The Anti-Inflammatory and Antioxidant Properties of Acebuche Oil Exert a Retinoprotective Effect in a Murine Model of High-Tension Glaucoma.

Glaucoma is characterized by cupping of the optic disc, apoptotic degeneration of retinal ganglion cells (RGCs) and their axons, and thinning of the retinal nerve fiber layer, with patchy loss of vision. Elevated intraocular pressure (IOP) is a major risk factor for hypertensive glaucoma and the only modifiable one. There is a need to find novel compounds that counteract other risk factors contributing to RGC degeneration. The oil derived from the wild olive tree (Olea europaea var. sylvestris), also called Acebuche (ACE), shows powerful anti-inflammatory, antioxidant and retinoprotective effects. We evaluated whether ACE oil could counteract glaucoma-related detrimental effects. To this aim, we fed mice either a regular or an ACE oil-enriched diet and then induced IOP elevation through intraocular injection of methylcellulose. An ACE oil-enriched diet suppressed glaucoma-dependent retinal glia reactivity and inflammation. The redox status of the glaucomatous retinas was restored to a control-like situation, and ischemia was alleviated by an ACE oil-enriched diet. Notably, retinal apoptosis was suppressed in the glaucomatous animals fed ACE oil. Furthermore, as shown by electroretinogram analyses, RGC electrophysiological functions were almost completely preserved by the ACE oil-enriched diet. These ameliorative effects were IOP-independent and might depend on ACE oil's peculiar composition. Although additional studies are needed, nutritional supplementation with ACE oil might represent an adjuvant in the management of glaucoma.

Exploring the Potential of Wild Olive (Acebuche) Oil as a Pharm-Food to Prevent Ocular Hypertension and Fibrotic Events in the Retina of Hypertensive Mice.

SCOPE: Our laboratory has previously described the antioxidant and anti-inflammatory potential of a wild olive (acebuche, ACE) oil against hypertension-associated vascular retinopathies. The current study aims to analyze the antifibrotic effect of ACE oil on the retina of hypertensive mice. METHODS AND RESULTS: Mice are rendered hypertensive by administration of NG-nitro-L-arginine-methyl-ester (L-NAME) and simultaneously subjected to dietary supplementation with ACE oil or a reference extra virgin olive oil (EVOO). Intraocular pressure (IOP) is measured by rebound tonometry, and retinal vasculature/layers are analyzed by fundus fluorescein angiography and optical coherence tomography. Different fibrosis-related parameters are analyzed in the retina and choroid of normotensive and hypertensive mice with or without oil supplementation. Besides preventing the alterations found in hypertensive animals, including increased IOP, reduced fluorescein signal, and altered retinal layer thickness, the ACE oil-enriched diet improves collagen metabolism by regulating the expression of major fibrotic process modulators (matrix metalloproteinases, tissue inhibitors of metalloproteinases, connective tissue growth factor, and transforming growth factor beta family). CONCLUSION: Regular consumption of EVOO and ACE oil (with better outcomes in the latter) might help reduce abnormally high IOP values in the context of hypertension-related retinal damage, with significant reduction in the surrounding fibrotic process.

Manipulation of Amino Acid Levels with Artificial Diets Induces a Marked Anticancer Activity in Mice with Renal Cell Carcinoma.

Targeted therapies with antiangiogenic drugs (e.g., sunitinib) and immune checkpoint inhibitors (e.g., anti-PD-1 antibodies) are the standard of care for patients with metastatic renal cell carcinoma. Although these treatments improve patient survival, they are rarely curative. We previously hypothesized that advanced cancers might be treated without drugs by using artificial diets in which the levels of specific amino acids (AAs) are manipulated. In this work, after showing that AA manipulation induces selective anticancer activity in renal cell carcinoma cells in vitro, we screened 18 artificial diets for anticancer activity in a challenging animal model of renal cell carcinoma. The model was established by injecting murine renal cell carcinoma (Renca) cells into the peritoneum of immunocompetent BALB/cAnNRj mice. Mice survival was markedly improved when their normal diet was replaced with our artificial diets. Mice fed a diet lacking six AAs (diet T2) lived longer than mice treated with sunitinib or anti-PD-1 immunotherapy; several animals lived very long or were cured. Controlling the levels of several AAs (e.g., cysteine, methionine, and leucine) and lipids was important for the anticancer activity of the diets. Additional studies are needed to further evaluate the therapeutic potential and mechanism of action of this simple and inexpensive anticancer strategy.

