A Citrus and Pomegranate Complex Reduces Methylglyoxal in Healthy Elderly Subjects:Secondary Analysis of a Double-Blind Randomized Cross-Over Clinical Trial

Reactive a-dicarbonyls (a-DCs), such as methylglyoxal (MGO), glyoxal (GO), and 3-deoxyglucosone (3-DG), are potent precursors in the formation of advanced glycation end products (AGEs). In particular, MGO and MGO-derived AGEs are thought to be involved in the development of vascular complications in diabetes. Experimental studies showed that citrus and pomegranate polyphenols can scavenge a-DCs. Therefore, the aim of this study was to evaluate the effect of a citrus and pomegranate complex (CPC) on the a-DCs plasma levels in a double-blind, placebo-controlled cross-over trial, where thirty-six elderly subjects were enrolled. They received either 500 mg of Citrus sinensis peel extract and 200 mg of Punica granatum concentrate in CPC capsules or placebo capsules for 4 weeks, with a 4-week washout period in between. For the determination of a-DCs concentrations, liquid chromatography tandem mass spectrometry was used. Following four weeks of CPC supplementation, plasma levels of MGO decreased by 9.8% (-18.7 nmol/L; 95% CI: -36.7, -0.7 nmol/L; p = 0.042). Our findings suggest that CPC supplementation may represent a promising strategy for mitigating the conditions associated with MGO involvement. This study was registered on clinicaltrials.gov as NCT03781999

The direct and sustained consequences of severe placental hypoxia on vascular contractility.

INTRODUCTION:Preeclampsia is a major health problem in human pregnancy, severely complicating 5-8% of all pregnancies. The emerging molecular mechanism is that conditions like hypoxic stress trigger the release of placental messengers into the maternal circulation, which causes preeclampsia. Our objective was to develop an in vitro model, which can be used to further elucidate the molecular mechanisms of preeclampsia and which might be used to find a remedy. METHODS:Human non-complicated term placentas were collected. Placental explants were subjected to severe hypoxia and the conditioned media were added to chorionic arteries that were mounted into a myograph. Contractile responses of the conditioned media were determined, as well as effects on thromboxane-A2 (U46619) induced contractility. To identify the vasoactive compounds present in the conditioned media, specific receptor antagonists were evaluated. RESULTS:Factors released by placental explants generated under severe hypoxia induced an increased vasoconstriction and vascular contractility to thromboxane-A2. It was found that agonists for the angiotensin-I and endothelin-1 receptor released by placental tissue under severe hypoxia provoke vasoconstriction. The dietary antioxidant quercetin could partially prevent the acute and sustained vascular effects in a concentration-dependent manner. DISCUSSION:Both the acute vasoconstriction, as well as the increased contractility to U46619 are in line with the clinical vascular complications observed in preeclampsia. Data obtained with quercetin supports that our model opens avenues for e.g. nutritional interventions aimed at treating or preventing preeclampsia

Histological villous maturation in placentas of complicated pregnancies

Chorioamnionitis and preeclampsia account for the majority of preterm births worldwide. Thus far, adequate methods for early detection or prevention of these diseases are lacking. In preeclampsia, accelerated villous maturation is believed to compensate placental insufficiency. However, little is known about the effects of placental inflammation in chorioamnionitis on villous maturation. Therefore, we established a set of morphological parameters to evaluate histological villous maturity in pregnancies complicated by chorioamnionitis and preeclampsia. Preterm placentas complicated by chorioamnionitis or preeclampsia were compared to idiopathic preterm placentas and term controls. Histological villous maturation was analyzed by means of 17 histological markers. Fourteen of these markers provided information on absolute and relative numbers of the terminal villi (TV), the extent of their vascularization (using CD31-stained sections) and their exchange capacity. In addition, the numbers of syncytial bridges, syncytial apoptotic knots and shed syncytiotrophoblasts were counted. Accelerated villous maturation in preeclampsia was demonstrated by means of histological villous remodeling and confirmed by 11 relevant markers. Chorioamnionitis, however, only showed increased area of fetal capillaries. In preeclampsia, placentas may transition from growth to maturation earlier than placentas in normal pregnancies, whereas in chorioamnionitis placental changes are more acute and therefore less elaborated at a structural level. Regression analysis suggests the number of all villi and the number of terminal villi as a percentage of all villi as parameters to evaluate histological villous maturity in preeclamptic placentas and to assist diagnosis. However, we would recommend to analyze all 11 relevant parameters to judge placental maturity in detail

Hypoxia-induced mitochondrial abnormalities in cells of the placenta.

IntroductionImpaired 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.MethodsWe 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.ResultsBoth 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.DiscussionThis 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