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Preeclampsia (PE) is a pregnancy-specific syndrome with multisystem involvement which leads to fetal, neonatal, and maternal morbidity and mortality. A model of salt-loaded pregnant rats has been previously studied, sharing several pathological characteristics of preeclamptic women. In this study, it was compared the effects of the treatment with an oral magnesium salt, magnesium gluconate (Mg-gluconate), on the osmotic fragility of red blood cells, lipid peroxidation, and PMCA activity of placental homogenates and red blood cell ghosts in salt-loaded pregnant rats. Mg-gluconate has a higher antioxidant capacity than MgSO

Preeclampsia is a pregnancy-specific syndrome with multisystem involvement which leads to foetal, neonatal, and maternal morbidity and mortality. This syndrome is characterized by the onset of clinical signs and symptoms and delivery before (early-onset preeclampsia, eoPE), or after (late-onset preeclampsia, loPE), the 34 weeks of gestation. Preeclampsia is a mitochondrial disorder where its differential involvement in eoPE and loPE is unclear. Mitochondria regulate cell metabolism and are a significant source of reactive oxygen species (ROS). The syncytiotrophoblast in eoPE and loPE show altered mitochondrial structure and function resulting in ROS overproduction, oxidative stress, and cell damage and death. Mitochondrial dysfunction in eoPE may result from altered expression of several molecules, including dynamin-related protein 1 and mitofusins, compared with loPE where these factors are either reduced or unaltered. Equally, mitochondrial fusion/fission dynamics seem differentially modulated in eoPE and loPE. It is unclear whether the electron transport chain and oxidative phosphorylation are differentially altered in these two subgroups of preeclampsia. However, the activity of complex IV (cytochrome c oxidase) and the expression of essential proteins involved in the electron transport chain are reduced, leading to lower oxidative phosphorylation and mitochondrial respiration in the preeclamptic placenta. Interventional studies in patients with preeclampsia using the coenzyme Q10, a key molecule in the electron transport chain, suggest that agents that increase the antioxidative capacity of the placenta may be protective against preeclampsia development. In this review, the mitochondrial dysfunction in both eoPE and loPE is summarized. Therapeutic approaches are discussed in the context of contributing to the understanding of mitochondrial dysfunction in eoPE and loPE.

Intercellular communication is a critical process in biological mechanisms. During pregnancy foetoplacental tissues release a heterogeneous group of extracellular vesicles (EVs) that include exosomes, microvesicles, apoptotic bodies, and syncytial nuclear aggregates. These vesicles contain a complex cargo (proteins, DNA, mRNA transcripts, microRNAs, noncoding RNA, lipids, and other molecules) that actively participate in the maternal-foetal communication by modulating different processes during gestation for a successful foetal development. Each stage of human gestation is marked by events such as immunomodulation, proliferation, invasion, migration, and differentiation, among others, requiring EVs-mediated signalling to be nearby or distant target cells. Furthermore, EVs also associate with pregnancy pathologies such as preeclampsia and intrauterine growth restriction. This review addresses the role of EVs in human foetomaternal communication in normal pregnancy and preeclampsia.

The role of oxidative stress in the physiopathology of human pregnancy is of particular interest. Pregnancy is well-known to increase the oxidative stress, mainly produced by a normal systemic inflammatory response, which results in high amounts of circulating reactive oxygen species (ROS) and reactive nitrogen species (RNS). Both ROS and RNS play an important role as secondary messengers in many intracellular signalling cascades. However, they can also exert critical effects on pathological processes involving the pregnant woman. ROS, RNS and antioxidants establish a balance that determines the oxidation status of animals and humans. This review focuses on the mechanism of oxidative stress in pregnancy as well as its involvement and consequences on the human pregnancy-specific clinical syndrome preeclampsia. Organización Mundial de la Salud H9/181/R427 Fondo Nacional de Ciencia Tecnología e Innovación (FONACIT) F-2005000222 Agencia Española de Cooperación Internacional para el Desarrollo (AECID) C/024225/09, D/031187/10, A1/036123/11 Junta de Andalucía CTS-584 Fondo Nacional de Desarrollo Científico y Tecnológico (FONDECYT) 1150377, 11150083

