Bioactive compounds of cooked tomato sauce modulate oxidative stress and arachidonic acid cascade induced by oxidized LDL in macrophage cultures

Sofrito is a mix of tomato, onion, garlic, and olive oil, which contains phenolic compounds and carotenoids. Consumption of tomato-based sofrito has been related to a lower risk of cardiovascular events, but the mechanisms behind such beneficial effects remain unclear. This study aimed to analyze the effects of representative sofrito compounds such as naringenin, hydroxytyrosol, lycopene, and β-carotene on mechanisms involved in the pathogenesis of atherosclerosis. We demonstrated that both phenolic compounds and both carotenoids studied were able to inhibit low density lipoproteins (LDL) oxidation, as well as oxidative stress and eicosanoid production induced by oxidized LDL (oxLDL) in macrophage cultures. These effects were not the consequences of disturbing oxLDL uptake by macrophages. Finally, we observed an additive effect of these sofrito compounds, as well as the activity of a main naringenin metabolite, naringenin 7-O-β-d-glucuronide on LDL oxidation and oxidative stress

Polyphenol fraction of extra virgin olive oil protects against endothelial dysfunction induced by high glucose and free fatty acids through modulation of nitric oxide and endothelin-1

Epidemiological and clinical studies have reported that olive oil reduces the incidence of cardiovascular disease. However, the mechanisms involved in this beneficial effect have not been delineated. The endothelium plays an important role in blood pressure regulation through the release of potent vasodilator and vasoconstrictor agents such as nitric oxide (NO) and endothelin-1 (ET-1), respectively, events that are disrupted in type 2 diabetes. Extra virgin olive oil contains polyphenols, compounds that exert a biological action on endothelial function. This study analyzes the effects of olive oil polyphenols on endothelial dysfunction using an in vitro model that simulates the conditions of type 2 diabetes. Our findings show that high glucose and linoleic and oleic acids decrease endothelial NO synthase phosphorylation, and consequently intracellular NO levels, and increase ET-1 synthesis by ECV304 cells. These effects may be related to the stimulation of reactive oxygen species production in these experimental conditions. Hydroxytyrosol and the polyphenol extract from extra virgin olive oil partially reversed the above events. Moreover, we observed that high glucose and free fatty acids reduced NO and increased ET-1 levels induced by acetylcholine through the modulation of intracellular calcium concentrations and endothelial NO synthase phosphorylation, events also reverted by hydroxytyrosol and polyphenol extract. Thus, our results suggest a protective effect of olive oil polyphenols on endothelial dysfunction induced by hyperglycemia and free fatty acids

Dealcoholized beers reduce atherosclerosis and expression of adhesion molecules in apoE-deficient mice

Polyphenols exert beneficial effects in atherosclerosis. The crucial step in atherosclerosis is the recruitment of monocytes to the subendothelial space, induced by endothelial adhesion molecules through the activation of factors such as NF-κB. We studied the effect of a dealcoholised lager beer (DLB) and a dealcoholised dark beer (DDB) on atherosclerotic lesions, and the underlying mechanisms. Dealcoholised beers were administered in the diet (42 ml/kg body weight per d) to 4-week-old male apoE knockout (apoE - / - ) mice for 20 weeks. The atherosclerotic lesions in the thoracic aorta were reduced by 44 % (P = 0·003) and 51 % (P < 0·001) in DLB- and DDB-treated mice, respectively. Also, the mRNA expressions of the endothelial adhesion molecules in the total aorta were decreased: P-selectin showed a 17 % (P = 0·004) reduction in DDB-treated mice; vascular cell adhesion molecule-1 (VCAM-1) was decreased by 20 % (P = 0·012) and 32 % (P = 0·001) in DLB- and DDB-treated mice, respectively; intercellular adhesion molecule-1 (ICAM-1) showed a 14 % (P = 0·014) reduction in DLB-treated mice. The protein expressions of these molecules and NF-κB were studied in the aortic root. P-selectin was decreased by 37 % (P = 0·012) in DDB-treated mice; VCAM-1 was reduced by 48 % (P = 0·001) and 54 % (P < 0·001) in DLB- and DDB-treated mice, respectively; ICAM-1 was decreased by 25 % (P = 0·028) and 30 % (P = 0·018) in DLB- and DDB-treated mice, respectively; NF-κB was reduced by 46 % (P = 0·042) in DDB-treated mice. In conclusion, dealcoholised beers protected apoE - / - mice against atherosclerosis, through the modulation of endothelial adhesion molecules, possibly induced by NF-κB

Hypoxia inducible factor-1α accumulation in steatotic liver preservation: role of nitric oxide

