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El presente trabajo de investigación tuvo como objetivo el análisis de los sistemas tecnológicos como herramienta de trabajo para la gestión eficiente de la toma de decisiones en el ámbito de la ingeniería comercial. La metodología empleada en esta indagación, seleccionó el enfoque cuantitativo, bajo un diseño no experimental, de campo, descriptivo, con apoyo documental bibliográfico. La unidad de análisis estuvo conformada por diez (10) ingenieros comerciales que cumplen roles directivos en los departamentos financieros y de inversiones de negocios en un Grupo de Entidades Financieras de la ciudad de Guayaquil, abordadas en esta indagación. El instrumento de recolección de datos fue la encuesta y el instrumento un cuestionario tipo escala Likert. El análisis y procesamiento de datos se efectuó mediante la técnica de les estadísticas descriptivas. Los resultados evidenciaron que, el 40% respondió que siempre los sistemas tecnológicos constituyen un aspecto clave en los procesos de toma de decisiones en la empresa; el 60% señaló que siempre es adecuada la gestión financiera del Grupo empresarial para el acceso a las nuevas tecnologías y el 70% considera que en el Grupo empresarial y sus diversos departamentos siempre se usa la información suministrada por la base de datos que brindan las plataformas digitales para la toma de decisiones. Se concluye que los profesionales de la ingeniería comercial son pieza clave para el éxito de las organizaciones pues están capacitados para desarrollar estrategias corporativas, de negocios para lograr que la institución funcione favorablemente y apoyados en los sistemas de tecnología de la información.

El objetivo de este artículo de investigación fue analizar la gestión de sistemas informáticos en el ámbito de la ingeniería comercial para encontrar oportunidades de negocios en las empresas. Para alcanzar tal objetivo, la metodología fue de carácter cuantitativo, diseño del estudio fue no experimental, transversal. La población estuvo conformada por 20 empresarios que manifestaron su intención de participar, siendo seleccionados al azar. La técnica del estudio estuvo conformada por una entrevista y el instrumento fue un cuestionario. Se utilizó el programa SPSS versión 24, los datos se realizaron mediante la estadística descriptiva en la cual se presentó en tablas de frecuencias de acuerdo con los niveles de cada variable. Se concluye que los empresarios consultados han señalado que el área responsable de la gestión empresarial emplean las tecnologías de la información; además poseen conocimiento y acceso a sistemas de información que faciliten su tarea en la gerencia. Además consideran que emplean sistemas informáticos específicos para la gestión empresarial y para la información gerencial. Por ultimo están conscientes del papel preponderante de la ingeniería comercial para facilitar las oportunidades a través de un sistema de gestión, para el incremento de oportunidades de negocios.

El objetivo de este artículo de investigación es analizar el Marketing digital un mix de estrategias y tácticas para conseguir buenos resultados a través de la revisión sistemática de trabajos de investigación con la finalidad de ampliar el conocimiento inherente a la temática en fuentes electrónica. Para ello se realizó un tipo de investigación cualitativa, el método fue de análisis y el método síntesis; el tipo de investigación es documental; el diseño es bibliográfico. La población fue seleccionada atendiendo a criterios de inclusión y exclusión. Las unidades de estudio estuvieron conformadas por veinte (20) fuentes y la muestra de seis 06. La técnica de recolección de datos fue la observación documental y en cuanto a los instrumentos se empleó el registro de datos y los archivos electrónicos. Para el análisis se empleó la técnica del análisis de contenido, a través de la matriz de análisis. Se concluye que, las aportaciones de los autores señalan que el escenario tecnológico se configura como el medio donde se desarrollan mayormente las actividades empresariales en los tiempos que transcurren, por ello, contar con un plan de marketing bien definido es crucial para ayudar a las empresas a mantenerse e incluso a crecer en los ambientes digitales. Dentro de las estrategias de Marketing Mix se encontraron las relacionadas con la Transmedia, siendo que en la actualidad la tecnología forma parte fundamental en los procesos cotidianos, de la misma manera lo hacen las redes sociales, las cuales han logrado un impacto en las personas.

