Oxidative stress (OS), an imbalance between free radical generation and antioxidant defence, is recognized as a key factor in the pathogenesis of adverse pregnancy outcomes. Although OS is a common future of normal pregnancy, persistent, overwhelming OS leads to consumption and decline of antioxidants, affecting placental antioxidant capacity and reducing systems. The accumulation of OS causes damage to lipids, proteins and DNA in the placental tissue that induces a form of accelerated ageing.Premature ageing of the placenta is associated with placental insufficiency that prevents the organ meeting the needs of the foetus, and as a consequence, the viability of the foetus is compromised. This review summarizes the literature regarding the role of OS and premature placental ageing in the pathophysiology of pregnancy complications. K E Y W O R D Sintrauterine growth restriction, oxidative stress, placental ageing, pre-eclampsia, preterm birth, senescence, stillbirth | INTRODUCTIONAll living organisms have limited life cycles, and ageing is part of that life cycle. Each organ within an organism also exhibits ageing-related changes; the placenta is no exception. The placenta, a specialized organ formed during pregnancy, grows throughout gestation, performs multiple functions, including endocrine regulation and nourishment of the foetus, 1 but also ages and is discarded at the end of pregnancy, while the foetus may live for another hundred years. So placental ageing is a normal physiologic phenomenon. 2 However, there are likely to be some placentas which show signs of ageing earlier than others, in the same way as some individuals age more quickly than others. Premature ageing and degenerative changes in the placenta may reduce the functional capacity of the placenta and lead to abnormal pregnancy outcomes. The placenta is the primary organ for transferring nutrients from the mother to the foetus, so growth and function of the placenta are precisely regulated and coordinated to ensure the optimal growth and development of the foetus. The placenta exchanges nutrients, for example oxygen, amino acids, carbohydrates, minerals and waste products, for example carbon dioxide between the maternal and foetal circulatory systems. 3 It releases hormones into both the maternal and foetal circulations to affect uterine function, maternal metabolism, foetal growth and development. Moreover, it metabolizes some substances and can release metabolic products into both foetal and maternal circulations. The placenta can help to protect the foetus against certain xenobiotic molecules, infections and maternal diseases. Therefore, the adequate function of this organ is crucial for a normal physiologic gestational process and a healthy baby as a final outcome.In this review, we focus on the role of OS in the pathophysiology of pregnancy complications, beginning with a brief overview of placental development at different stages of gestation. We then discuss the biochemical markers of ageing and OS-induced placental ageing.Finally, we disc...

The placenta ages as pregnancy advances, yet its continued function is required for a successful pregnancy outcome. Placental aging is a physiological phenomenon; however, there are some placentas that show signs of aging earlier than others. Premature placental senescence and aging are implicated in a number of adverse pregnancy outcomes, including fetal growth restriction, preeclampsia, spontaneous preterm birth, and intrauterine fetal death. Here we discuss cellular senescence, a state of terminal proliferation arrest, and how senescence is regulated. We also explore the role of physiological placental senescence and how aberrant placental senescence alters placental function, contributing to the pathophysiology of fetal growth restriction, preeclampsia, spontaneous preterm labor/birth, and unexplained fetal death.

Our data are consistent with a role for aldehyde oxidase 1 and G-protein-coupled estrogen receptor 1 in mediating aging of the placenta that may contribute to stillbirth. The placenta is a tractable model of aging in human tissue.

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This is an open access article. Unrestricted non-commercial use is permitted provided the original work is properly cited.Aberrant microRNA activity has been reported in many diseases, and studies often find numerous microRNAs concurrently dysregulated. Most target genes have binding sites for multiple microRNAs, and mounting evidence indicates that it is important to consider their combinatorial effect on target gene repression. A recent study associated the coincident loss of expression of six microRNAs with metastatic potential in breast cancer. Here, we used a new computational method, miR-AT!, to investigate combinatorial activity among this group of microRNAs. We found that the set of transcripts having multiple target sites for these microRNAs was significantly enriched with genes involved in cellular processes commonly perturbed in metastatic tumors: cell cycle regulation, cytoskeleton organization, and cell adhesion. Network analysis revealed numerous target genes upstream of cyclin D1 and c-Myc, indicating that the collective loss of the six microRNAs may have a focal effect on these two key regulatory nodes. A number of genes previously implicated in cancer metastasis are among the predicted combinatorial targets, including TGFB1, ARPC3, and RANKL. In summary, our analysis reveals extensive combinatorial interactions that have notable implications for their potential role in breast cancer metastasis and in therapeutic development.

