Age-Related Changes in the Behavior of Apolipoprotein E Knockout Mice.
Fuentes D, Fernández N, García Y, García T, Morales AR, Menéndez R. Behav Sci (Basel). 2018 Mar 3;8(3). pii: E33. DOI: 10.3390/bs8030033.
The knockout mouse model, B6.129P2-Apoetm1Unc is homozygotic for the Apolipoprotein E (ApoE) deletion; thus, it is capable of developing hyperlipidemia and atherosclerosis but ApoE is also a lipid-transport protein abundantly expressed in most neurons in the central nervous system, so these animals could also be models of neurodegenerative diseases. The aim of this study was to determine age-related changes in spontaneous behavior and in learning and memory of Apolipoprotein E knockout mice. Spontaneous behavioral measurements included sleeping pattern, motor coordination and balance by rotarod and open field activity, whereas learning and memory tests included forced alternation in Y-maze, novel object recognition and passive avoidance conditioning. Significant behavioral differences between aged knockout mice and age-matched wild type strain, C57Bl/6 were found in all the behavioral tests, except for the rotarod test. Genetically’ modified mice exhibited less huddling contact during sleeping, decreased locomotor activity in novel environments and in learning and memory deficits. These results are consistent with the cognitive impairment and memory loss seen as the earliest clinical symptoms in neurodegenerative disorders such as Alzheimer’s disease. The ApoE knockout mice might therefore be an appropriate model for studying the underlying mechanisms involved in behavioral changes caused by neurodegenerative diseases as well as for evaluating new therapies for these pathologies.
Anti-inflammatory effect of two Lactobacillus strains during infection with Gardnerella vaginalis and Candida albicans in a HeLa cell culture model.
Santos CMA, Pires MCV, Leão TL, Silva AKS, Miranda LS, Martins FS. Microbiology. 2018 Mar;164(3):349–58.
Lactobacilli are the dominant bacteria of the vaginal tract of healthy women and they play a major role in the maintenance of mucosal homeostasis, preventing genital infections, such as bacterial vaginosis (BV) and vulvovaginal candidiasis (VVC). It is now known that one mechanism of this protection is the influence that lactobacilli can exert on host immune responses. In this context, we evaluated two Lactobacillus strains (L. plantarum 59 and L. fermentum 137) for their immunomodulatory properties in response to Gardnerella vaginalis (BV) or Candida albicans (VVC) infections in a HeLa cell infection model. G. vaginalis and C. albicans triggered the secretion of pro-inflammatory cytokines (TNF-α, IL-1β, IL-6 and IL-8) and the activation of NF-κB in HeLa cells, in contrast to L. plantarum 59 and L. fermentum 137. Treatments with the Lactobacillus strains or their cell-free supernatants before (pre-treatment) or after (post-treatment) the challenge with the pathogens resulted in decreased secretion of pro-inflammatory cytokines and decreased activation of NF-κB. The treatments with Lactobacillus strains not only decreased the secretion of IL-8, but also its expression, as confirmed by gene reporter luciferase assay, suggesting transcription-level control by lactobacilli. In conclusion, L. plantarum 59 and L. fermentum 137 were confirmed to have an anti-inflammatory effect against G. vaginalis and C. albicans and they were able to influence signalling in NF-κB pathway, making them interesting candidates as probiotics for the prevention or treatment of BV and VVC.
Clinical characteristics and outcomes of cancer patients requiring intensive care unit admission: a prospective study.
Martos-Benítez FD, Soto-García A, Gutiérrez-Noyola A. J Cancer Res Clin Oncol. 2018 Apr;144(4):717–23.
