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We compare the relative efficacy of virtual reality therapy exposure (VRET) versus in vivo therapy exposure among individuals suffering from phobias. A systematic search was completed up to 03 April 2020, using the following databases: ACM Digital Library, ResearchGate, IEEE, Science Direct, MIT PressJournals, Center for Direct Scientific Communication (CCSD) and Mary Ann Liebert Publishers. Five authors searched the databases using the following terms: Virtual Reality, Phobia, Mental health, Computing, Therapy, HMD, CAVE, Virtual ambient, in virtuo, Avoidance, Exposure, VRET, in vivo, Anxiety, Agoraphobia, Social Phobia, Stimuli, Cognitive-behaviour. All studies that evaluate the effect of in virtuo exposure towards phobia rehabilitation were selected. By reviewing the article, each author then applied the inclusion and exclusion criteria, and 30 articles were selected. Data extracted included the number of samples, amount of sessions, study variables that may affect the final outcome, therapy technology. The data provided was synthesized using a meta-analysis based on the results. The results demonstrated a positive outcome of Virtual Reality Exposure Treatment in the treatment of most phobias. In contrast, some of these treatments did not work for a few specific phobias in which the standard procedures were more effective. The findings suggest that for some specific phobias treatment, Virtual Reality Exposure Treatment does not reach the in vivo exposure level of immersion and presence. Further research is needed to perform studies with higher-dimension samples, since many papers report a low sample size and that is probably why many of them have inconclusive results.

Oxidative stress is known to be a key factor in many neurodegenerative diseases. Inflammation also plays a relevant role in a myriad of pathologies such as diabetes and atherosclerosis. Polyphenols coming from dietary sources, such as pterostilbene, may be beneficial in this type of diseases. However, most of them are rapidly metabolized and excreted, yielding very low phenolic bioavailability what makes it difficult to find out which are the mechanisms responsible for the observed bioactivity. Herein, we evaluate the effects of pterostilbene and its metabolites against H2O2-induced cell damage in human neuroblastoma SH-SY5Y cells and against lipopolysaccharide (LPS)-challenged RAW 264.7 macrophages. Among the metabolites tested, 3-methyl-4'-glucuronate-resveratrol (also called 4'-glucuronate pinostilbene, PIN-GlcAc, 11) prevented neuronal death via attenuation of reactive oxygen species (ROS) levels and increased REDOX activity in neurons. This compound is also able to ameliorate LPS-mediated inflammation on macrophages via inhibition of IL-6 and NO production. Thus, polyphenol from dietary sources could be part of potential functional foods designed to ameliorate the onset and progression of certain neurodegenerative diseases via oxidative stress reduction.

Small interfering RNA (siRNA) application in therapy still faces a major challenge with the lack of an efficient and specific delivery system. Current vehicles are often responsible for poor efficacy, safety concerns, and burden costs of siRNA-based therapeutics. Here, we describe a novel strategy for targeted delivery of siRNA molecules to inhibit human immunodeficiency virus (HIV) infection. Specific membrane translocation of siRNA inhibitor was addressed by an engineered nanobody targeting the HIV co-receptor CXCR4 (NbCXCR4) in fusion with a single-chain variable fragment (4M5.3) that carried the FITC-conjugated siRNA. 4M5.3-NbCXCR4 conjugate (4M5.3X4) efficiently targeted CXCR4+ T lymphocytes, specifically translocating siRNA by receptor-mediated endocytosis. Targeted delivery of siRNA directed to the mRNA of HIV transactivator tat silenced Tat-driven viral transcription and inhibited the replication of distinct virus clades. In summary, we have shown that the engineered nanobody chimera developed in this study constitutes an efficient and specific delivery method of siRNAs through CXCR4 receptor.