Cocoa, rich in polyphenols, has been reported to provide many health benefits due to its antioxidant properties. In this study, we investigated the effect of Cocoa polyphenols extract (CPE) against oxidative stress-induced cellular senescence using a hydrogen peroxide (H2O2)-induced cellular senescence model in three auditory cells lines derived from the auditory organ of a transgenic mouse: House Ear Institute-Organ of Corti 1 (HEI-OC1), Organ of Corti-3 (OC-k3), and Stria Vascularis (SV-k1) cells. Our results showed that CPE attenuated senescent phenotypes, including senescence-associated β-galactosidase expression, cell proliferation, alterations of morphology, oxidative DNA damage, mitochondrial dysfunction by inhibiting mitochondrial reactive oxygen species (mtROS) generation, and related molecules expressions such as forkhead box O3 (FOXO3) and p53. In addition, we determined that CPE induces expression of sirtuin 1 (SIRT1) and sirtuin 3 (SIRT3), and it has a protective role against cellular senescence by upregulation of SIRT1 and SIRT3. These data indicate that CPE protects against senescence through SIRT1, SIRT3, FOXO3, and p53 in auditory cells. In conclusion, these results suggest that Cocoa has therapeutic potential against age-related hearing loss (ARHL). Instituto de Salud Carlos III, Ministerio de Ciencia, Innovación y Universidades (P19/01524) 6.706 JCR (2021) Q1, 15/90 Nutrition & Dietetics 1.287 SJR (2021) Q1, 19/338 Food Science No data IDR 2021 UEM

Entre 2006 y 2007 se realizaron muestreos mensuales de las capturas de peces obtenidas con chinchorro de arrastre tradicional, donde se registró una porción importante de la ictiofauna caribeña de la plataforma continentalː 10 114 individuos pertenecientes a 16 familias y 31 especies. Las familias Carangidae y Sciaenidae se mencionan entre las de mayor representación del Caribe, mientras que la especie más abundante fue Oligoplites saurus. Del listado de especies, siete se encuentran incluidas en el Libro Rojo de Peces Marinos de Colombia; cinco entre las categorías de En Peligro Crítico (CR) y Vulnerable (VU), y dos en la categoría Casi Amenazada (NT). Estos resultados son un soporte técnico y científico para la toma de decisiones, cumpliendo así con la misión y gestión de conservación para la cual ha sido creada esta área protegida.

Currently, new treatments are required to supplement the current standard of care for head and neck squamous cell carcinoma (HNSCC). The phosphatidylinositol3-kinase (PI3K) signaling pathway is commonly altered and activated in HNSCC. PHT-427 is a dual PI3K-mammalian target of the AKT/PDK1 inhibitor; however, to the best of our knowledge, the effect of the PHT-427 inhibitor on HNSCC has not been investigated. This study aims to evaluate the antitumoral effect of PHT-427-loaded polymeric nanoparticles based on α-tocopheryl succinate (α-TOS). The in vitro activity of PHT-427 was tested in hypopharynx carcinoma squamous cells (FaDu) to measure the cell viability, PI3KCA/AKT/PDK1 gene expression, and PI3KCA/AKT/PDK1 levels. Apoptosis, epidermal growth factor receptor (EGFR), and reactive oxygen species (ROS) were also measured. The presence of PHT-427 significantly enhances its antiproliferative and proapoptotic activity by inactivating the PI3K/AKT/PDK1 pathway. Nanoparticles (NPs) effectively suppress AKT/PDK1 expression. Additionally, NPs loaded with PHT-427 produce high oxidative stress levels that induce apoptosis. In conclusion, these results are promising in the use of this nanoformulation as a PHT-427 delivery system for effective HNSCC treatment., This research was funded by the Spanish Ministry of Science, Innovation, and Universities and CIBER-BBN, grant number MAT2017-84277-R, and by the European University of Madrid, grant numbers 2017/UEM21 and 2019/UEM06

