defence leads to chronic molecular impairment. Abnormal placentation has been considered the primary source for reactive species; however, placental dysfunction has been deemed secondary to maternal cardiovascular maladaptation in pregnancy. While various therapeutic interventions, aimed at combating deregulated oxidative stress during pregnancy have shown promise in experimental models, they often result as inconclusive or detrimental in clinical trials, warranting the need for further research to identify candidates. The strengths and limitations of current experimental methods in redox research are discussed. Assessment of redox status and oxidative stress in experimental models and in clinical practice remains challenging; the state-of-the-art of computational models in this field is presented in this review, comparing static and dynamic models which provide functional information such as protein-protein interactions, as well as the impact of changes in molecular species on the redox-status of the system, respectively. Enhanced knowledge of redox biology in during pregnancy through computational modelling such as generation of Systems Biology Markup Language model which integrates existing models to a larger network in the context of placenta physiology. Full article

Despite Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) -induced Oxidative Stress (OxS) being well documented in different organs, the molecular pathways underlying placental OxS in late-pregnancy women with SARS-CoV-2 infection are poorly understood. Herein, we performed an observational study to determine whether placentae of women testing positive for SARS-CoV-2 during the third trimester of pregnancy showed redox-related alterations involving Catalase (CAT) and Superoxide Dismutase (SOD) antioxidant enzymes as well as placenta morphological anomalies relative to a cohort of healthy pregnant women. Next, we evaluated if placental redox-related alterations and mitochondria pathological changes were correlated with the presence of maternal symptoms. We observed ultrastructural alterations of placental mitochondria accompanied by increased levels of oxidative stress markers Thiobarbituric Acid Reactive Substances (TBARS) and Hypoxia Inducible Factor-1 α (HIF-1α) in SARS-CoV-2 women during the third trimester of pregnancy. Importantly, we found an increase in placental CAT and SOD antioxidant enzymes accompanied by physiological neonatal outcomes. Our findings strongly suggest a placenta-mediated OxS inhibition in response to SARS-CoV-2 infection, thus contrasting the cytotoxic profile caused by Coronavirus Disease 2019 (COVID-19). Full article