AIM: To examine the relevance of hypoxia inducible factor (HIF-1) and nitric oxide (NO) on the preservation of fatty liver against cold ischemia-reperfusion injury (IRI). METHODS: We used an isolated perfused rat liver model and we evaluated HIF-1α in steatotic and non-steatotic livers preserved for 24 h at 4°C in University of Wisconsin and IGL-1 solutions, and then subjected to 2 h of normothermic reperfusion. After normoxic reperfusion, liver enzymes, bile production, bromosulfophthalein clearance, as well as HIF-1α and NO [endothelial NO synthase (eNOS) activity and nitrites/nitrates] were also measured. Other factors associated with the higher susceptibility of steatotic livers to IRI, such as mitochondrial damage and vascular resistance were evaluated. RESULTS: A significant increase in HIF-1α was found in steatotic and non-steatotic livers preserved in IGL-1 after cold storage. Livers preserved in IGL-1 showed a significant attenuation of liver injury and improvement in liver function parameters. These benefits were enhanced by the addition of trimetazidine (an anti-ischemic drug), which induces NO and eNOS activation, to IGL-1 solution. In normoxic reperfusion, the presence of NO favors HIF-1α accumulation, promoting also the activation of other cytoprotective genes, such as heme-oxygenase-1. CONCLUSION: We found evidence for the role of the HIF-1α/NO system in fatty liver preservation, especially when IGL-1 solution is used

Biliobronchial Fistula after Liver Surgery for Giant Hydatid Cyst

Background. Biliobronchial fistula (BBF) is a rare complication in the natural history of liver hydatid disease by Echinococcus granulosus. We present a case of BBF after resection of a giant liver hydatid cyst in a 72-year-old woman. Case Report. A total cystpericystectomy was done, leaving the left lateral section of the liver that was fixed to the diaphragm. Postoperatively, the patient developed obstructive jaundice. An ERCP showed an obstruction at the junction of the left biliary duct and the main biliary duct and contrast leak. At reoperation, the main duct was ischemic, likely due to torsion along its longitudinal axis. A hepatotomy was done at the hilar plate, and the biliary duct was dissected and anastomosed to a Roux-en-Y jejunal loop. She was discharged without complications. Five months later, the patient developed cholangitis and was successfully treated with antibiotics. However, she suffered repeated respiratory infections, and four months later she was admitted to the hospital with fever, cough, bilioptysis, and right lower lobe pneumonia. The diagnosis of BBF was confirmed with 99mTc Mebrofenin scintigraphy. At transhepatic cholangiography, bile duct dilation was seen, with a biliothoracic leak. She underwent dilatation of cholangiojejunostomy stricture with placement of an external-internal catheter. The catheter was removed 3.5 months later, and two years later the patient remains in very good condition. Conclusion. An indirect treatment of the BBF by percutaneous transhepatic dilation of the biliary stenosis avoided a more invasive treatment, with satisfactory outcome

Primary prevention of cardiovascular disease with a Mediterranean diet supplemented with extra-virgin olive oil or nuts

BACKGROUND: Observational cohort studies and a secondary prevention trial have shown inverse associations between adherence to the Mediterranean diet and cardiovascular risk. METHODS: In a multicenter trial in Spain, we assigned 7447 participants (55 to 80 years of age, 57% women) who were at high cardiovascular risk, but with no cardiovascular disease at enrollment, to one of three diets: a Mediterranean diet supplemented with extra-virgin olive oil, a Mediterranean diet supplemented with mixed nuts, or a control diet (advice to reduce dietary fat). Participants received quarterly educational sessions and, depending on group assignment, free provision of extra-virgin olive oil, mixed nuts, or small nonfood gifts. The primary end point was a major cardiovascular event (myocardial infarction, stroke, or death from cardiovascular causes). After a median follow-up of 4.8 years, the trial was stopped on the basis of a prespecified interim analysis. In 2013, we reported the results for the primary end point in the Journal. We subsequently identified protocol deviations, including enrollment of household members without randomization, assignment to a study group without randomization of some participants at 1 of 11 study sites, and apparent inconsistent use of randomization tables at another site. We have withdrawn our previously published report and now report revised effect estimates based on analyses that do not rely exclusively on the assumption that all the participants were randomly assigned. RESULTS: A primary end-point event occurred in 288 participants; there were 96 events in the group assigned to a Mediterranean diet with extra-virgin olive oil (3.8%), 83 in the group assigned to a Mediterranean diet with nuts (3.4%), and 109 in the control group (4.4%). In the intention-to-treat analysis including all the participants and adjusting for baseline characteristics and propensity scores, the hazard ratio was 0.69 (95% confidence interval [CI], 0.53 to 0.91) for a Mediterranean diet with extra-virgin olive oil and 0.72 (95% CI, 0.54 to 0.95) for a Mediterranean diet with nuts, as compared with the control diet. Results were similar after the omission of 1588 participants whose study-group assignments were known or suspected to have departed from the protocol. CONCLUSIONS: In this study involving persons at high cardiovascular risk, the incidence of major cardiovascular events was lower among those assigned to a Mediterranean diet supplemented with extra-virgin olive oil or nuts than among those assigned to a reduced-fat diet. (Funded by Instituto de Salud Carlos III, Spanish Ministry of Health, and others; Current Controlled Trials number, ISRCTN35739639 .)