Purpose The study was aimed to describe the characteristics of cancer patients admitted to the oncological ICU and to identify clinical features associated with outcomes. Methods This is a prospective study (January 2014 to December 2015) of 522 cancer patients consecutively admitted to the oncological ICU. Patients with a length of oncological ICU stay ≤ 1 day were excluded. Demographic and clinical variables were obtained at oncological ICU admission. The primary outcome of interest was hospital mortality. Logistic regression analysis was performed to identify independent risk factors for hospital mortality. Results The study cohort consisted of 492 (94.3%) patients with solid tumours and 30 patients (5.7%) with haematological malignancies. Advanced cancer was observed in 53.3%. Unplanned admission accounted for 25.3%. Hospital mortality rate was 13.0% (n = 68), and it was higher for patients with unplanned admission than those for electively admitted patients (35.6% vs. 5.4; p < 0.0001). Stage IV of cancer (OR 5.28; 95% CI 2.71-10.28; p < 0.0001), patients from the emergency department (OR 3.33; 95% CI 1.68-6.61; p = 0.001), unplanned admission (OR 7.99; 95% CI 4.45-14.33; p < 0.0001), non-malignancy-related admission (OR 5.80; 95% CI 3.26-10.32; p < 0.0001), sepsis (OR 4.81; 95% CI 2.28-10.16; p < 0.0001), chemotherapy-induced adverse event (OR 5.64; 95% CI 2.33-13.66; p < 0.0001), and invasive mechanical ventilation (OR 18.70; 95% CI 9.93-35.21; p < 0.0001) were independently associated with increased hospital mortality in multivariate logistic regression analysis. Conclusion ICU admission of cancer patients should be based on potential.
C-Phycocyanin and Phycocyanobilin as Remyelination Therapies for Enhancing Recovery in Multiple Sclerosis and Ischemic Stroke: A Preclinical Perspective.
Pentón-Rol G, Marín-Prida J, Falcón-Cama V. Behav Sci (Basel). 2018 Jan 18;8(1). pii: E15. DOI: 10.3390/bs8010015.
Myelin loss has a crucial impact on behavior disabilities associated to Multiple Sclerosis (MS) and Ischemic Stroke (IS). Although several MS therapies are approved, none of them promote remyelination in patients, limiting their ability for chronic recovery. With no available therapeutic options, enhanced demyelination in stroke survivors is correlated with a poorer behavioral recovery. Here, we show the experimental findings of our group and others supporting the remyelinating effects of C-Phycocyanin (C-PC), the main biliprotein of Spirulina platensis and its linked tetrapyrrole Phycocyanobilin (PCB), in models of these illnesses. C-PC promoted white matter regeneration in rats and mice affected by experimental autoimmune encephalomyelitis. Electron microscopy analysis in cerebral cortex from ischemic rats revealed a potent remyelinating action of PCB treatment after stroke. Among others biological processes, we discussed the role of regulatory T cell induction, the control of oxidative stress and pro-inflammatory mediators, gene expression modulation and COX-2 inhibition as potential mechanisms involved in the C-PC and PCB effects on the recruitment, differentiation and maturation of oligodendrocyte precursor cells in demyelinated lesions. The assembled evidence supports the implementation of clinical trials to demonstrate the recovery effects of C-PC and PCB in these diseases.
Genetic characteristics of VanA-type vancomycin-resistant Enterococcus faecalis and Enterococcus faecium in Cuba.
Quiñones D, Aung MS, Sousa Martins JP, Urushibara N, Kobayashi N. New Microbes New Infect. 2017 Dec 8;21:125–7.
DOI: 10.1016/j.nmni.2017.12.001. eCollection 2018 Jan.
VanA-type vancomycin-resistant enterococci isolates from bloodstream infections in Cuba were genetically characterized. Enterococcus faecalis isolates were assigned to sequence type (ST) 28, closely related to Eastern Europe, while Enterococcus faecium belonged to ST262, ST656 and ST1349, and showed different genetic profiles.
In vitro anti-diabetic effect of flavonoids and pheophytins from Allophylus cominia Sw. on the glucose uptake assays by HepG2, L6, 3T3-L1 and fat accumulation in 3T3-L1 adipocytes.
Semaan DG, Igoli JO, Young L, Gray AI, Rowan EG, Marrero E. J Ethnopharmacol. 2018 Apr 24;216:8–17. pii: S0378-8741(17)33331-7. DOI: 10.1016/j.jep.2018.01.014. Epub 2018 Jan 12.
