Asperulosidic Acid, a Bioactive Iridoid, Alleviates Placental Oxidative Stress and Inflammatory Responses in Gestational Diabetes Mellitus by Suppressing NF-κB and MAPK Signaling Pathways

<b><i>Background:</i></b> Asperulosidic acid (ASP) is a bioactive iridoid exerting broad pharmacological and medicinal properties. However, it is still unknown if ASP has therapeutical effects on gestational diabetes mellitus (GDM). This study aims to evaluate the effects of ASP on GDM as well as its underlying mechanism. <b><i>Methods:</i></b> A mouse model of GDM was established and orally administrated ASP (10, 20, and 40 mg/kg) on gestation day (GD) 0. The mice were sacrificed on GD 18. <b><i>Results:</i></b> Blood glucose and serum insulin were then determined. The inflammatory cytokines including IL-6 and TNF-α and oxidative stress biomarkers including MDA, SOD, GSH, and GPx were determined by using specific ELISAs. In addition, the expressions of NF-κB and MAPK signaling pathway-related proteins were determined by using Western blotting. Treatment with ASP decreased blood glucose in the mouse model of GDM. Besides, ASP also increased serum insulin and attenuated β-cell function. Treatment with ASP suppressed IL-6 and TNF-α and regulated oxidative stress-related biomarkers. Western blotting analysis showed that treatment with ASP suppressed phosphorylation of NF-κB p65, ERK1/2, and p38 in placental tissues. <b><i>Conclusion:</i></b> ASP alleviates placental oxidative stress and inflammatory responses in GDM by the inhibition of the NF-κB and MAPK signaling pathways.

The Impact of Oxidative Stress of Environmental Origin on the Onset of Placental Diseases

Oxidative stress (OS) plays a pivotal role in placental development; however, abnormal loads in oxidative stress molecules may overwhelm the placental defense mechanisms and cause pathological situations. The environment in which the mother evolves triggers an exposure of the placental tissue to chemical, physical, and biological agents of OS, with potential pathological consequences. Here we shortly review the physiological and developmental functions of OS in the placenta, and present a series of environmental pollutants inducing placental oxidative stress, for which some insights regarding the underlying mechanisms have been proposed, leading to a recapitulation of the noxious effects of OS of environmental origin upon the human placenta.

Maternal Obesity Increases Oxidative Stress in Placenta and It Is Associated With Intestinal Microbiota

Maternal obesity induces placental dysfunction and intestinal microbial dysbiosis. However, the associations between intestinal microbiota and placental dysfunction are still unclear. In the present study, a gilt model was used to investigate the role of maternal obesity on placental oxidative stress, mitochondrial function, and fecal microbiota composition, meanwhile identifying microbiota markers associated with placental oxidative stress. Twenty gilts were divided into two groups based on their backfat thickness on parturition day: namely Con group (average backfat thickness = 33 mm), and Obese group (average backfat thickness = 39 mm). The results showed that Obese group was lower than Con group in the birth weight of piglets. Compared with the Con group, the Obesity group exhibited an increased oxidative damage and inflammatory response in placenta, as evidenced by the increased concentrations of placental reactive oxygen species (ROS), protein carboxyl, and interleukin-6 (IL-6). Obesity group was lower than Con group in the concentrations of placental adenosine triphosphate, citrate synthase, and complex I activity. In addition, lower propionate level and Bacteroidetes abundance in feces were seen in the Obese Group. Furthermore, the concentrations of placental ROS, protein carboxyl, and IL-6 were positively correlated with the abundance of Christensenellaceae_R-7_group and negatively correlated with that of norank_f_Bacteroidales_S24-7_group. In conclusion, these findings suggest that maternal obesity might impair oxidative and inflammatory response in placenta through modulating intestinal microbiota composition.