Hypertension secondary to nitric oxide depletion produces oxidative imbalance and inflammatory/fibrotic outcomes in the cornea of C57BL/6 mice

Arterial hypertension (AH) leads to oxidative and inflammatory imbalance that contribute to fibrosis development in many target organs. Here, we aimed to highlight the harmful effects of severe AH in the cornea. Our experimental model was established by administration of NG-nitro-L-arginine-methyl-ester (L-NAME) to C57BL/6 mice, which were monitored weekly for arterial blood pressure and intraocular pressure (IOP). Morphological studies of ocular tissues were accompanied by analyses of reactive oxygen species generation, and localization/expression of NAPDH oxidase isoforms (NOX1, NOX2, NOX4) and inflammatory biomarkers (PPARα, PPARγ, IL-1β, IL-6, IL-10, TNF-α, and COX-2). Masson’s trichrome and Sirius Red staining were used to explore the fibrotic status of the cornea. The expression of collagen isoforms (COL1α1, COL1α2, COL3α1, COL4α1, COL4α2) and relevant metalloproteinases (MMPs) and their tissue inhibitors (TIMPs) were also quantified to evaluate the participation of collagen metabolism in AH-related corneal damage. Hypertensive animals showed an increase in IOP values, and a thinner cornea compared with normotensive controls. Moreover, AH increased NADPH oxidase activity and reactive oxygen species generation in the cornea, which was accompanied by transcriptional upregulation of NOX isoforms and inflammatory biomarkers, while reducing PPAR expression. L-NAME-treated animals also developed corneal fibrosis with overexpression of collagen isoforms and reduction of factors responsible for collagen degradation. This is the first study reporting structural changes in the cornea and elevated IOP in L-NAME-treated mice. Overexpression of the NADPH oxidase system and collagen deposition might play a substantial role in the pathogenic mechanisms contributing to ocular disturbances in a context of severe hypertension. (AU)

Oxidative and Inflammatory Imbalance in Placenta and Kidney of sFlt1-Induced Early-Onset Preeclampsia Rat Model.

Preeclampsia (PE) is a pregnancy-specific disorder characterized by the new onset of hypertension plus proteinuria and/or end-organ dysfunction. Here, we investigate the role of the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase system as a major component of reactive oxygen species generation, in a rodent model of early-onset preeclampsia induced by excess sFlt1 (soluble fms-like tyrosine kinase 1). Placenta and kidney samples were obtained from normal pregnant and PE rats to measure the sFlt1/PlGF (placental growth factor) ratio in addition to oxidative stress-related parameters, including the activities and expressions of NADPH oxidase isoforms (NOX1, NOX2, and NOX4), components of nitric oxide (NO) metabolism, and antioxidant enzymes. Peroxisome proliferator-activated receptors (PPARα, PPARγ) and cytokines IL1ß, IL3, IL6, IL10, and IL18 were also measured to evaluate the inflammation status in our experimental setting. Excessive O2●- production was found in rats that were treated with sFlt1; interestingly, this alteration appears to be mediated mainly by NOX2 in the placenta and by NOX4 in the kidney. Altered NO metabolism and antioxidant defense systems, together with mitochondrial dysfunction, were observed in this model of PE. Preeclamptic animals also exhibited overexpression of proinflammatory biomarkers as well as increased collagen deposition. Our results highlight the role of NADPH oxidase in mediating oxidative stress and possibly inflammatory processes in the placenta and kidney of an sFlt1-based model of early-onset preeclampsia.

Hypertension secondary to nitric oxide depletion produces oxidative imbalance and inflammatory/fibrotic outcomes in the cornea of C57BL/6 mice.