Prevalence of major depression in preschool children

The prevalence of preschool major depressive disorder (MDD) was studied in the community. The whole population of children between 3 and 6 years attending preschool nurseries in three areas (one urban, one rural and one suburban) in Spain (n = 1,427) were contacted. Selection was by a two-stage procedure. At stage I, the ESDM 3-6, a screening measure for preschool depression, was used to identify a sample for more intensive interviewing. Sensitivity and specificity of the cut-off point of the ESDM 3–6 had been previously tested in a pilot study (n = 229). During the first stage, 222 preschool children (15.6%) were found to be probable depressives, because they scored 27 or more, the cut-off used. At stage II, the children were interviewed and diagnosed by the consensus of two clinicians, blind to the ESDM 3-6 results. DSM-IV diagnostic criteria were used to define caseness. A total of 16 children (1.12%) met the MDD criteria. The prevalence by areas was urban 0.87%, rural 0.88%, suburban 1.43%. Sex distribution prevalence was 1:1. This study is a contribution to the scarce epidemiology of preschool depression in the community

The HOXB4 Homeoprotein Promotes the Ex Vivo Enrichment of Functional Human Embryonic Stem Cell-Derived NK Cells

Human embryonic stem cells (hESCs) can be induced to differentiate into blood cells using either co-culture with stromal cells or following human embryoid bodies (hEBs) formation. It is now well established that the HOXB4 homeoprotein promotes the expansion of human adult hematopoietic stem cells (HSCs) but also myeloid and lymphoid progenitors. However, the role of HOXB4 in the development of hematopoietic cells from hESCs and particularly in the generation of hESC-derived NK-progenitor cells remains elusive. Based on the ability of HOXB4 to passively enter hematopoietic cells in a system that comprises a co-culture with the MS-5/SP-HOXB4 stromal cells, we provide evidence that HOXB4 delivery promotes the enrichment of hEB-derived precursors that could differentiate into fully mature and functional NK. These hEB-derived NK cells enriched by HOXB4 were characterized according to their CMH class I receptor expression, their cytotoxic arsenal, their expression of IFNγ and CD107a after stimulation and their lytic activity. Furthermore our study provides new insights into the gene expression profile of hEB-derived cells exposed to HOXB4 and shows the emergence of CD34+CD45RA+ precursors from hEBs indicating the lymphoid specification of hESC-derived hematopoietic precursors. Altogether, our results outline the effects of HOXB4 in combination with stromal cells in the development of NK cells from hESCs and suggest the potential use of HOXB4 protein for NK-cell enrichment from pluripotent stem cells

The endothelium, a key actor in organ development and hPSC-derived organoid vascularization

International audienceAbstract Over the last 4 decades, cell culture techniques have evolved towards the creation of in vitro multicellular entities that incorporate the three-dimensional complexity of in vivo tissues and organs. As a result, stem cells and adult progenitor cells have been used to derive self-organized 3D cell aggregates that mimic the morphological and functional traits of organs in vitro. These so-called organoids were first generated from primary animal and human tissues, then human pluripotent stem cells (hPSCs) arose as a new tool for organoid generation. Due to their self-renewal capacity and differentiation potential, hPSCs are an unlimited source of cells used for organoids. Today, hPSC-derived small intestinal, kidney, brain, liver, and pancreas organoids, among others, have been produced and are promising in vitro human models for diverse applications, including fundamental research, drug development and regenerative medicine. However, achieving in vivo-like organ complexity and maturation in vitro remains a challenge. Current hPSC-derived organoids are often limited in size and developmental state, resembling embryonic or fetal organs rather than adult organs. The use of endothelial cells to vascularize hPSC-derived organoids may represent a key to ensuring oxygen and nutrient distribution in large organoids, thus contributing to the maturation of adult-like organoids through paracrine signaling. Here, we review the current state of the art regarding vascularized hPSC-derived organoids (vhPSC-Orgs). We analyze the progress achieved in the generation of organoids derived from the three primary germ layers (endoderm, mesoderm and ectoderm) exemplified by the pancreas, liver, kidneys and brain. Special attention will be given to the role of the endothelium in the organogenesis of the aforementioned organs, the sources of endothelial cells employed in vhPSC-Org protocols and the remaining challenges preventing the creation of ex vivo functional and vascularized organs