Epithelial barrier alteration is a central event in the pathogenesis of inflammatory bowel diseases. Lipopolysaccharide, correlated to the pathogenesis of such pathologies, has been demonstrated to cause altered membrane permeability, through the disruption and/or relocation of tight junction proteins, following redox-sensitive mitogen-activated protein kinases (MAPKs) modulation. Pterostilbene and its metabolite pinostilbene are natural stilbenoids which may reach relevant concentrations at intestinal level, together with their glucuronide and sulfate metabolites. The aim of our study was to evaluate the ability of these compounds to inhibit lipopolysaccharide-induced toxic effects on intestinal cell monolayer integrity and to explore the mechanism of action. Caco-2 cells, differentiated as enterocytes, were treated with lipopolysaccharide following pretreatment with the phenolic compounds at 1 μM physiological concentration. Caco-2 monolayer's permeability was monitored with time, measuring the transepithelial electrical resistance. Tight junction proteins were assessed by western blotting and immunofluorescence in lipopolysaccharide-treated cells, in relation to MAPK p38 and ERK1/2 activation. Pretreatment with all the phenolic compounds significantly slowed lipopolysaccharide-induced transepithelial electrical resistance decrease, preserved tight junction proteins levels and reduced MAPKs phosphorylation. The reported findings indicate that pterostilbene and its metabolites may counteract lipopolysaccharide-induced alteration of epithelial permeability, one of the initial events in the intestinal inflammatory process.

Background Benign multicystic mesothelioma is a rare benign tumour derived from the peritoneal mesothelium. The aim of this paper is to present a case of this rare tumour and review the clinical features, diagnosis and treatment of this disease. Clinical case The case is presented of a 22-year-old female diagnosed with multicystic mesothelioma after an urgent resection of intra-abdominal tumour in the context of acute abdominal pain. In the subsequent follow-up, the patient had a recurrence of the lesion, and at 2 years was treated by further resection. Conclusions Benign multicystic mesothelioma is a benign tumour of unknown origin, and with a non-specific clinical manifestation. The most effective treatment is surgical, although there is a high tendency to local recurrence.

22 Páginas; 6 Figuras, Tyrosol (Tyr) is a phenolic compound found in virgin olive oil. After ingestion, Tyr undergoes extensive first pass intestinal/hepatic metabolism. However, knowledge about the biological effects of Tyr metabolites is scarce. We chemically synthesized Tyr glucuronate (Tyr-GLU) and sulphate (Tyr-SUL) metabolites and explored their properties against oxidative stress and inflammation in TNF-α-treated human umbilical vein endothelial cells (hECs). Tyr and Tyr-SUL prevented the rise of reactive oxygen species, the depletion of glutathione, and the down-regulation of glutathione peroxidase 1, glutamate-cysteine ligase catalytic subunit, and heme oxygenase-1 genes. Tyr-SUL and to a lower extent Tyr and Tyr-GLU prevented the phosphorylation of NF-κB signaling proteins. Tyr-GLU and Tyr-SUL also prevented the over-expression of adhesion molecules at gene, protein, and secretory levels, and the adhesion (Tyr-SUL > Tyr-GLU) of human monocytes to hECs. In vivo, Tyr, and most notably Tyr-SUL in a dose-dependent manner, ameliorated plantar and ear edemas in mice models of acute and chronic inflammation. This study demonstrates the antioxidant and/or anti-inflammatory properties of Tyr metabolites, with Tyr-SUL being the most effective., We thank Angela Palma Pacheco for technical assistance. This study and the contracts of RL and APP were supported by the research Grant of the Junta de Andalucia, Spain (P09-CVI-5007). SM had the benefit of a FPI fellowship of the MICINN (BES-2012-056104) and BB of the “V Own Research Plan” of the University of Seville. SL had Juan de la Cierva contract cofunded by the European Social Fund (ESF) from the Spanish MINECO (JCI-2012-13084,) and the Spanish Research Council/JAEdoc Program (JAEDOC089).