Preeclampsia is a syndrome characterised by vascular dysfunction, impaired angiogenesis, and hypertension during pregnancy. Even when the precise pathophysiology of preeclampsia remains elusive, impaired vascular remodelling and placental angiogenesis in the placental villi and defective trophoblast invasion of the uterus are proposed as crucial mechanisms in this syndrome. Reduced trophoblast invasion leads to reduced uteroplacental blood flow and oxygen availability and increased oxidative stress. These phenomena trigger the release of soluble factors into the maternal and foetoplacental circulation that are responsible of the clinical features of preeclampsia. New blood vessels generation as well as vascular remodelling are mechanisms that require expression and activity of different proteases, including matrix metalloproteases, a-disintegrin and metalloproteases, and a-disintegrin and metalloprotease with thrombospondin motifs. These proteases exert proteolysis of the extracellular matrix. Additionally, cathepsins, a family of proteolytic enzymes, are primarily located in lysosomes but are also released by cells to the extracellular space. This review focuses on the role that these proteases play in the regulation of the uterine trophoblast invasion and the placental vascular remodelling associated with preeclampsia.

Preeclampsia is a heterogeneous pregnancy-specific syndrome associated with abnormal trophoblast invasion and endothelial dysfunction. Magnesium (Mg2+) level may be normal or decreased in women with preeclampsia. However, the use of Mg2+ salts, such as Mg2+ sulphate, are useful in reducing the pathophysiological consequences of preeclampsia with severe features and eclampsia. Although the mechanism of action of this Mg2+ salt is not well understood, the available evidence suggests a beneficial effect of Mg2+ for the mother and foetus. The mechanisms include a lower level of soluble fms-like tyrosine kinase 1 and endoglin, blockage of brain N-methyl-D-aspartate receptors, decreased inflammation mediators, activation of nitric oxide synthases, blockage of arginases, and reduced free radicals level. The maintenance of Mg2+ homeostasis in pregnancy is crucial for an appropriate pregnancy progression. Oral Mg2+ salts can be used for this purpose which could result in mitigating the deleterious consequences of this syndrome to the mother, foetus, and newborn.

Objective: To evaluate the osmotic fragility of red blood cells and the level of lipid peroxidation, the Ca2+-ATPase activity of red cell ghosts and placental homogenates from salt-loaded pregnant rats.Methods: Salt-loaded pregnant rats received 1.8% NaCl solution ad libitum as a beverage for seven days, starting on 15th day of pregnancy. Then, it was evaluated the level of lipid peroxidation and the Ca2+-ATPase activity of placental homogenates and red blood cell ghosts from control and experimental rats. Furthermore, the osmotic fragility of the red blood cells was evaluated by measuring the lysis of these cells when incubated with a NaCl solution with different osmolarities.Results: It was found that placental homogenates and red blood cell ghosts from experimental pregnant rats showed an increased level of lipid peroxidation and a lowered Ca2+-ATPase activity, as compared to control pregnant rats. They also presented an increased osmotic fragility of their red blood cells.Conclusions: Salt-loa...

Insulin resistance is characteristic of pregnancies where the mother shows metabolic alterations, such as preeclampsia (PE) and gestational diabetes mellitus (GDM), or abnormal maternal conditions such as pregestational maternal obesity (PGMO). Insulin signalling includes activation of insulin receptor substrates 1 and 2 (IRS1/2) as well as Src homology 2 domain-containing transforming protein 1, leading to activation of 44 and 42 kDa mitogen-activated protein kinases and protein kinase B/Akt (Akt) signalling cascades in the human foetoplacental vasculature. PE, GDM, and PGMO are abnormal conditions coursing with reduced insulin signalling, but the possibility of the involvement of similar cell signalling mechanisms is not addressed. This review aimed to determine whether reduced insulin signalling in PE, GDM, and PGMO shares a common mechanism in the human foetoplacental vasculature. Insulin resistance in these pathological conditions results from reduced Akt activation mainly due to inhibition of IRS1/2, likely due to the increased activity of the mammalian target of rapamycin (mTOR) resulting from lower activity of adenosine monophosphate kinase. Thus, a defective signalling via Akt/mTOR in response to insulin is a central and common mechanism of insulin resistance in these diseases of pregnancy. In this review, we summarise the cell signalling mechanisms behind the insulin resistance state in PE, GDM, and PGMO focused in the Akt/mTOR signalling pathway in the human foetoplacental endothelium. Unión Europea Framework Grant Agreement no. 295185–EULAMDIMA