Arterial hypertension (AH) leads to oxidative and inflammatory imbalance that contribute to fibrosis development in many target organs. Here, we aimed to highlight the harmful effects of severe AH in the cornea. Our experimental model was established by administration of NG-nitro-L-arginine-methyl-ester (L-NAME) to C57BL/6 mice, which were monitored weekly for arterial blood pressure and intraocular pressure (IOP). Morphological studies of ocular tissues were accompanied by analyses of reactive oxygen species generation, and localization/expression of NAPDH oxidase isoforms (NOX1, NOX2, NOX4) and inflammatory biomarkers (PPARα, PPARγ, IL-1ß, IL-6, IL-10, TNF-α, and COX-2). Masson's trichrome and Sirius Red staining were used to explore the fibrotic status of the cornea. The expression of collagen isoforms (COL1α1, COL1α2, COL3α1, COL4α1, COL4α2) and relevant metalloproteinases (MMPs) and their tissue inhibitors (TIMPs) were also quantified to evaluate the participation of collagen metabolism in AH-related corneal damage. Hypertensive animals showed an increase in IOP values, and a thinner cornea compared with normotensive controls. Moreover, AH increased NADPH oxidase activity and reactive oxygen species generation in the cornea, which was accompanied by transcriptional upregulation of NOX isoforms and inflammatory biomarkers, while reducing PPAR expression. L-NAME-treated animals also developed corneal fibrosis with overexpression of collagen isoforms and reduction of factors responsible for collagen degradation. This is the first study reporting structural changes in the cornea and elevated IOP in L-NAME-treated mice. Overexpression of the NADPH oxidase system and collagen deposition might play a substantial role in the pathogenic mechanisms contributing to ocular disturbances in a context of severe hypertension.

Daily consumption of wild olive (acebuche) oil reduces blood pressure and ameliorates endothelial dysfunction and vascular remodelling in rats with NG-nitro-L-arginine methyl ester-induced hypertension.

Despite numerous reports on the beneficial effects of olive oil in the cardiovascular context, very little is known about the olive tree's wild counterpart (Olea europaea, L. var. sylvestris), commonly known as acebuche (ACE) in Spain. The aim of this study was to analyse the possible beneficial effects of an extra virgin ACE oil on vascular function in a rodent model of arterial hypertension (AH) induced by NG-nitro-l-arginine methyl ester (L-NAME). Four experimental groups of male Wistar rats were studied: (1) normotensive rats (Control group); (2) normotensive rats fed a commercial diet supplemented with 15 % (w/w) ACE oil (Acebuche group); (3) rats made hypertensive following administration of L-NAME (L-NAME group); and (4) rats treated with L-NAME and simultaneously supplemented with 15 % ACE oil (LN + ACE group). All treatments were maintained for 12 weeks. Besides a significant blood pressure (BP)-lowering effect, the ACE oil-enriched diet counteracted the alterations found in aortas from hypertensive rats in terms of morphology and responsiveness to vasoactive mediators. In addition, a decrease in hypertension-related fibrotic and oxidative stress processes was observed in L-NAME-treated rats subjected to ACE oil supplement. Therefore, using a model of AH via nitric oxide depletion, here we demonstrate the beneficial effects of a wild olive oil based upon its vasodilator, antihypertensive, antioxidant, antihypertrophic and antifibrotic properties. We postulate that regular inclusion of ACE oil in the diet can alleviate the vascular remodelling and endothelial dysfunction processes typically found in AH, thus resulting in a significant reduction of BP.

Anti-Inflammatory Action of Dietary Wild Olive (Acebuche) Oil in the Retina of Hypertensive Mice.

Inflammation plays a crucial role in the course of eye diseases, including many vascular retinopathies. Although olive oil is known to have beneficial effects against inflammatory processes, there is no information available on the anti-inflammatory potential of the wild olive tree (namely, acebuche (ACE) for the primitive Spanish lineages). Here we investigate the anti-inflammatory effects of ACE oil in the retina of a mouse model of arterial hypertension, which was experimentally induced by administration of L-NAME (NG-nitro-L-arginine-methyl-ester). The animals were fed supplements of ACE oil or extra virgin olive oil (EVOO, for comparative purposes). Retinal function was assessed by electroretinography (ERG), and different inflammation-related parameters were measured in the retina and choroid. Besides significant prevention of retinal dysfunction shown in ERG recordings, ACE oil-enriched diet upregulated the expression of the anti-inflammatory markers PPARγ, PPARα and IL-10, while reducing that of major proinflammatory biomarkers, IL-1ß, IL-6, TNF-α and COX-2. This is the first report to highlight the anti-inflammatory properties of an ACE oil-enriched diet against hypertension-related retinal damage. Noteworthy, dietary supplementation with ACE oil yielded better results compared to a reference EVOO.