OBJECTIVE: To identify esophageal sensitivity phenotypes relative to acid (S Acid ), bolus (SBolus), acid and bolus (S Acid+Bolus ), and none (S None ) exposures in infants suspected with gastroesophageal reflux disease (GERD). METHODS: Symptomatic infants (N=279) were evaluated for GERD at 42(40–45) weeks postmenstrual age using 24-hour pH-impedance. Symptom associated probability (SAP) for acid and bolus components defined esophageal sensitivity: 1) S Acid as SAP≥95% for acid (pH<4), 2) S Bolus as SAP≥95% for bolus, 3) S Acid+Bolus as SAP≥95% for acid and bolus, or 4) S None as SAP<95% for acid and bolus. RESULTS: Esophageal sensitivity prevalence (S Acid , SBolus, SAcid+Bolus, S None ) was 28(10%), 94(34%), 65(23%), and 92(33%) respectively. Emesis occured more in SBolus and S Acid+Bolus vs S None (p<0.05). Magnitude (#/day) of cough and emesis events increased with S Bolus and S Acid+Bolu s vs S None (p<0.05). S Acid+Bolus had increased acid exposure vs S None (p<0.05). Distributions of feeding and breathing methods were distinct in infants with S Bolus vs S None (both, p<0.05). Multivariate analysis revealed that arching and irritability events/day were lesser at higher PMAs (p<0.001), greater for infants on NCPAP (p<0.01), with S Bolus and S Acid+Bolu s (p<0.05). Coughs/day was greater at higher PMAs (p<0.001), for infants with gavage and transitional feeding methods (p<0.02), with S Bolu s and S Acid+Bolus (p<0.05) but lesser with Trach (p<0.001). Number of emesis events/day were greater with SBolus and SAcid+Bolus (p<0.001). Sneezes/day decreased for infants on Trach (p=0.02). CONCLUSIONS: Feeding and breathing methods can influence the frequency and type of aerodigestive symptoms. We differentiated esophageal sensitivity phenotypes in NICU infants referred for GERD symptoms using pH-Impedance. Acid sensitivity alone was rare, which may explain poor response to acid suppressives; aerodigestive symptoms were predominantly linked with bolus spread. Magnitude of esophageal acid exposure and esophageal sensitivity to bolus spread may explain the pathophysiological basis for symptoms.

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Videofluoroscopy swallow studies (VFSS) and high-resolution manometry (HRM) methods complement to ascertain mechanisms of infant feeding difficulties. We hypothesized that: (a) an integrated approach (study: parent-preferred feeding therapy based on VFSS and HRM) is superior to the standard-of-care (control: provider-prescribed feeding therapy based on VFSS), and (b) motility characteristics are distinct in infants with penetration or aspiration defined as penetration-aspiration scale (PAS) score ≥ 2. Feeding therapies were nipple flow, fluid thickness, or no modification. Clinical outcomes were oral-feeding success (primary), length of hospital stay and growth velocity. Basal and adaptive HRM motility characteristics were analyzed for study infants. Oral feeding success was 85% [76–94%] in study (N = 60) vs. 63% [50–77%] in control (N = 49), p = 0.008. Hospital-stay and growth velocity did not differ between approaches or PAS ≥ 2 (all P > 0.05). In study infants with PAS ≥ 2, motility metrics differed for increased deglutition apnea during interphase (p = 0.02), symptoms with pharyngeal stimulation (p = 0.02) and decreased distal esophageal contractility (p = 0.004) with barium. In conclusion, an integrated approach with parent-preferred therapy based on mechanistic understanding of VFSS and HRM metrics improves oral feeding outcomes despite the evidence of penetration or aspiration. Implementation of new knowledge of physiology of swallowing and airway protection may be contributory to our findings.