A Coruña, Spain
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Carrera I.,EuroEspes Biotechnology | Etcheverria I.,EuroEspes Biotechnology | Fernandez-Novoa L.,EuroEspes Biotechnology | Lombardi V.,EuroEspes Biotechnology | And 2 more authors.
International Journal of Alzheimer's Disease | Year: 2012

A novel vaccine addressing the major hallmarks of Alzheimer's disease (AD), senile plaque-like deposits of amyloid beta-protein (Aβ), neurofibrillary tangle-like structures, and glial proinflammatory cytokines, has been developed. The present vaccine takes a new approach to circumvent failures of previous ones tested in mice and humans, including the Elan-Wyeth vaccine (AN1792), which caused massive T-cell activation, resulting in a meningoencephalitis-like reaction. The EB101 vaccine consists of A β 1 - 42 delivered in a novel immunogen-adjuvant composed of liposomes-containing sphingosine-1-phosphate (S1P). EB101 was administered to APPswe/PS1dE9 transgenic mice before and after AD-like pathological symptoms were detectable. Treatment with EB101 results in a marked reduction of Aβ plaque burden, decrease of neurofibrillary tangle-like structure density, and attenuation of astrocytosis. In this transgenic mouse model, EB101 reduces the basal immunological interaction between the T cells and immune activation markers in the affected hippocampal/cortical areas, consistent with decreased amyloidosis-induced inflammation. Therefore, immunization with EB101 prevents and reverses AD-like neuropathology in a significant manner by halting disease progression without developing behavioral spatial deficits in transgenic mice. © 2012 Iván Carrera et al.


Carrera I.,EuroEspes Biotechnology | Etcheverria I.,EuroEspes Biotechnology | Fernandez-Novoa L.,EuroEspes Biotechnology | Lombardi V.R.M.,EuroEspes Biotechnology | And 3 more authors.
BioMed Research International | Year: 2015

Immunization against amyloid-beta-peptide (Aβ) has been widely investigated as a potential immunotherapeutic approach for Alzheimer's disease (AD). With the aim of developing an active immunogenic vaccine without need of coadjuvant modification for human trials and therefore avoiding such side effects, we designed the Aβ 1-42 vaccine (EB101), delivered in a liposomal matrix, that based on our previous studies significantly prevents and reverses the AD neuropathology, clearing Aβ plaques while markedly reducing neuronal degeneration, behavioral deficits, and minimizing neuroinflammation in APP/PS1 transgenic mice. Here, the efficacy of our immunogenic vaccine EB101 was compared with the original immunization vaccine cocktail Aβ 42 + CFA/IFA (Freund's adjuvant), in order to characterize the effect of sphingosine-1-phosphate (S1P) in the immunotherapeutic response. Quantitative analysis of amyloid burden showed a notable decrease in the neuroinflammation reaction against Aβ plaques when S1P was compared with other treatments, suggesting that S1P plays a key role as a neuroprotective agent. Moreover, EB101 immunized mice presented a protective immunogenic reaction resulting in the increase of Aβ-specific antibody response and decrease of reactive glia in the affected brain areas, leading to a Th2 immunological reaction. © 2015 Iván Carrera et al.


PubMed | Camilo José Cela University, Hospital Infantil Universitario Nino Jesus, EuroEspes Biotechnology and University of Alcalá
Type: Journal Article | Journal: Journal of neurochemistry | Year: 2016