Objective It has been observed during recent decades that a large percentage of the population has an inadequate lifestyle and that there is a need for identifying factors determining such behavior pattern. This study was thus aimed at determining the association between lifestyle and sociodemographic variables of freshmen attending a state university in southern Brazil.Methods The sample consisted of 716 students (59.6 % female). The Fantastic questionnaire was used for evaluating the students’ lifestyles; their lifestyle was classified as being suitable or inadequate. The sociodemographic variables of interest were gender, age group ( and lt;20 and ≥20 years), paid work (yes or no), maternal education (≤4 years of study, 5-8 years and ≥9 years), study shift (daytime or night-time) and marital status (single and married). Binary logistic regression was used for determining associations between lifestyle and sociodemographic characteristics (p and lt;0.05 being significant).Results Inadequate lifestyle prevalence was 5.3 %. Adjusted analysis results indicated that students over 20 years-old (OR=2.87: 1.37-6.03 95 %CI) whose mothers’ formal education had lasted less than nine years (OR=2.23: 1.29-3.88 95 %CI) had a higher risk of having an inadequate lifestyle.Conclusion These findings may be useful for developing university healthcare promotion programs, paying special attention to older freshmen whose mothers have had less formal education.

Background:Very few studies have comprehensively analyzed the physical activity of children and adolescents in Brazil. The purpose of this article is to show the methodology and summarize findings from the first Brazilian Report Card on Physical Activity for Children and Youth.Methods:Three Brazilian research institutions coordinated the activities to develop the Brazilian 2016 Report Card. The data available were collected independently and then synthesized by the Research Work Group using the grade system developed for the First Global Matrix released in 2014, which included 9 indicators of physical activity. Where possible, grades were assigned based on the percentage of children and youth meeting each indicator: A is 81% to 100%; B is 61% to 80%; C is 41% to 60%; D is 21% to 40%; F is 0% to 20%; INC is incomplete data.Results:Among the 9 indicators, only 5 had sufficient data for grading. Overall Physical Activity received a C- grade, Active Transportation received a C+ grade, Sedentary Behavior received a D+ grade, and Government Strategies and Investments received a D grade.Conclusions:The low grades observed highlight the need for continued efforts aimed at improving physical activity in Brazilian children.

Trypanosomiasis and leishmaniasis keep being a real challenge for health and development of African countries. Existing treatments have considerable side effects and increase resistance of the parasites. We have measured antitrypanosomal and antileishmanial activity of natural phenols, tyrosol (TYR) and hydroxytyrosol (HT) and several of their esters and metabolites. We found significant IC50 values against Trypanosoma brucei for HT decanoate ester and HT dodecanoate ester (0.6 and 0.36 μM, respectively). This represents a large increase in activity with respect to HT (79 and 132 fold, respectively). Moreover, both compounds displayed a high selectivity index against MRC-5, a non-tumoral human cell line (118 and 106, respectively). Then, we synthesized a focused library of compounds to explore structure-activity. We found the ether and thiourea analogs of HT decanoate ester and HT dodecanoate ester also showed IC50 values against T. brucei in the low micromolar range. In conclusion, the di-ortho phenolic ring and medium size alkyl chain are essential for activity whereas the nature of the chemical bond among them seems less important., We gratefully acknowledge to Junta de Andalucía (Grant No. FQM-7316 (JCM), BIO-1786 (JMPV), CTS-7282 (FG)) and Spanish Ministry of Economy and Competitiveness (Grant No. SAF2011-28215 (JMPV) and SAF2012-34267 (FG)) for financial support.