Background and Purpose Based on ethno-botanical information collected from diabetic patients in Cuba and firstly reported inhibition of PTP1B and DPPIV enzymes activities, Allophylus cominia (A. cominia) was identified as possible source of new drugs that could be used for the treatment of type 2 diabetes mellitus (T2-DM). Experimental Approach In this study, the activity of the characterised extracts from A. cominia was tested on the glucose uptake using HepG2 and L6 cells, 3T3-L1 fibroblasts and adipocytes as well as their effect on the fat accumulation using 3T3-L1 adipocytes. Key Results On 2-NBDG glucose uptake assay using HepG2 and L6 cells, extracts from A. cominia enhanced insulin activity by increasing glucose uptake. On HepG2 cells Insulin EC50 of 93 ± 21nM decreased to 13 ± 2nM in the presence of the flavonoids mixture from A.cominia. In L6 cells, insulin also produced a concentration-dependent increase with an EC50 of 28.6 ± 0.7nM; EC50 decreased to 0.08 ± 0.02nM and 5 ± 0.9nM in the presence of 100μg/ml of flavonoids and pheophytins mixtures, respectively. In 3T3-L1 fibroblasts, insulin had an EC50 of >1000nM that decreased to 38 ± 4nM in the presence of the flavonoids extract. However, in adipocytes, insulin produced a significant concentration-dependent increase and an EC50 of 30 ± 8nM was a further confirmation of the insulin responsiveness of the adipocytes to the insulin. At 100µg/ml, flavonoids and pheophytins extracts decreased fat accumulation in 3T3-L1 adipocytes by two folds in comparison to the control differentiated cells (p<0.05). The crude extract of A. cominia did not show any enhancement of 2-NBDG uptake by 3T3-L1 adipocytes in the presence or absence of 100nM insulin. In addition, in fully differentiated adipocytes, both extracts produced significant decrease in lipid droplets in the cells and no lipid accumulation were seen after withdrawal of the extracts from the cell growth medium. However, there was no effect of both extracts on total protein concentration in cells as well as on Glut-4 transporters. Conclusions and Implications The pharmacological effects of the extracts from A. cominia observed in experimental diabetic models were shown in this study. A. cominia is potentially a new candidate for the treatment and management of T2-DM.
Mapping Brain Activity with Electrocorticography: Resolution Properties and Robustness of Inverse Solutions.
Todaro C, Marzetti L, Valdés Sosa PA, Valdés Hernández PA, Pizzella V. Brain Topogr. 2018 Jan 23. DOI: 10.1007/s10548-018-0623-1. [Epub ahead of print]
Electrocorticography (ECoG) is an electrophysiological technique that records brain activity directly from the cortical surface with high temporal (ms) and spatial (mm) resolution. Its major limitations are in the high invasiveness and in the restricted field-of-view of the electrode grid, which partially covers the cortex. To infer brain activity at locations different from just below the electrodes, it is necessary to solve the electromagnetic inverse problem. Limitations in the performance of source reconstruction algorithms from ECoG have been, to date, only partially addressed in the literature, and a systematic evaluation is still lacking. The main goal of this study is to provide a quantitative evaluation of resolution properties of widely used inverse methods (eLORETA and MNE) for various ECoG grid sizes, in terms of localization error, spatial dispersion, and overall amplitude. Additionally, this study aims at evaluating how the use of simultaneous electroencephalography (EEG) affects the above properties. For these purposes, we take advantage of a unique dataset in which a monkey underwent a simultaneous recording with a 128 channel ECoG grid and an 18 channel EEG grid. Our results show that, in general conditions, the reconstruction of cortical activity located more than 1 cm away from the ECoG grid is not accurate, since the localization error increases linearly with the distance from the electrodes. This problem can be partially overcome by recording simultaneously ECoG and EEG. However, this analysis enlightens the necessity to design inverse algorithms specifically targeted at taking into account the limited field-of-view of the ECoG grid.
Moderate Physical Activity in an Aquatic Environment During Pregnancy (SWEP Study) and Its Influence in Preventing Postpartum Depression.
Aguilar-Cordero MJ, Sánchez-García JC, Rodríguez-Blanque R, Sánchez-López AM, Mur-Villar N. J Am Psychiatr Nurses Assoc. 2018 Feb 1:1078390317753675. DOI: 10.1177/1078390317753675. [Epub ahead of print]
Introduction Postpartum depression (PPD) can begin within 6 weeks postpartum (International Classification of Diseases, 10th Revision) and represents a significant health problem for mothers. Aim To determine whether physical activity during pregnancy alleviates PPD. Method Randomized controlled trial in which the exercise group practiced moderate physical exercise in an aquatic environment (1-hour sessions, 3 days a week), following the recommendations of the SWEP method. Results The results observed in the Edinburgh Postnatal Depression Scale were significant between the exercise group and the control group (p < .001). In addition, significant differences were observed according in body mass index between the exercise group and control group in the overweight and obesity categories (p < .05). Conclusion Women who perform moderate physical exercise in an aquatic environment are at lower risk of PPD than sedentary women. Overweight and obesity among sedentary women during pregnancy are closely associated with positive screening for PPD.