Placental Oxidative Stress in the pathogenesis of Hypertensive Disorders of Pregnancy

Background: Hypertensive disorders of pregnancy are a major complication of pregnancies and can lead to fetal growth retardation, premature delivery and maternal morbidity and mortality. The study aimed at assessing the potential role of the placenta in the pathogenesis of hypertensive disorders of pregnancy. Methods: This study was a case-control study conducted at the Upper East Regional Hospital, Ghana from September, 2016 to March 2017. Twenty (20) pregnant women with hypertensive disorders of pregnancy (i.e., Pregnancy induced hypertension, preeclampsia and eclampsia) as cases and 30 normotensive pregnancies as controls, were included in the study. The placenta was excised after delivery, homogenized and assayed for malondialdehyde, catalase, total peroxide, oxidative stress index, total antioxidant capacity and placental lipid profile. Results: The ages of the two groups were similar, with malondialdehyde (p = 0.001) and Oxidative Stress Index (p < 0.001) being significantly higher in the hypertensive group compared to the control group whereas Total Antioxidant Capacity (p < 0.001) and Catalase (p = 0.011) were significantly higher in the control group compared to the hypertensive group. The proportion of normal, term and livebirth deliveries were significantly higher among controls compared to the hypertensive disorders of pregnancy group. Among the estimated oxidative stress markers, total antioxidant capacity turned out to be the best predictor of the hypertensive disorders of pregnancy. Conclusion: Our findings suggest oxidative stress in women with hypertensive disorders of pregnancy and that placental oxidative stress could be the driving factor for the pathogenesis and severity of these hypertensive disorders of pregnancy.

Hypoxia-induced mitochondrial abnormalities in cells of the placenta

Introduction Impaired utero-placental perfusion is a well-known feature of early preeclampsia and is associated with placental hypoxia and oxidative stress. Although aberrations at the level of the mitochondrion have been implicated in PE pathophysiology, whether or not hypoxia-induced mitochondrial abnormalities contribute to placental oxidative stress is unknown. Methods We explored whether abnormalities in mitochondrial metabolism contribute to hypoxia-induced placental oxidative stress by using both healthy term placentae as well as a trophoblast cell line (BeWo cells) exposed to hypoxia. Furthermore, we explored the therapeutic potential of the antioxidants MitoQ and quercetin in preventing hypoxia-induced placental oxidative stress. Results Both in placental explants as well as BeWo cells, hypoxia resulted in reductions in mitochondrial content, decreased abundance of key molecules involved in the electron transport chain and increased expression and activity of glycolytic enzymes. Furthermore, expression levels of key regulators of mitochondrial biogenesis were decreased while the abundance of constituents of the mitophagy, autophagy and mitochondrial fission machinery was increased in response to hypoxia. In addition, placental hypoxia was associated with increased oxidative stress, inflammation, and apoptosis. Moreover, experiments with MitoQ revealed that hypoxia-induced reactive oxygen species originated from the mitochondria in the trophoblasts. Discussion This study is the first to demonstrate that placental hypoxia is associated with mitochondrial-generated reactive oxygen species and significant alterations in the molecular pathways controlling mitochondrial content and function. Furthermore, our data indicate that targeting mitochondrial oxidative stress may have therapeutic benefit in the management of pathologies related to placental hypoxia.

Astragaloside IV alleviates placental oxidative stress and inflammation in GDM mice

Background: Our previous study revealed that astragaloside IV (AS-IV) effectively improved gestational diabetes mellitus (GDM) by reducing hepatic gluconeogenesis. Due to the importance of placental oxidative stress, we further explored the protective role of AS-IV on placental oxidative stress in GDM. Methods: First, non-pregnant mice were orally administrated with AS-IV to evaluate its safety and effect. Then GDM mice were orally administered with AS-IV for 20 days and its effect on the symptoms of GDM, placental oxidative stress, secretions of inflammatory cytokines, as well as toll-like receptor 4 (TLR4)/NF-κB signaling pathway, were evaluated. Results: AS-IV had no adverse effect on non-pregnant mice. On the other hand, AS-IV significantly attenuated the GDM-induced hyperglycemia, glucose intolerance, insulin resistance, placental oxidative stress, productions of inflammatory cytokines and the activation of TLR4/NF-κB pathway. Conclusion: AS-IV effectively protected against GDM by alleviating placental oxidative stress and inflammation, in which TLR4/NF-κB might be involved.