Impact of maternal nutrition in viral infections during pregnancy.

Other than being a physiological process, pregnancy is a condition characterized by major adaptations of maternal endocrine and metabolic homeostasis that are necessary to accommodate the fetoplacental unit. Unfortunately, all these systemic, cellular, and molecular changes in maternal physiology also make the mother and the fetus more prone to adverse outcomes, including numerous alterations arising from viral infections. Common infections during pregnancy that have long been recognized as congenitally and perinatally transmissible to newborns include toxoplasmosis, rubella, cytomegalovirus, and herpes simplex viruses (originally coined as ToRCH infections). In addition, enterovirus, parvovirus B19, hepatitis virus, varicella-zoster virus, human immunodeficiency virus, Zika and Dengue virus, and, more recently, coronavirus infections including Middle Eastern respiratory syndrome (MERS) and severe acute respiratory syndrome (SARS) infections (especially the novel SARS-CoV-2 responsible for the ongoing COVID-19 pandemic), constitute relevant targets for current research on maternal-fetal interactions in viral infections during pregnancy. Appropriate maternal education from preconception to the early postnatal period is crucial to promote healthy pregnancies in general and to prevent and/or reduce the impact of viral infections in particular. Specifically, an adequate lifestyle based on proper nutrition plans and feeding interventions, whenever possible, might be crucial to reduce the risk of virus-related gestational diseases and accompanying complications in later life. Here we aim to provide an overview of the emerging literature addressing the impact of nutrition in the context of potentially harmful viral infections during pregnancy.

NADPH oxidase-induced oxidative stress in the eyes of hypertensive rats.

Purpose: Increased reactive oxygen species (ROS) released by NADPH oxidase and inflammation are associated with arterial hypertension and eye diseases associated with high blood pressure, including glaucoma, retinopathies (e.g., age-related macular degeneration), and choroidopathies affecting ocular function; however, the mechanisms underlying these adverse outcomes remain undefined. The present study was designed to highlight the importance of oxidative stress in severe hypertension-related eye damage. Methods: Male Wistar rats (n = 7, unless otherwise specified for specific experiments) were administered an oral dose of 30 mg of Nω-nitro-L-arginine methyl ester (L-NAME) per kilogram of bodyweight and day for 3 weeks; chronic administration with L-NAME is a validated experimental approach resulting in severe hypertension secondary to nitric oxide (NO) depletion and subsequent vasoconstriction in the systemic circulation. Upon treatment completion, histomorphometric studies, NADPH oxidase activity, and ROS production were measured in eyecup homogenates and paraffin-embedded sections from control and L-NAME-treated animals. In addition, immunohistofluorescence, western blotting, and real-time PCR (RT-qPCR) analyses were performed in the eye and the retina to evaluate the expression of i) NADPH oxidase main isoforms (NOX1, NOX2, and NOX4) and subunits (p22phox and p47phox); ii) glial fibrillary acidic protein (GFAP), as a marker of microglial activation in the retina; iii) antioxidant enzymes; and iv) endothelial constitutive (eNOS) and inflammation inducible (iNOS) nitric oxide synthase isoforms, and nitrotyrosine as a versatile biomarker of oxidative stress. Results: Increased activity of NADPH oxidase and superoxide anion production, accompanied by transcriptional upregulation of this enzyme isoforms, was found in the retina and choroid of the hypertensive rats in comparison with the untreated controls. Histomorphometric analyses revealed a significant reduction in the thickness of the ganglion cell layer and the outer retinal layers in the hypertensive animals, which also showed a positive strong signal of GFAP in the retinal outer segment and plexiform layers. In addition, L-NAME-treated animals presented with upregulation of nitric oxide synthase (including inducible and endothelial isoforms) and abnormally elevated nitrotyrosine levels. Experiments on protein and mRNA expression of antioxidant enzymes revealed depletion of superoxide dismutase and glutathione peroxidase in the eyes of the hypertensive animals; however, glutathione reductase was significantly higher than in the normotensive controls. Conclusions: The present study demonstrated structural changes in the retinas of the L-NAME-treated hypertensive animals and strengthens the importance of NADPH oxidase as a major ROS-generating enzyme system in the oxidative and inflammatory processes surrounding hypertensive eye diseases. These observations might contribute to unveiling pathogenic mechanisms responsible for developing ocular disturbances in the context of severe hypertension.