The prognosis of patients with recurrent or metastatic head and neck squamous cell cancer (HNSCC) is generally poor. New treatments are required to supplement the current standard of care. Paclitaxel (PTX), an effective chemotherapeutic for HNSCC, has serious side effects. A polymeric nanocarrier system was developed for the delivery of PTX to improve HNSCC treatment. This study aimed to evaluate the antitumor efficacy of PTX-loaded polymeric nanoparticles based on α-TOS (PTX-NPs) administered by direct intratumoral injection into a Hypopharynx carcinoma squamous cells (FaDu) tumor xenograft mouse model. The nanocarrier system based on block copolymers of polyethylene glycol (PEG) and a methacrylic derivative of α-TOS was synthesized and PTX was loaded into the delivery system. Tumor volume was measured to evaluate the antitumor effect of the PTX-NPs. The relative mechanisms of apoptosis, cell proliferation, growth, angiogenesis, and oxidative and nitrosative stress were detected by Western blotting, fluorescent probes, and immunohistochemical analysis. The antitumor activity results showed that compared to free PTX, PTX-NPs exhibited much higher antitumor efficacy and apoptosis-inducing in a FaDu mouse xenograft model and demonstrated an improved safety profile. Ki-67, EGFR, and angiogenesis markers (Factor VIII, CD31, and CD34) expression were significantly lower in the PTX-NPs group compared with other groups (p, This work was supported by the Universidad Europea de Madrid under Grant 2016/UEM06 and 2017/UEM21; and Error! Hyperlink reference not valid., Biomateriales y Nanomedicina (CIBER-BBN) y la Fundación para la Excelencia y la Calidad en Oncología (ECO).

Age-related hearing loss (ARHL) is an increasing and gradual sensorineural hearing dysfunction. Oxidative stress is an essential factor in developing ARHL, additionally, premature senescence of auditory cells induced by oxidative stress can produce hearing loss. Hydrogen peroxide (H2O2) represents a method commonly used to generate cellular senescence in vitro. The objective of the present paper is to study H2O2-induced senescence patterns in three auditory cell lines (House Ear Institute-Organ of Corti 1, HEI-OC1, organ of Corti, OC-k3, and stria vascularis, SV-k1 cells) to elucidate the intrinsic mechanisms responsible for ARHL. The auditory cells were exposed to H2O2 at different concentrations and times. The results obtained show different responses of the hearing cells concerning cell growth, β-galactosidase activity, morphological changes, mitochondrial activation, levels of oxidative stress, and other markers of cell damage (Forkhead box O3a, FoxO3a, and 8-oxoguanine, 8-oxoG). Comparison between the responses of these auditory cells to H2O2 is a helpful method to evaluate the molecular mechanisms responsible for these auditory cells’ senescence. Furthermore, this in vitro model could help develop anti-senescent therapeutic strategies for the treatment of AHRL.

Dietary antioxidants, polyphenols, have been found to be beneficial in protecting against the generation of oxidative stress in various diseases associated with aging. Age-related hearing loss (AHL) is the number one neurodegenerative disorder on our aged population. Sprague–Dawley rats divided into five groups according to their age (3, 6, 12, 18 and 24 months old) and treated with 100 mg/day/kg body weight of polyphenols were used. Then, cochleae were harvested to measure caspase activities (- 3, - 8 and - 9), caspase-3 gene expression, ATP levels, Bax, BcL-2 and p53 levels. 8-OHdG levels (marker of DNA oxidative damage) and annexin-V were also measured in cochleae. Increased levels of caspase-3 and 9 in cochlea were observed with age and this effect was attenuated by polyphenol treatment. In addition, ATP and Bcl-2 levels in older rats were recovered after administration of polyphenols, while Bax and p53 levels protein decreased. Oral supplementation with polyphenols also reduces DNA oxidative damage of cochlear cell. Treatment with polyphenols inhibits the activation of age-related apoptotic signaling by decreasing oxidative stress inside the rat cochlea. Spanish Fondo de Investigaciones Sanitarias FIS PI09/02472 European University of Madrid 3.805 JCR (2018) Q2, 15/53 Geriatrics & Gerontology 1.301 SJR (2018) Q1, 3/43 Gerontology, 22/114 Geriatrics and Gerontology; Q2, 15/36 Aging No data IDR 2018 UEM