Several studies indicate that 17-estradiol (E2) protects against amyloid -peptide (A)-induced cell death and activates factors associated with learning and memory, a function involving the hippocampal somatostatinergic system. As alterations in somatostatin have been demonstrated in Alzheimers disease, we examined whether E2 prevents changes in the hippocampal somatostatinergic system induced by A25-35 and cell death, as well as the possible involvement of leptin and insulin-like growth factor (IGF)-I signaling. We also measured the levels of A proteases neprilysin and insulin-degrading-enzyme. Co-administration of E2 with A25-35 reduced both its levels and cell death, in addition to preventing the A-induced depletion of some somatostatinergic parameters. Activation of leptin and IGF-I pathways increased after E2 co-administration, and this correlated with changes in the somatostatinergic system. Changes in some components of this system were inversely related with A levels and cell death. Moreover, neprilysin levels were increased only in A plus E2-treated rats and E2 prevented the A-induced insulin-degrading-enzyme reduction. Our results suggest that the E2-induced reduction in cell death is related to lower A levels, probably because of IGF-I and somatostatin modulation of A proteases. We asked how 17-estradiol (E2) protects against -amyloid (A)-induced cell death. E2 co-administration prevents A-produced depletion of hippocampal somatostatin (SRIF) by an IGF-I-mediated mechanism, being related this protective effect with an increase in A proteases. Our results suggest that the E2-induced reduction in cell death is related to lower A levels, probably because of SRIF modulation of A proteases. CREB, cAMP response element-binding protein; IGF-I, insulin-like growth factor-I; STAT3, signal transducer and activator of transcription-3.


PubMed | Atlas Pharmaceuticals, Camilo José Cela University, Torrey Pines Institute for Molecular Studies and EuroEspes Biotechnology
Type: | Journal: BioMed research international | Year: 2015

Immunization against amyloid-beta-peptide (A) has been widely investigated as a potential immunotherapeutic approach for Alzheimers disease (AD). With the aim of developing an active immunogenic vaccine without need of coadjuvant modification for human trials and therefore avoiding such side effects, we designed the A 1-42 vaccine (EB101), delivered in a liposomal matrix, that based on our previous studies significantly prevents and reverses the AD neuropathology, clearing A plaques while markedly reducing neuronal degeneration, behavioral deficits, and minimizing neuroinflammation in APP/PS1 transgenic mice. Here, the efficacy of our immunogenic vaccine EB101 was compared with the original immunization vaccine cocktail A 42 + CFA/IFA (Freunds adjuvant), in order to characterize the effect of sphingosine-1-phosphate (S1P) in the immunotherapeutic response. Quantitative analysis of amyloid burden showed a notable decrease in the neuroinflammation reaction against A plaques when S1P was compared with other treatments, suggesting that S1P plays a key role as a neuroprotective agent. Moreover, EB101 immunized mice presented a protective immunogenic reaction resulting in the increase of A-specific antibody response and decrease of reactive glia in the affected brain areas, leading to a Th2 immunological reaction.


Lillsunde K.-E.,University of Helsinki | Festa C.,University of Naples Federico II | Adel H.,National Institute of Oceanography of India | De Marino S.,University of Naples Federico II | And 7 more authors.
Marine Drugs | Year: 2014

Marine organisms and their metabolites represent a unique source of potential pharmaceutical substances. In this study, we examined marine-derived substances for their bioactive properties in a cell-based Chikungunya virus (CHIKV) replicon model and for in vitro anti-inflammatory activity. In the screening of a marine sample library, crude extracts from the Indian soft coral, Sinularia kavarattiensis, showed promising activity against the CHIKV replicon. Bioassay-guided chemical fractionation of S. kavarattiensis resulted in the isolation of six known norcembranoids (1-6) and one new compound, named kavaranolide (7). The structures were elucidated on the basis of NMR and MS spectroscopic data. Compounds 1-3 and 5-7 were evaluated for their replicon-inhibiting potential in the CHIKV model by using a luminescence-based detection technique and live cell imaging. Compounds 1 and 2 showed moderate inhibition of the CHIKV replicon, but imaging studies also revealed cytotoxic properties. Moreover, the effects of the isolated compounds on primary microglial cells, an experimental model for neuroinflammation, were evaluated. Compound 2 was shown to modulate the immune response in microglial cells and to possess potential anti-inflammatory properties by dose-dependently reducing the release of pro- and anti-inflammatory cytokines. © 2014 by the authors; licensee MDPI.