Echinomycin mitigates ocular angiogenesis by transcriptional inhibition of the hypoxia-inducible factor-1.

BACKGROUND: Echinomycin (EKN), an inhibitor of hypoxia-inducible factor (HIF)-1 DNA-binding activity, has been implied as a possible therapeutic agent in ischemic diseases. Here, we assess EKN in hypoxia-driven responses in vitro using human primary adult retinal pigment epithelium cells (aRPE) and retinal endothelial cells (hREC), and in vivo using the laser-induced mouse choroidal neovascularization (CNV) model. METHODS: Effects of EKN on hypoxia-mediated pathways in aRPE were analyzed by Western blotting for HIF-1α protein, quantitative PCR of HIF-target genes, and proteome array for soluble angiogenic factors. In vitro inhibition of angiogenesis by EKN was determined in hREC. In vivo inhibition of angiogenesis by EKN was determined in the mouse laser-induced CNV, as a model of HIF-associated ocular neovascularization. CNV lesion area was determined by fundus fluorescein angiography. RESULTS: aRPE treated with EKN showed hypoxia-dependent significantly decreased cell recovery in the wound healing assay. These results were supported by lower levels of HIF-mediated transcripts detected in hypoxic aRPE cells treated with EKN compared with non-treated controls, and confirmed by proteome profiler for angiogenic factors. hREC exposed to aRPE EKN-conditioned medium displayed reduced sprouting angiogenesis. Mice with laser-induced CNV treated with intravitreally injected EKN showed significantly decreased vascular lesion area when compared with a mouse equivalent of aflibercept, or vehicle-treated controls. CONCLUSIONS: Our data proposes EKN as a potent inhibitor of HIF-mediated angiogenesis in retinal cells and in the mouse model of CNV, which could have future implications in the treatment of patients with neovascular age-related macular degeneration.

Lifestyle, Maternal Nutrition and Healthy Pregnancy.

Healthy lifestyle habits spanning from preconception to postpartum are considered as a major safeguard for achieving successful pregnancies and for the prevention of gestational diseases. Among preconception priorities established by the World Health Organization (WHO) are healthy diet and nutrition, weight management, physical activity, planned pregnancy and physical, mental and psychosocial health. Most studies covering the topic of healthy pregnancies focus on maternal diet because obesity increases the risks for adverse perinatal outcomes, including gestational diabetes mellitus, large for gestational age newborns, or preeclampsia. Thus, foods rich in vegetables, essential and polyunsaturated fats and fibre-rich carbohydrates should be promoted especially in overweight, obese or diabetic women. An adequate intake of micronutrients (e.g. iron, calcium, folate, vitamin D and carotenoids) is also crucial to support pregnancy and breastfeeding. Moderate physical activity throughout pregnancy improves muscle tone and function, besides decreasing the risk of preeclampsia, gestational diabesity (i.e. diabetes associated with obesity) and postpartum overweight. Intervention studies claim that an average of 30 min of exercise/day contributes to long-term benefits for maternal overall health and wellbeing. Other factors such as microbiome modulation, behavioural strategies (e.g. smoking cessation, anxiety/stress reduction and sleep quality), maternal genetics and age, social class and education might also influence the maternal quality of life. These factors contribute to ensure a healthy pregnancy, or at least to reduce the risk of adverse maternal and foetal outcomes during pregnancy and later in life.

Insulin requires A2B adenosine receptors to modulate the L-arginine/nitric oxide signalling in the human fetoplacental vascular endothelium from late-onset preeclampsia.