Objective: The aim of this study is to evaluate the effect of preeclampsia on the level of lipid peroxidation, activity and expression of both plasma membrane Ca2+- and Na+, K+-ATPases in syncytiotrophoblast. Methods: The level of lipid peroxidation was estimated by measuring TBARS. ATPase activities were quantified by a colorimetric method measuring the amount of inorganic phosphate during the assay. Expression of Ca2+- and Na+, K+-ATPases in syncytiotrophoblast plasma membranes and term placenta tissue sections was investigated using Western blot and immunohistochemistry, respectively. Results: Our results show a higher level of lipid peroxidation of syncytiotrophoblast plasma membranes from preeclamptic, as compared to uncomplicated pregnant women. Preeclampsia also significantly reduced the activity of Ca2+- and Na+, K+-ATPases; however, expression of both ATPases was unaffected. Conclusion: Our findings suggest that the reduction of Ca2+- and Na+, K+-ATPase activities during preeclampsia could be at ...

Exosomes associate with immune tolerance and regulation of glucose concentration and oxygen tension in normal pregnancies. Late onset preeclampsia (LOPE) results in lower endothelial nitric oxide synthase (eNOS) activity at the foetoplacental circulation

Adenosine has broad activities in organisms due to the existence of multiple receptors, the differential adenosine concentrations necessary to activate these receptors and the presence of proteins able to synthetize, degrade or transport this nucleoside. All adenosine receptors have been reported to be involved in glucose homeostasis, inflammation, adipogenesis, insulin resistance, and thermogenesis, indicating that adenosine could participate in the process of obesity. Since adenosine seems to be associated with several effects, it is plausible that adenosine participates in the initiation and development of obesity or may function to prevent it. Thus, the purpose of this review was to explore the involvement of adenosine in adipogenesis, insulin resistance and thermogenesis, with the aim of understanding how adenosine could be used to avoid, treat or improve the metabolic state of obesity. Treatment with specific agonists and/or antagonists of adenosine receptors could reverse the obesity state, since adenosine receptors normalizes several mechanisms involved in obesity, such as lipolysis, insulin sensitivity and thermogenesis. Furthermore, obesity is a preventable state, and the specific activation of adenosine receptors could aid in the prevention of obesity. Nevertheless, for the treatment of obesity and its consequences, more studies and therapeutic strategies in addition to adenosine are necessary.

Adenosine is an endogenous nucleoside with pleiotropic effects in different physiological processes including circulation, renal blood flow, immune function, or glucose homeostasis. Changes in adenosine membrane transporters, adenosine receptors, and corresponding intracellular signalling network associate with development of pathologies of pregnancy, including preeclampsia. Preeclampsia is a cause of maternal and perinatal morbidity and mortality affecting 3-5% of pregnancies. Since the proposed mechanisms of preeclampsia development include adenosine-dependent biological effects, adenosine membrane transporters and receptors, and the associated signalling mechanisms might play a role in the pathophysiology of preeclampsia. Preeclampsia associates with increased adenosine concentration in the maternal blood and placental tissue, likely due to local hypoxia and ischemia (although not directly demonstrated), microthrombosis, increased catecholamine release, and platelet activation. In addition, abnormal expression and function of equilibrative nucleoside transporters is described in foetoplacental tissues from preeclampsia; however, the role of adenosine receptors in the aetiology of this disease is not well understood. Adenosine receptors activation may be related to abnormal trophoblast invasion, angiogenesis, and ischemia/reperfusion mechanisms in the placenta from preeclampsia. These mechanisms may explain only a low fraction of the associated abnormal transformation of spiral arteries in preeclampsia, triggering cellular stress and inflammatory mediators release from the placenta to the maternal circulation. Although increased adenosine concentration in preeclampsia may be a compensatory or adaptive mechanism favouring placental angiogenesis, a poor angiogenic state is found in preeclampsia. Thus, preeclampsia-associated complications might affect the cell response to adenosine due to altered expression and activity of adenosine receptors, membrane transporters, or cell signalling mechanisms. This review summarizes the evidence available on the potential involvement of the adenosine in the clinical, pathophysiology, and therapeutic features of preeclampsia.