Wang H.,Section of Neurobiology | Dey D.,Euroespes Biotechnology | Carrera I.,Euroespes Biotechnology | Minond D.,Torrey Pines Institute for Molecular Studies | And 4 more authors.
Journal of Biological Chemistry | Year: 2013

Background: Increased generation of toxic amyloidβpeptide (Aβ) in the brain is central to the pathogenesis of Alzheimer's disease (AD). Results: COPS5 (Jab1) is a novel RanBP9-interacting protein that robustly increases Aβgeneration Conclusion: COPS5 increases Aβgeneration by stabilizing RanBP9 protein levels. Significance: Lowering COPS5 levels may be an effective therapeutic approach for AD. © 2013 by The American Society for Biochemistry and Molecular Biology, Inc.


PubMed | VTT Technical Research Center of Finland, University of Helsinki, Ege University, Euroespes Biotechnology and National Institute of Oceanography of India
Type: Journal Article | Journal: New biotechnology | Year: 2016

Marine organisms constitute approximately one-half of the total global biodiversity, being rich reservoirs of structurally diverse biofunctional components. The potential of cyanobacteria, micro- and macroalgae as sources of antimicrobial, antitumoral, anti-inflammatory, and anticoagulant compounds has been reported extensively. Nonetheless, biological activities of marine fauna and flora of the Aegean Sea have remained poorly studied when in comparison to other areas of the Mediterranean Sea. In this study, we screened the antimicrobial, antifouling, anti-inflammatory and anticancer potential of in total 98 specimens collected from the Aegean Sea. Ethanol extract of diatom Amphora cf capitellata showed the most promising antimicrobial results against Candida albicans while the extract of diatom Nitzschia communis showed effective results against Gram-positive bacterium, S. aureus. Extracts from the red alga Laurencia papillosa and from three Cystoseira species exhibited selective antiproliferative activity against cancer cell lines and an extract from the brown alga Dilophus fasciola showed the highest anti-inflammatory activity as measured in primary microglial and astrocyte cell cultures as well as by the reduction of proinflammatory cytokines. In summary, our study demonstrates that the Aegean Sea is a rich source of species that possess interesting potential for developing industrial applications.


Lombardi V.R.M.,Euroespes Biotechnology | Etcheverria I.,Euroespes Biotechnology | Carrera I.,Euroespes Biotechnology | Cacabelos R.,Euroespes | Chacn A.R.,Laboratorios Geamed
Journal of Biomedicine and Biotechnology | Year: 2012

One of the main treatments currently used in humans to fight cancer is chemotherapy. A huge number of compounds with antitumor activity are present in nature, and many of their derivatives are produced by microorganisms. However, the search for new drugs still represents a main objective for cancer therapy, due to drug toxicity and resistance to multiple chemotherapeutic drugs. In animal models, a short-time oral administration of dextran sulfate sodium (DSS) induces colitis, which exhibits several clinical and histological features similar to ulcerative colitis (UC). However, the pathogenic factors responsible for DSS-induced colitis and the subsequent colon cancer also remain unclear. We investigated the effect of FR91, a standardized lysate of microbial cells belonging to the Bacillus genus which has been previously shown to have significant immunomodulatory effects, against intestinal inflammation. Colitis was induced in mice during 5 weeks by oral administration 2 (DSS). Morphological changes in the colonic mucosa were evaluated by hematoxylin-eosin staining and immunohistochemistry methods. Adenocarcinoma and cryptal cells of the dysplastic epithelium showed cathenin-β, MLH1, APC, and p53 expression, together with increased production of IFN-γ. In our model, the optimal dose response was the 20 FR91 concentration, where no histological alterations or mild DSS-induced lesions were observed. These results indicate that FR91 may act as a chemopreventive agent against inflammation in mice DSS-induced colitis. Copyright 2012 Valter R. M. Lombardi et al.