Resveratrol (RES) is a natural polyphenol with relevant and varied biological activity. However, its low bioavailability and rapid metabolism to its glucuronate and sulfate conjugates has opened a debate on the mechanisms underlying its bioactivity. RES prodrugs are being developed to overcome these problems. We have synthesized a series of RES prodrugs and RES sulfate metabolites (RES-S) and evaluated their biological activities. RES glucosylated prodrugs (RES-Glc) were more cytotoxic in HT-29 and MCF-7 cells than RES itself whereas RES-S showed similar or higher cytotoxicity than RES. VEGF production was decreased by RES-Glc, and RES-disulfate (RES-diS) diminished it even more than RES. Finally, RES-Glc and RES-diS inhibited hTERT gene expression to a higher extent than RES. In conclusion, resveratrol prodrugs are promising candidates as anticancer drugs. In addition, RES-S showed distinct biological activity, thus indicating they are not simply RES reservoirs., Financial support has been granted by the Spanish Government (Ministerio de Economía y Competitividad, projects CTQ2011–27560 and CTQ2012–35360), by the Consellería d'Empresa, Universitat i Ciencia de la Generalitat Valenciana (projects PROMETEO/2013/027) and by the Universitat Jaume I (project PI‐1B‐2011–37).

The presence of replication-competent HIV-1 -which resides mainly in resting CD4+ T cells--is a major hurdle to its eradication. While pharmacological approaches have been useful for inducing the expression of this latent population of virus, they have been unable to purge HIV-1 from all its reservoirs. Additionally, many of these strategies have been associated with adverse effects, underscoring the need for alternative approaches capable of reactivating viral expression. Here we show that engineered transcriptional modulators based on customizable transcription activator-like effector (TALE) proteins can induce gene expression from the HIV-1 long terminal repeat promoter, and that combinations of TALE transcription factors can synergistically reactivate latent viral expression in cell line models of HIV-1 latency. We further show that complementing TALE transcription factors with Vorinostat, a histone deacetylase inhibitor, enhances HIV-1 expression in latency models. Collectively, these findings demonstrate that TALE transcription factors are a potentially effective alternative to current pharmacological routes for reactivating latent virus and that combining synthetic transcriptional activators with histone deacetylase inhibitors could lead to the development of improved therapies for latent HIV-1 infection.

Background The development of pancreatic metastases in renal carcinoma is very uncommon. The aim of the paper is to present a clinical case of this disease and review the clinical presentation, diagnosis, and treatment. Clinical case A case is presented of a 72-year-old female, with a history of renal carcinoma in the right kidney treated by total nephrectomy. At follow-up, in a radiological control, a suspicious metastatic pancreatic lesion was detected. A distal pancreatectomy with splenectomy was performed, and histopathology confirmed the origin as metastatic renal cancer. Conclusions Pancreatic metastases from renal cancer are very rare, and are usually diagnosed in the monitoring the primary cancer (because most of them are asymptomatic). The treatment for isolated resectable pancreatic metastases without extra-pancreatic extension is surgical resection.

The aim of this study was to investigate the ability of the sulfate metabolites of hydroxytyrosol (HT) and tyrosol (TYR) to act as antioxidants counteracting the pro-oxidant effect of oxidized cholesterol in intestinal cells. For this purpose, we synthesized sulfate metabolites of HT and TYR using a chemical methodology and examined their antioxidant activity in Caco-2 monolayers in comparison with the parent compounds. Exposure to oxidized cholesterol led to ROS production, oxidative damage, as indicated by the MDA increase, a decrease of reduced glutathione concentration and an enhancement of glutathione peroxidase activity. All the tested compounds were able to counteract the oxidizing action of oxidized cholesterol; HT and TYR sulfate metabolites showed an efficiency in protecting intestinal cells comparable to that of the parent compounds, strengthening the assumption that the potential beneficial effect of the parent compounds is retained, although extensive metabolisation occurs, the resulting metabolites being able to exert a biological action themselves., We gratefully acknowledge financial support from the Regione Autonoma della Sardegna (LR7-CRP-25300), Fondazione Banco di Sardegna and Junta de Andalucía (CVI-5007).