Late-onset preeclampsia (LOPE) associates with reduced umbilical vein reactivity and endothelial nitric oxide synthase (eNOS) activity but increased human cationic amino acid (hCAT-1)-mediated L-arginine transport involving A2A adenosine receptor in the fetoplacental unit. This study addresses the A2B adenosine receptor (A2BAR)-mediated response to insulin in the fetoplacental vasculature from LOPE. Umbilical veins and HUVECs were obtained from women with normal (n = 37) or LOPE (n = 35) pregnancies. Umbilical vein rings reactivity to insulin was assayed in the absence or presence of adenosine and MRS-1754 (A2BAR antagonist) in a wire myograph. HUVECs were exposed to insulin, MRS-1754, BAY60-6583 (A2BAR agonist), NECA (general adenosine receptors agonist) or NG-nitro-L-arginine methyl ester (NOS inhibitor). A2BAR, hCAT-1, total and phosphorylated eNOS, Akt and p44/42mapk protein abundance were determined by Western blotting. Insulin receptors A (IR-A) and B (IR-B), eNOS and hCAT-1 mRNA were determined by qPCR. Firefly/Renilla luciferase assay was used to determine -1606 bp SLC7A1 (hCAT-1) promoter activity. L-Citrulline content was measured by HPLC, L-[3H]citrulline formation from L-[3H]arginine by the Citrulline assay, and intracellular cGMP by radioimmunoassay. LOPE-reduced dilation of vein rings to insulin was restored by MRS-1754. HUVECs from LOPE showed higher A2BAR, hCAT-1, and IR-A expression, Akt and p44/42mapk activation, and lower NOS activity. MRS-1754 reversed the LOPE effect on A2BAR, hCAT-1, Akt, and eNOS inhibitory phosphorylation. Insulin reversed the LOPE effect on A2BAR, IR-A and eNOS, but increased hCAT-1-mediated transport. Thus, LOPE alters endothelial function, causing an imbalance in the L-arginine/NO signalling pathway to reduce the umbilical vein dilation to insulin requiring A2BAR activation in HUVECs.

Retinoprotective Effect of Wild Olive (Acebuche) Oil-Enriched Diet against Ocular Oxidative Stress Induced by Arterial Hypertension.

Oxidative stress plays an important role in the pathogenesis of ocular diseases, including hypertensive eye diseases. The beneficial effects of olive oil on cardiovascular diseases might rely on minor constituents. Currently, very little is known about the chemical composition and/or therapeutic effects of the cultivated olive tree's counterpart, wild olive (also known in Spain as acebuche-ACE). Here, we aimed to analyze the antioxidant and retinoprotective effects of ACE oil on the eye of hypertensive mice made hypertensive via administration of NG-nitro-L-arginine-methyl-ester (L-NAME), which were subjected to a dietary supplementation with either ACE oil or extra virgin olive oil (EVOO) for comparison purposes. Deep analyses of major and minor compounds present in both oils was accompanied by blood pressure monitoring, morphometric analyses, as well as different determinations of oxidative stress-related parameters in retinal layers. Aside from its antihypertensive effect, an ACE oil-enriched diet reduced NADPH (nicotinamide adenine dinucleotide phosphate) oxidase activity/gene/protein expression (with a major implication of NADPH oxidase (NOX)2 isoform) in the retinas of hypertensive mice. Supplementation with ACE oil in hypertensive animals also improved alterations in nitric oxide bioavailability and in antioxidant enzyme profile. Interestingly, our findings show that the use of ACE oil resulted in better outcomes, compared with reference EVOO, against hypertension-related oxidative retinal damage.

Mechanism of Vascular Toxicity in Rats Subjected to Treatment with a Tyrosine Kinase Inhibitor.