Age-related hearing loss (AHL) –presbycusis– is the number one neurodegenerative disorder and top communication deficit of our aged population. Experimental evidence suggests that mitochondrial dysfunction associated with reactive oxygen species (ROS) plays a central role in the aging process of cochlear cells. Dietary antioxidants, in particular polyphenols, have been found to be beneficial in protecting against the generation of ROS in various diseases associated with oxidative stress, such as cancer, neurodegenerative diseases and aging. Objectives This study was designed to investigate the effects of polyphenols on AHL and to determine whether oxidative stress plays a role in the pathophysiology of AHL. Methods Sprague-Dawley rats (n = 100) were divided into five groups according to their age (3, 6, 12, 18 and 24 months old) and treated with 100 mg/kg/day body weight of polyphenols dissolved in tap water for half of the life of the animal. Auditory steady-state responses (ASSR) threshold shifts were measured before sacrificing the rats. Then, cochleae were harvested to measure total superoxide dismutase (SOD) and glutathione peroxidase (GPx) activities, reactive oxidative and nitrogen species levels, superoxide anions and nitrotyrosine levels. Results Increased levels of ROS and RNS in cochlea observed with age decreases with polyphenol treatment. In addition, the activity of SOD and GPx enzymes in older rats recovered after the administration of polyphenols. Conclusion: The reduction in oxidative and nitrosative stress in the presence of polyphenols correlates with significant improvements in ASSR threshold shifts.

The aim of this work is to study, in an in vitro head and neck squamous cell carcinomas model the anti-angiogenic and anti-migratory properties of self-assembled polymeric nanoparticles (NPs) with demonstrated selective anticancer activity. The NPs are based on &alpha, tocopheryl succinate (&alpha, TOS) encapsulated in the hydrophobic core of the NPs. We analyzed the effect of the newly synthetized &alpha, TOS-loaded NPs in proliferating endothelial cells and hypopharynx carcinoma squamous cells and measured markers of angiogenesis, apoptosis and reactive oxygen species (ROS). &alpha, TOS-loaded NPs suppressed angiogenesis by inducing accumulation of ROS and inducing apoptosis of proliferating endothelial cells. These NPs also decrease the number and quality of capillary-like tubes in an in vitro three-dimensional (3D) experiment, decrease the production of the pro-angiogenic vascular endothelial growth factor and down-regulate the expression of its receptor. The anti-migratory efficacy of &alpha, TOS is corroborated in hypopharynx carcinoma cells by decreasing the secretion of matrix metalloproteases 2 and 9 (MMP-2 and MMP-9) and inhibiting cell migration. These results confirm that &alpha, TOS-based NPs not only present anticancer properties, but also antiangiogenic properties, therefore making them promising candidates for multi-active combinatorial anticancer therapy.

Mechanisms contributing to pulmonary and systemic injury induced by high tidal volume (VT) mechanical ventilation are not well known. We tested the hypothesis that increased peroxynitrite formation is involved in organ injury and dysfunction induced by mechanical ventilation. Male Sprague-Dawley rats were subject to low- (VT, 9 mL/kg; positive end-expiratory pressure, 5 cmH2O) or high- (VT, 25 mL/kg; positive end-expiratory pressure, 0 cmH2O) VT mechanical ventilation for 120 min, and received 1 of 3 treatments: 3-aminobenzamide (3-AB, 10 mg/kg, intravenous, a poly adenosine diphosphate ribose polymerase [PARP] inhibitor), or the metalloporphyrin manganese(III) tetrakis(1-methyl-4-pyridyl)porphyrin (MnTMPyP, 5 mg/kg intravenous, a peroxynitrite scavenger), or no treatment (control group), 30 min before starting the mechanical ventilation protocol (n = 8 per group, 6 treatment groups). We measured mean arterial pressure, peak inspiratory airway pressure, blood chemistry, and gas exchange. Oxidation (fluorescence for oxidized dihydroethidium), protein nitration (immunofluorescence and Western blot for 3-nitrotyrosine), PARP protein (Western blot) and gene expression of the nitric oxide (NO) synthase (NOS) isoforms (quantitative real-time reverse transcription polymerase chain reaction) were measured in lung and vascular tissue. Lung injury was quantified by light microscopy. High-VT mechanical ventilation was associated with hypotension, increased peak inspiratory airway pressure, worsened oxygenation; oxidation and protein nitration in lung and aortic tissue; increased PARP protein in lung; up-regulation of NOS isoforms in lung tissue; signs of diffuse alveolar damage at histological examination. Treatment with 3AB or MnTMPyP attenuated the high-VT mechanical ventilation-induced changes in pulmonary and cardiovascular function; down-regulated the expression of NOS1, NOS2, and NOS3; decreased oxidation and nitration in lung and aortic tissue; and attenuated histological changes. Increased peroxynitrite formation is involved in mechanical ventilation-induced pulmonary and vascular dysfunction. Sin financiación 3.048 JCR (2015) Q1, 33/200 Surgery; Q2, 12/33 Critical care medicine, 29/70 Hematology, 23/63 Peripheral vascular disease UEM