The breast cancer resistance protein (BCRP/ABCG2) is a drug efflux transporter that can affect the pharmacological and toxicological properties of many molecules. Urolithins, metabolites produced by the gut microbiota from ellagic acid (EA) and ellagitannins, have been acknowledged with in vivo anti-inflammatory and cancer chemopreventive properties. This study evaluated whether urolithins (Uro-A, -B, -C, and -D) and their main phase II metabolites Uro-A sulfate, Uro-A glucuronide, and Uro-B glucuronide as well as their precursor EA were substrates for ABCG2/BCRP. Parental and Bcrp1-transduced MDCKII cells were used for active transport assays. Uro-A and, to a lesser extent, Uro-A sulfate showed a significant increase in apically directed translocation in Bcrp1-transduced cells. Bcrp1 did not show affinity for the rest of the tested compounds. Data were confirmed for murine, human, bovine, and ovine BCRP-transduced subclones as well as with the use of the selective BCRP inhibitor Ko143. The transport inhibition by Uro-A was analyzed by flow cytometry compared to Ko143 using the antineoplastic agent mitoxantrone as a model substrate. Results showed that Uro-A was able to inhibit mitoxantrone transport in a dose-dependent manner. This study reports for the first time that Uro-A and its sulfate conjugate are ABCG2/BCRP substrates. The results suggest that physiologically relevant concentrations of these gut microbiota-derived metabolites could modulate ABCG2/BCRP-mediated transport processes and mechanisms of cancer drug resistance. Further in vivo investigations are warranted.

Quadruplex DNA structures are attracting an enormous interest in many areas of chemistry, ranging from chemical biology, supramolecular chemistry to nanoscience. We have prepared carbohydrate-DNA conjugates containing the oligonucleotide sequences of G-quadruplexes (thrombin binding aptamer (TBA) and human telomere (TEL)), measured their thermal stability and studied their structure in solution by using NMR and molecular dynamics. The solution structure of a fucose-TBA conjugate shows stacking interactions between the carbohydrate and the DNA G-tetrad in addition to hydrogen bonding and hydrophobic contacts. We have also shown that attaching carbohydrates at the 5′-end of a quadruplex telomeric sequence can alter its folding topology. These results suggest the possibility of modulating the folding of the G-quadruplex by linking carbohydrates and have clear implications in molecular recognition and the design of new G-quadruplex ligands. Copyright © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim., We thank the MICINN (grants CTQ2009–13705, CTQ2010–20451, CTQ2010–21567-C02–02), EU COST project MP0802, Generalitat de Catalunya (2009/SGR/208), and Instituto de Salud Carlos III (CIBERBNN, CB06 01 0019) for financial support. IGP and RL thank CSIC for a JAE contract. EVC thanks the Ministry of Education for an FPU doctoral fellowship.

Oligoribonucleotide conjugates carrying apolar carbohydrates at the 5′-end and the corresponding siRNA duplexes have been prepared using phosphoramidite chemistry. All the carbohydrate-siRNA derivatives were compatible with RNA interference machinery if transfected with oligofectamine. In the absence of a transfection agent, some of them exerted certain reduction of gene expression. Double-tailed permethylated glucose conjugated to siRNA through a long spacer inhibited gene expression up to 26% compared to the scrambled duplex. Such modifications contribute positively to the stability of oligoribonucleotides against 5′-exonuclease degradation., This study was supported by the Spanish Ministry of Economy and Competitiveness (grants CTQ2009-13705, CTQ2010-20541), Generalitat de Catalunya (2009/SGR/208). RL thanks CSIC for a JAE contract and EVC thanks Ministry of Education, Culture and Sports for a FPU grant. MT acknowledges a Juan de la Cierva contract (MICINN, Spain) for financial support.