Nitric oxide plays several roles in cellular physiology, including control of the vascular tone and defence against pathogen infection. Neuronal, inducible and endothelial nitric oxide synthase (NOS) isoforms synthesize nitric oxide. Cells generate acid and base equivalents, whose physiological intracellular concentrations are kept due to membrane transport systems, including Na+/H+ exchangers and Na+/HCO3 − transporters, thus maintaining a physiological pH at the intracellular (~7.0) and extracellular (~7.4) medium. In several pathologies, including cancer, cells are exposed to an extracellular acidic microenvironment, and the role for these membrane transport mechanisms in this phenomenon is likely. As altered NOS expression and activity is seen in cancer cells and because this gas promotes a glycolytic phenotype leading to extracellular acidosis in gynaecological cancer cells, a pro-inflammatory microenvironment increasing inducible NOS expression in this cell type is feasible. However, whether abnormal control of intracellular and extracellular pH by cancer cells regards with their ability to synthesize or respond to nitric oxide is unknown. We, here, discuss a potential link between pH alterations, pH controlling membrane transport systems and NOS function. We propose a potential association between inducible NOS induction and Na+/H+ exchanger expression and activity in human ovary cancer. A potentiation between nitric oxide generation and the maintenance of a low extracellular pH (i.e. acidic) is proposed to establish a sequence of events in ovarian cancer cells, thus preserving a pro-proliferative acidic tumour extracellular microenvironment. We suggest that pharmacological therapeutic targeting of Na+/H+ exchangers and inducible NOS may have benefits in human epithelial ovarian cancer. Fondo Nacional de Desarrollo Científico y Tecnológico 3140516, 1150377, 1150344, 3160194, 11150083

To evaluate the osmotic fragility of red blood cells and the level of lipid peroxidation, the Ca(2+)-ATPase activity of red cell ghosts and placental homogenates from salt-loaded pregnant rats.Salt-loaded pregnant rats received 1.8% NaCl solution ad libitum as a beverage for seven days, starting on 15th day of pregnancy. Then, it was evaluated the level of lipid peroxidation and the Ca(2+)-ATPase activity of placental homogenates and red blood cell ghosts from control and experimental rats. Furthermore, the osmotic fragility of the red blood cells was evaluated by measuring the lysis of these cells when incubated with a NaCl solution with different osmolarities.It was found that placental homogenates and red blood cell ghosts from experimental pregnant rats showed an increased level of lipid peroxidation and a lowered Ca(2+)-ATPase activity, as compared to control pregnant rats. They also presented an increased osmotic fragility of their red blood cells.Salt-loaded pregnant rats showed, similar to preeclamptic women, an increased level of lipid peroxidation and a lowered Ca(2+)-ATPase activity in placental and red blood cells membranes, as well as an increased osmotic fragility of the red blood cells.

The role of magnesium sulfate as an inhibitor of lipid peroxidation has been poorly understood, although this salt has been intensively used in a wide range of diseases related to lipid peroxidation, for example, preeclampsia. Classical molecular dynamics (MD) simulations of a lipid bilayer in the presence of •OH radicals and MgSO4 were performed to study their effects on membrane properties. Additionally, quantum chemistry (QC) calculations for MgSO4, •OH, MgSO4•OH, [MgSO4(H2O)4], and [MgSO4(H2O)4•OH] were performed to analyze the interactions between •OH…Mg. The MD results showed that the Mg salt is hydrated, forming a contact ion pair (CIP) that is adsorbed on the membrane surface close to phosphate groups. Comparisons of MD calculations for MgO distances indicate good agreement with theoretical QC and experimental studies. MD results also reveal that MgSO4 increases the thickness and the compressibility modulus of the membrane, indicating that it is less compressible. In contrast, DFT calculations show important •OH…MgSO4 interactions in hydrated systems that inhibit the radical action by resonance in the SO4= group (smearing the spin density). These results, together with the reported experimental findings of •OH high mobility in water and fast water exchange in Mg+2, may explain the MgSO4 protective effect against lipid peroxidation on cellular membranes.