Background: Recurrent tonsillitis might reduce the immunological capability of fighting against the infection of tonsil tissue. Polypodium leucotomos (Anapsos) immunomodulating effect has been subject of research in the last years. The aim of this research is to test the in vitro immunomodulating capacity of Anapsos in a child palatine tonsil explants model. Methods: Palatine tonsils explants of children undergoing amigdalectomy were stimulated with mononuclear cells obtained from their own blood by density gradient centrifugation. Some were then treated with Anapsos while others rest untreated. Cytokines were measured by ELISA, immune cells activation was measured by flow cytometry and activation of immunoglobulins was appreciated by indirect immunofluorescence in tonsils tissue. Results: Anapsos activates Natural Killers cells. It increases IL-2 and IFN-γ levels by the activation of Th2 lymphocytes, and IL-10, by the Th1 lymphocytes. Anapsos also increases immunoglobulins IgM, IgD and IgG4 by Blymphocyte activation in tonsils tissue. Conclusion: Anapsos has an immunomodulating effect, both in humoral and cellular responses, which might benefit children suffering of recurrent tonsillitis as it could enhance their immune system. This effect might reduce the number of episodes suffered and therefore the number of children undergoing surgery. ASAC Pharma Laboratorios Centrum S. A. Alicante 1.225 JCR (2018) Q3, 89/125 Pediatrics; Q4, 34/42 Otorhinilaryngology 0.648 SJR (2018) Q2, 101/318, 37/113 Otorhinolaryngology, 1022/2844 Medicine (miscellaneous) No data IDR 2018 UEM

Resumen El cancer escamoso de cabeza y cuello se caracteriza por su tendencia a la invasion local y a distancia, ademas de una alta predisposicion a la aparicion de segundas neoplasias. El proceso de invasion y metastasis es complejo y tiene multiples etapas. Las metaloproteinasas de matriz 2 y 9, se sobreexpresan en el cancer escamoso de cabeza y cuello donde actuan degradando la membrana extracelular favoreciendo asi la invasion tumoral y la metastasis. El bacilo de Calmette-Guerin (BCG) ha sido usado como inmunomodulador en el tratamiento de algunos tipos de cancer con buenos resultados. El proposito de este estudio es determinar el efecto de la activacion inmune mediada por el BCG sobre la migracion e invasion usando un modelo in vitro 3 D de cultivos de celulas tumorales de faringe cocultivadas con celulas mononucleares de sangre periferica en contacto o no con el BCG. Para determinar la expresion de las metaloproteinasas y p53 se realizo Western blot y para la migracion e invasion, kits comerciales. Los resultados muestran disminucion en la expresion de metaloproteinasas, p53 y en la migracion en el grupo BCG.

The results support the idea that auditory steady-state response (ASSR) is a more accurate test for studying age-related hearing loss (ARHL) in Sprague-Dawley rats. Differences in the rat middle ear may explain the variations of the click properties, with a displacement of the energy toward the 8 and 10 kHz frequencies compared with humans.The purpose of this study was to evaluate ARHL in older and younger Sprague-Dawley rats using auditory clicks and tone burst with auditory brainstem response (ABR), in addition to ASSR.This was a prospective cohort study with 50 animals divided into 5 groups based on their age in months. A total of 100 registers were elicited from each one of the 3 auditory measurements systems in an electrically shielded, double-walled, sound-treated cabin. Nine frequencies, from 0.5 to 16 kHz were analyzed with the auditory steady-state response and compared with the results elicited by the clicks and tone-burst ABR.Comparisons between the different frequencies showed lower thresholds in those frequencies below 2 kHz, independently of their age in months. The ARHL was detected by each one of the three auditory measurement systems, but with lower thresholds with the ASSR test. Finally, auditory clicks showed better correlations with 8 and 10 kHz elicited by ASSR, which was different to what was expected, based on human studies.