The efficacy of resveratrol and some glucosyl, glucosylacyl, and glucuronide derivatives in inhibiting the adhesion of Salmonella Typhimurium, Escherichia coli O157:H7, and Listeria monocytogenes Scott A to Caco-2 and HT-29 colonic cells was investigated. The three bacteria strains were capable of adhering to both colonic epithelial cell lines, which responded by producing the pro-inflammatory interleukin 8 (IL-8). Adhesion inhibition of E. coli O157:H7 and S. Typhimurium to colonic cells was ≥60 and ≥40%, respectively, when resveratrol and most of the resveratrol derivatives were applied. Lower adhesion inhibition was observed for the bacteria with higher adherence potential, L. monocytogenes (≥20%). Resveratrol-3-O-(6'-O-butanoyl)-β-D-glucopyranoside (BUT) (50 and 100 μM) and resveratrol-3-O-(6'-O-octanoyl)-β-D-glucopyranoside (OCT) (50 μM) reduced IL-8 secretion by 100%. These results suggest that one mechanism for the beneficial attributes of resveratrol and especially the derivatives BUT and OCT could be the ability to reduce the adhesion and consequent pro-inflammatory cytokine production in intestinal epithelial cells in response to pathogen adhesion. The potential use of these compounds in the prevention of foodborne infections, intestinal homeostasis loss, and inflammatory bowel diseases could be another step in finding coadjuvants or alternatives to antibiotic treatments.

12 páginas, 7 figuras, 2 esquemas., There is no pharmaceutical or definitive surgical cure for inflammatory bowel diseases (IBDs). The naturally occurring polyphenol resveratrol exerts anti-inflammatory properties. However, its rapid metabolism diminishes its effectiveness in the colon. The design of prodrugs to targeting active molecules to the colon provides an opportunity for therapy of IBDs. Herein we explore the efficacy of different resveratrol prodrugs and pro-prodrugs to ameliorate colon inflammation in the murine dextran sulfate sodium (DSS) model. Mice fed with a very low dose (equivalent to 10 mg for a 70 kg-person) of either resveratrol-3-O-(6′-O-butanoyl)-β-d-glucopyranoside (6) or resveratrol-3-O-(6′-O-octanoyl)-β-d-glucopyranoside (7) did not develop colitis symptoms and improved 6-fold the disease activity index (DAI) compared to resveratrol. Our results indicate that these pro-prodrugs exerted a dual effect: (1) they prevented the rapid metabolism of resveratrol and delivered higher quantities of resveratrol to the colon and (2) they reduced mucosal barrier imbalance and prevented diarrhea, which consequently facilitated the action of the delivered resveratrol in the colon mucosa., This work was supported by the projects 200670F0131 (CSIC), CICYT-BFU2007-60576, and CSD2007-00063 (Fun-C-Food; Consolider Ingenio 2010). M.L. and R.L. are holders of a JAE-DOC grant from CSIC and M.V.S of a “Ramón y Cajal” grant from MCINN. J.T.C. is holder of a predoctoral grant from MCINN.

7 páginas, 3 figuras, 5 tablas., The effect of lipophilization of the antioxidant efficiency of hydroxytyrosol on fish oil enriched systems was studied. Hydroxytyrosol fatty acid esters with increasing size of the alkyl chain and different lipophilicity were tested in bulk fish oils and fish oil-in-water emulsions. Results showed a significant antioxidant activity of hydroxytyrosol esters in both systems especially in emulsions. The introduction of a lipophilic chain decreased the antioxidant effectiveness of hydroxytyrosol in homogeneous systems as fish oils. In emulsion systems, the presence of a short−medium lipophilic chain (acetate, butyrate or octanoate) improved the antioxidant efficiency of hydroxytyrosol favoring the physical location of the antioxidant in the interface, but longer alkyl chain (laurate) maintained or even decreased their antioxidant activity. A maximum of antioxidant efficiency seems to appear when the chain length of the hydroxytyrosol derivative is that of eight carbons which is probably associated with a preferential location of the diorthophenolic moiety in the right geometry. These results are of high importance for the optimum design of effective antioxidants for omega 3 enriched foods, which are very susceptible to suffer oxidation and, then, rancidity., We would like to thank JAE-Doc program (RL) and Intramural Frontier Project (200680F0132) from CSIC for financial support.