PubMed | Florida Institute of Technology, Torrey Pines Institute for Molecular Studies and Euroespes Biotechnology
Type: Journal Article | Journal: eNeuro | Year: 2016

Transcription factor EB (TFEB) was recently shown to be a master regulator of autophagy lysosome pathway. Here, we successfully generated and characterized transgenic mice overexpressing flag-TFEB. Enhanced autophagy in the flag-TFEB transgenic mice was confirmed by an increase in the cellular autophagy markers, as determined by both immunoblots and transmission electron microscopy. Surprisingly, in the flag-TFEB mice we observed increased activity of senescence-associated -galactosidase by 66% of neurons in the cortex (p < 0.001) and 73% of neurons in the hippocampus (p < 0.001). More importantly, flag-TFEB expression remarkably reduced the levels of paired-helical filament (PHF)-tau from 372% in the P301S model of tauopathy to 171% (p < 0.001) in the cortex, and from 436% to 212% (p < 0.001) in the hippocampus. Significantly, reduced levels of NeuN in the cortex (38%, p < 0.001) and hippocampus (25%, p < 0.05) of P301S mice were almost completely restored to WT levels in the P301S/flag-TFEB double-transgenic mice. Also, levels of spinophilin in both the cortex (p < 0.001) and hippocampus (p < 0.001) were restored almost to WT levels. Most importantly, the age-associated lipofuscin granules, which are generally presumed to be nondegradable, were reduced by 57% (p < 0.001) in the cortex and by 55% (p < 0.001) in the hippocampus in the double-transgenic mice. Finally, TFEB overexpression in the P301S mice markedly reversed learning deficits in terms of spatial memory (Barnes maze), as well as working and reference memories (T maze). These data suggest that the overexpression of TFEB can reliably enhance autophagy in vivo, reduce levels of PHF-tau, and thereby reverse the deposition of lipofuscin granules and memory deficits.


PubMed | Florida Institute of Technology, Torrey Pines Institute for Molecular Studies and Euroespes Biotechnology
Type: Journal Article | Journal: The Journal of biological chemistry | Year: 2015

Brain accumulation of neurotoxic amyloid (A) peptide because of increased processing of amyloid precursor protein (APP), resulting in loss of synapses and neurodegeneration, is central to the pathogenesis of Alzheimer disease (AD). Therefore, the identification of molecules that regulate A generation and those that cause synaptic damage is crucial for future therapeutic approaches for AD. We demonstrated previously that COPS5 regulates A generation in neuronal cell lines in a RanBP9-dependent manner. Consistent with the data from cell lines, even by 6 months, COPS5 overexpression in APE9 mice (APE9/COPS5-Tg) significantly increased A40 levels by 32% (p < 0.01) in the cortex and by 28% (p < 0.01) in the hippocampus, whereas the increases for A42 were 37% (p < 0.05) and 34% (p < 0.05), respectively. By 12 months, the increase was even more robust. A40 levels increased by 63% (p < 0.001) in the cortex and by 65% (p < 0.001) in the hippocampus. Similarly, A42 levels were increased by 69% (p < 0.001) in the cortex and by 71% (p < 0.011) in the hippocampus. Increased A levels were translated into an increased amyloid plaque burden both in the cortex (54%, p < 0.01) and hippocampus (64%, p < 0.01). Interestingly, COPS5 overexpression increased RanBP9 levels in the brain, which, in turn, led to increased amyloidogenic processing of APP, as reflected by increased levels of sAPP and decreased levels of sAPP. Furthermore, COPS5 overexpression reduced spinophilin in both the cortex (19%, p < 0.05) and the hippocampus (20%, p < 0.05), leading to significant deficits in learning and memory skills. Therefore, like RanBP9, COPS5 also plays a pivotal role in amyloid pathology in vivo.

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