Head and neck squamous cell carcinoma (HNSCC) is one of the most frequent cancers worldwide and is associated with poor survival and significant treatment morbidity. The immune profile in patients with HNSCC is immunosuppressive and presents cytokine-mediated adaptive immune responses, triggered apoptosis of T cells, and alterations in antigen processing machinery. Bacille Calmette-Guerin (BCG) immunotherapy has been used successfully as a treatment for several types of cancer. In the present study, we sought to determine the antitumor effect of soluble mediators from peripheral blood mononuclear immune cells (PBMCs) activated with BCG vaccine in a three-dimensional coculture model of HNSCC growth using FaDu hypopharynx carcinoma squamous cells. BCG activation of PBMCs led to an increase in CD4+ and CD8+ lymphocyte subsets concomitant with an elevation in the levels of the antitumor cytokines IL-6, TNF-α and IFN-γ, and a EGFR in FaDu cells. In addition, coculture with BCG-activated PBMCs reduced FaDu proliferation and increased cytotoxicity and apoptosis in parallel with an increase in caspase-3 activity and p53 expression. Finally, conditioned medium from BCG-activated PBMCs reduced the levels of the angiogenic factors vascular endothelial growth factor and angiopoietin-2 produced by human aortic endothelial cells (HAECs), and inhibited their proliferation and differentiation into capillary-like structures. Taken together, these results demonstrate that BCG vaccination induces antitumor responses in an HNSCC in vitro model and suggest that the BCG vaccine could be an effective alternative therapy for the treatment of HNSCC. Sin financiación 3.285 JCR (2017) Q2, 73/155 Immunology, 52/133 Medicine, Research and Experimental UEM

Background: Apoptosis and inflammatory/oxidative stress have been associated with hyperglycemia in human peritoneal mesothelial cells (HPMCs) and other cell types. We and others have highlighted the role of early products of non-enzymatic protein glycation in inducing proinflammatory conditions and increasing apoptotic rates in HPMCs. Loss of HPMCs seems to be a hallmark of complications associated with peritoneal membrane dysfunction. The aim of this work is to elucidate the mechanisms by which Amadori adducts may act upon HPMC apoptosis. Methods: HPMCs isolated from different patients were exposed to different Amadori adducts, i.e. highly glycated hemoglobin (10 nM) and glycated bovine serum albumin (250 µg/ml), to study cell death and several proapoptotic markers by different experimental approaches. Results: Amadori adducts, but not their respective controls, impaired cell proliferation and cell viability by means of apoptosis in a time-dependent manner. They regulated the intrinsic mitochondrial cell death signaling pathway and modulated activation of caspases, Bax, iNOS, p53, NF-ĸB, and mitogen-activated protein kinases (p38 and JNK) through different reactive oxygen and nitrosative species. Conclusions: Our data strongly support the idea that long-term hyperglycemia could act as an inducer of apoptosis in HPMCs through Amadori adducts, involving different oxidative and nitrosative reactive species.

EGb761 treatment has a significant benefit with an early and preventive effect, reversing the deleterious effect of aging in the integrity of the rat cochlea, even in the late stage of the rat lifespan.We previously reported a significant relationship between aging and apoptosis in the rat cochlea. This study was designed to investigate the effects of Ginkgo biloba leaf extract (EGb761) on age-associated cochlear caspase activation.Sprague-Dawley rats (n = 80) divided into two groups according to their age (4 months old, younger, YR, and 12 months old, aged-mature, AM) were treated with 100 mg/kg/day body weight of EGb761 extract dissolved in tap water for two periods: 4 and 12 months. Then cochleae were harvested to measure caspase activities, ATP levels, total superoxide dismutase (SOD) activity, and caspase-3 gene expression. Auditory steady-state responses (ASSR) threshold shifts were also measured before sacrifice of the rats.EGb761 treatment prevents significantly aging-related caspase-induced activities within the cochleae in YR and AM rats. In the short EGb761 treatment, YR rats showed lower levels of caspase-3/7 than AM rats. In contrast, longer treatment did not show significant differences between YR and AM rats. Reduced caspase-3/7 activity in presence of EGb761 correlates with significant improvements of ASSR threshold shifts.