Cholesterol traffic from maternal to foetal circulation occurs in placental trophoblast and microvascular endothelial cells (hPMECs). Maternal physiological hypercholesterolemia (MPH) occurs in pregnancy assuring fetal development, but maternal supraphysi

The aim of this study is to evaluate the effect of preeclampsia on the level of lipid peroxidation, activity and expression of both plasma membrane Ca(2+)- and Na(+), K(+)-ATPases in syncytiotrophoblast.The level of lipid peroxidation was estimated by measuring TBARS. ATPase activities were quantified by a colorimetric method measuring the amount of inorganic phosphate during the assay. Expression of Ca(2+)- and Na(+), K(+)-ATPases in syncytiotrophoblast plasma membranes and term placenta tissue sections was investigated using Western blot and immunohistochemistry, respectively.Our results show a higher level of lipid peroxidation of syncytiotrophoblast plasma membranes from preeclamptic, as compared to uncomplicated pregnant women. Preeclampsia also significantly reduced the activity of Ca(2+)- and Na(+), K(+)-ATPases; however, expression of both ATPases was unaffected.Our findings suggest that the reduction of Ca(2+)- and Na(+), K(+)-ATPase activities during preeclampsia could be at least partially due to an increased level of lipid peroxidation of the syncytiotrophoblast plasma membranes.

In the current study the possible relationship between the Ca2+/Mg2+ratio of human syncytiotrophoblast plasma membranes and their lipid peroxidation and Ca2+-ATPase activity was determined. Syncytiotrophoblast plasma membranes of placental explants cultured under hypoxia increased their lipid peroxidation and Ca2+content, diminished their Ca2+-ATPase activity, and kept their Mg2+content unchanged. Membranes preincubated with different concentrations of Ca2+increased their Ca2+content without changes in their Mg2+content. There is a direct relationship between Ca2+content and lipid peroxidation of the membranes, as well as an inverse relationship between their Ca2+content and Ca2+-ATPase activity. On the contrary, preincubation of membranes with different concentrations of Mg2+showed a higher Mg2+content without changing their lipid peroxidation and Ca2+-ATPase activity. Explants cultured under hypoxia in the presence of 4 mM MgSO4showed similar values of lipid peroxidation and Ca2+-ATPase activity of their membranes compared to those of explants cultured under normoxia. Increased Ca2+content of the membranes by interacting with negatively charged phospholipids could result in destabilizing effects of the membrane structure, exposing hydrocarbon chains of fatty acids to the action of free radicals. Mg2+might exert a stabilizing effect of the membranes, avoiding their exposure to free radicals.

Objective: The aim of this study is to summarize the reported evidence on the possible relationship between preeclampsia, placenta, oxidative stress and plasma membrane Ca-ATPase (PMCA) activity, responsible for fine control of intracellular calcium concentration. Methods: Literature search was conducted in MEDLINE/PubMed and several unpublished results from our laboratory were included. Results: Lipid peroxidation in placental and red blood cell plasma membranes during preeclampsia and a concomitant diminution of their PMCA activity are described. Conclusions: Uteroplacental hypoperfusion raises lipid peroxidation by-products in the blood plasma that could alter structure and functionality of the cell membranes of the endothelium and several tissues.

Objective: To evaluate the osmotic fragility and level of lipid peroxidation of red blood cells from pregnant women with severe preeclampsia, treated or not with MgSO4. Methods: Osmotic fragility and lipid peroxidation of red blood cells was evaluated in 11 normotensive pregnant women and eleven pregnant women with severe preeclampsia. Results: MgSO4 therapy, either in vivo or in vitro, leads to a reduction of the osmotic fragility and the level of lipid peroxidation of red blood cells from pregnant women with severe preeclampsia. Conclusions: Interaction of MgSO4 with free radicals, by avoiding an excessive lipid peroxidation of the red blood cell membrane, would protect the membrane structure, avoiding in this way the increase in osmotic fragility.