Nasal route favors the induction of CD4+ T cell responses in the liver of HBV-carrier mice immunized with a recombinant hepatitis B surface- and core-based therapeutic vaccine.
Bourgine M, Crabe S, Lobaina Y, Guillén G, Aguilar JC, Michel ML. Antiviral Res. 2018 Mar 3;153 :23–32 . DOI: 10.1016/j.antiviral.2018.02.019. [Epub ahead of print]
Immunization routes and number of doses remain largely unexplored in therapeutic vaccination. The aim of the present work is to evaluate their impact on immune responses in naïve and hepatitis B virus (HBV)-carrier mouse models following immunization with a non-adjuvanted recombinant vaccine comprising the hepatitis B surface (HBsAg) and core (HBcAg) antigens. Mice were immunized either by intranasal (i.n.), subcutaneous (s.c.) or simultaneous (i.n. + s.c.) routes. Humoral immunity was detected in all the animal models with the induction of a potent antibody (Ab) response against HBcAg, which was stronger than the anti-HBs response. In the HBV-carrier mouse model, the anti-HBs response was predominantly subtype-specific and preferentially induced by the i.n. route. However, the Ab titers were not sufficient to clear the high concentration of HBsAg present in the sera of these mice. The i.n. route was the most efficacious at inducing cellular immune responses, in particular CD4+ T cells. In naïve mice, cellular responses in spleen were strong and mainly due to CD4+ T cells whereas the CD8+ T-cell response was low. In HBV-carrier mice, high frequencies of HBs-specific CD4+ T cells secreting interferon (IFN)-γ, interleukin (IL)-2 and tumor necrosis factor (TNF)-α were found in liver only after i.n. immunization. Increased frequencies of CD4+ T cells expressing the integrin CD49a in liver suggest a role of nasal route in the cellular homing process. Multiple dose schedules appear to be a prerequisite for protein-based immunization in order to overcome immunotolerance in HBV-carrier mice. These findings provide new avenues for further preclinical and clinical development.
Non-Clinical Contribution to Clinical Trials during Lead Optimization Phase.
Martínez Muñoz L. Behav Sci (Basel). 2018 Jan 24;8(1). pii: E17. DOI: 10.3390/bs8010017.
This manuscript comments on guidelines related to requirements for clinical trials for new drugs and the importance of considering regulatory criteria in the planning phase, in order to enhance the utility of data generated in basic research. Suggestions are made for optimizing regulatory management to improve the likelihood of acceptance of pre-clinical data prior to Clinical Phase I trials (early clinical trials).
“Understanding the Role of Hypoxia inducible factor during neurodegeneration for new therapeutics opportunities”.
Merelli A, Rodríguez JCG, Folch J, Regueiro MR, Camins A, Lazarowski A. Curr Neuropharmacol. 2018 Jan 10.
DOI: 10.2174/1570159X16666180110130253. [Epub ahead of print]
Neurodegeneration (NDG) is linked with the progressive loss of neural function with intellectual and/or motor impairment. Several diseases affecting older individuals, including Alzheimer’s disease, Amyotrophic Lateral Sclerosis, Huntington’s disease, Parkinson’s disease, stroke, Multiple Sclerosis and many others, are the most relevant disorders associated with NDG. Since other pathologies such as refractory epilepsy, brain infections, or hereditary diseases such as “neurodegeneration with brain iron accumulation”, also lead to chronic brain inflammation with loss of neural cells, NDG can be said to affect all ages. Owing to an energy and/or oxygen supply imbalance, different signaling mechanisms including MAPK/PI3K-Akt signaling pathways, glutamatergic synapse formation, and/or translocation of phosphatidylserine, might activate some central executing mechanism common to all these pathologies and also related to oxidative stress. Hypoxia inducible factor 1-a (HIF-1a) plays a twofold role through gene activation, in the sense that this factor has to “choose” whether to protect or to kill the affected cells. Most of the afore-mentioned processes follow a protracted course and are accompanied by progressive iron accumulation in the brain. We hypothesize that the neuroprotective effects of iron chelators are acting against the generation of free radicals derived from iron, and also induce sufficient -but not excessive- activation of HIF-1a, so that only the hypoxia-rescue genes will be activated. In this regard, the expression of the erythropoietin receptor in hypoxic/inflammatory neurons could be the cellular “sign” to act upon by the nasal administration of pharmacological doses of Neuro-EPO, inducing not only neuroprotection, but eventually, neurorepair as well.