Background:Exposure to cisplatin leads to cochlear cell death by apoptosis; these changes are most marked on the seventh day after exposure. Heat shock proteins are induced in inner ear cells in response to a variety of stimuli. This study examined the role of heat shock protein 70 in cisplatin-induced cochlear cell death.Methods:Fifty-six Sprague–Dawley rats were involved. Some were injected with cisplatin (5 mg/kg body weight), some with cisplatin plus the caspase inhibitor Z-Asp(OMe)-Glu(OMe)-Val-Asp(OME)-fluoromethylketone (5 mg/kg body weight) and others were left as controls (being injected only with saline). Seven days later, we examined the expression of heat shock protein 70 and several other apoptosis-related proteins within the rat cochlear cells; we also assessed total superoxide dismutase activity, auditory brainstem response and auditory steady state response.Results:Seven days after cisplatin injection, significantly increased expression of heat shock protein 70 was found within the rat cochleae. This correlated with increased executioner caspase levels, total superoxide dismutase activity and auditory brainstem response thresholds, and a significant elevation in auditory steady state response thresholds. Inhibition of caspase-3 activity significantly reduced cochlear heat shock protein 70 expression and total superoxide dismutase activity, and improved auditory brainstem response and auditory steady state response thresholds.Conclusions:Seven days after cisplatin exposure, we found disturbances of the cochlear cellular machinery involving heat shock protein 70, other apoptotic proteins and total superoxide dismutase.

Background and purpose: Ototoxicity is a known adverse effect of cisplatin (CDDP). Since apoptosis is involved in the development of some pathological conditions associated with the administration of anticancer drugs, we examined, using immunohistochemical and electrophysiological techniques, the apoptotic changes in the cochlea of Sprague-Dawley (SD) rats after an injection of CDDP (5 mgkg-1 body weight). Experimental approach: Luciferase assays were used to determine the different caspase activities and ATP levels in protein extracts of whole cochleae. The expression of several apoptotic-related proteins was measured by means of Western blotting. These analyses were performed 2, 7 and 30 days after the CDDP injection. The auditory brain stem response was obtained before and at the different times after the injection of CDDP, before the animals were killed. Key results: CDDP significantly increased the levels of caspase-3/7 activity and active caspase-3 protein expression and caspase-3 immunofluorescence staining, caspase-9 activity, and Bax protein expression but decreased Bcl-2 protein expression within the rat cochleae. Threshold shifts were significantly elevated 2 days after CDDP treatment. Conclusions and implications: These findings support the hypothesis that cisplatin-related apoptosis evokes an intrinsic pathway of pro-apoptotic signalling within the rat cochleae. Thus, selective inhibition of the sequence of events involved in the intrinsic apoptotic pathway could provide a strategy to minimize cisplatin-induced ototoxicity. British Journal of Pharmacology (2007) 152, 1012–1020; doi:10.1038/sj.bjp.0707405; published online 1 October 2007