Sunitinib (Su) is a tyrosine kinase inhibitor with antiangiogenic and antineoplastic effects that is recommended therapy for renal cell carcinoma, gastrointestinal stromal tumors, and pancreatic neuroendocrine tumors. Arterial hypertension is one of the adverse effects observed in the treatment with Su. The aim of this work was to deepen our understanding of the underlying mechanisms involved in the development of this side effect. Studies on endothelial function, vascular remodeling and nicotinamide adenine dinucleotide phosphate oxidase (NADPH oxidase) system were carried out in thoracic aortas from rats treated with Su for three weeks. Animals subjected to Su treatment presented with increased blood pressure and reduced endothelium-dependent vasodilation, the latter being reverted by NADPH oxidase blockade. Furthermore, vascular remodeling and stronger Masson trichrome staining, together with enhanced immunofluorescence signal for collagen 1 alpha 1 (Col1α1), were observed in aortas from treated animals. These results were accompanied by a significant elevation in superoxide anion production and the activity/protein/gene expression of NADPH oxidase isoforms (NOX1, NOX2, and NOX4), which was also prevented by NOX inhibition. Furthermore, a decrease in nitric oxide (NO) levels and endothelial nitric oxide synthase (eNOS) activation was observed in aortas from Su-treated animals. All these results indicate that endothelial dysfunction secondary to changes in vascular remodeling and oxidative stress might be responsible for the typical arterial hypertension that develops following treatment with Su.

Sunitinib-induced oxidative imbalance and retinotoxic effects in rats.

AIMS: Sunitinib (Su), a tyrosine kinase inhibitor, is one of the most commonly used anti-angiogenic drugs. Some studies have described retinal detachment and photoreceptor damage following systemic exposure to Su, despite beneficial effects achieved with local treatment of ocular pathologies. The aim of this study was to explore the role of NADPH oxidase system and oxidative stress in eyes from Su-treated animals. MAIN METHODS: Male Wistar rats were administered 25 mg Su/kg body weight/day incorporated in the chow for 3 weeks. Upon treatment completion, NADPH oxidase activity and ROS levels were measured in ocular tissue by chemiluminescence and dihydroethidium (DHE) staining, respectively. The expression of NADPH oxidase isoforms (NOX1, NOX2 and NOX4), antioxidant enzymes and endothelial/inducible nitric oxidase isoforms (eNOS/iNOS) in the eyecup and/or retina were measured via immunofluorescence, immunoblotting and RT-qPCR. KEY FINDINGS: NADPH oxidase activity/expression increased in eyecup and retinas from Su-treated rats. Immunohistofluorescence studies in retinal layer confirmed a higher signal of NADPH oxidase isoforms after Su treatment. Treated animals also presented with reductions in NO levels and eNOS expression, whereas iNOS was upregulated. Finally, a significant depletion of antioxidant enzyme glutathione peroxidase was measured in eyecups of rats following Su exposure, and the opposite pattern was seen for glutathione reductase and superoxide dismutase. SIGNIFICANCE: This study demonstrates that Su treatment is associated with NADPH oxidase-derived oxidative stress in the eye. Long-term treatment of Su should be properly monitored to avoid retinotoxic effects that might result in ocular pathologies and sight-threatening conditions.

Oxidative stress: Normal pregnancy versus 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.

Insulin Therapy in Pregnancy Hypertensive Diseases and its Effect on the Offspring and Mother Later in Life.

Pregnancy hypertensive disorders such as Preeclampsia (PE) are strongly correlated with insulin resistance, a condition in which the metabolic handling of D-glucose is deficient. In addition, the impact of preeclampsia is enhanced by other insulin-resistant disorders, including polycystic ovary syndrome and obesity. For this reason, there is a clear association between maternal insulin resistance, polycystic ovary syndrome, obesity and the development of PE. However, whether PE is a consequence or the cause of these disorders is still unclear. Insulin therapy is usually recommended to pregnant women with diabetes mellitus when dietary and lifestyle measures have failed. The advantage of insulin therapy for Gestational Diabetes Mellitus (GDM) patients with hypertension is still controversial; surprisingly, there are no studies in which insulin therapy has been used in patients with hypertension in pregnancy without or with an established GDM. This review is focused on the use of insulin therapy in hypertensive disorders in the pregnancy and its effect on offspring and mother later in life. PubMed and relevant medical databases have been screened for literature covering research in the field especially in the last 5-10 years.

Foetoplacental communication via extracellular vesicles in normal pregnancy and preeclampsia.

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.