The aim of this work is the preparation of an active nanovehicle for the effective administration of α-tocopheryl succinate (α-TOS). α-TOS is loaded in the core of nanoparticles (NPs) based on amphiphilic pseudo-block copolymers of N-vinyl pyrrolidone and a methacrylic derivative of α-TOS. These well-defi ned spherical NPs have sizes below 165 nm and high encapsulation effi - ciencies. In vitro activity of NPs is tested in hypopharynx squamous carcinoma (FaDu) cells and nonmalignant epithelial cells, demonstrating that the presence of additional α-TOS signifi cantly enhances its antiproliferative activity; however, a range of selective concentrations is observed. These NPs induce apoptosis of FaDu cells by activating the mitochondria death pathway (via caspase-9). Both loaded and unloaded NPs act via complex II and produce high levels of reactive oxygen species that trigger apoptosis. Additionally, these NPs effectively suppress the vascular endothelial growth factor (VEGF) expression of human umbilical vein endothelial cells (HUVECs). These results open the possibility to use this promising nanoformulation as an α-TOS delivery system for the effective cancer treatment, effectively resolving the current limitations of free α-TOS administration. Ministerio de Economía y Competitividad MAT2010-18155; Proyecto Fundación CIBER BBN-ECO; Universidad Europea de Madrid 3.238 JCR (2016) Q1, 17/86 Polymer Science; Q2, 112/290 Biochemistry and Mollecular Biology, 13/33 Materials Science, Biomaterials UEM

Background and purpose: Diabetes mellitus is prevalent in the elderly population. It is also a disease causing tissue damage through several different mechanisms. Some of these mechanisms are also activated by ageing and this overlap raises questions about how diabetes induces damage in the elderly. Early products of non-enzymatic glycation of proteins (Amadori adducts), and the ageing process share the capacity to induce oxidative stress and inflammation in human peritoneal mesothelial cells (HPMCs). We have evaluated the interactions between the age of the donor of the HPMCs and the pro-inflammatory effects of Amadori adducts in those cells. Experimental approach: HPMCs were isolated from 20 individuals (age range 21–81 years) and grown in culture. Using different experimental approaches we determined NF-κB dependent transcriptional activity and different NF-κB-related pro-inflammatory gene and protein expressions in basal (or non-stimulated) conditions and after stimulation with two Amadori adducts; highly-glycated haemoglobin and glycated bovine serum albumin. Key results: Amadori-induced effects on NF-κB dependent-transcription and on the activity of NOS, COX and several NF-κB-related pro-inflammatory genes (iNOS, COX-2, TNF-α, IL-1β, and IL6) diminished as the donor's age increased, being practically absent in cells from donors more than 65 years old. Such decreased effects were inversely correlated with an increased basal expression and activity of these pro-inflammatory markers with age. Conclusions and implications: Pro-inflammatory effects of Amadori-adducts in HPMCs were strongly dependent on cell donor's age. This may have significant implications for the mechanisms underlying diabetes-induced tissue damage in patients of different ages. British Journal of Pharmacology (2006) 149, 979–987. doi:10.1038/sj.bjp.0706864

¿-Tocopheryl succinate (¿-TOS) is a well-known mitochondrially targeted anticancer compound, however, it is highly hydrophobic and toxic. In order to improve its activity and reduce its toxicity, new surfactant-free biologically active nanoparticles (NP) were synthesized. A methacrylic derivative of ¿-TOS (MTOS) was prepared and incorporated in amphiphilic pseudoblock copolymers when copolymerized with N-vinylpyrrolidone (VP) by free radical polymerization (poly(VP-co-MTOS)). The selected poly(VP-co-MTOS) copolymers formed surfactant-free NP by nanoprecipitation with sizes between 96 and 220 nm and narrow size distribution, and the in vitro biological activity was tested. In order to understand the structure-activity relationship three other methacrylic monomers were synthesized and characterized: MVE did not have the succinate group, SPHY did not have the chromanol ring, and MPHY did not have both the succinate group and the chromanol ring. The corresponding families of copolymers (poly(VP-co-MVE), poly(VP-co-SPHY), and poly(VP-co-MPHY)) were synthesized and characterized, and their biological activity was compared to poly(VP-co-MTOS). Both poly(VP-co-MTOS) and poly(VP-co-MVE) presented triple action: reduced cell viability of cancer cells with little or no harm to normal cells (anticancer), reduced viability of proliferating endothelial cells with little or no harm to quiescent endothelial cells (antiangiogenic), and efficiently encapsulated hydrophobic molecules (nanocarrier). The anticancer and antiangiogenic activity of the synthesized copolymers is demonstrated as the active compound (vitamin E or ¿-tocopheryl succinate) do not need to be cleaved to trigger the biological action targeting ubiquinone binding sites of complex II. Poly(VP-co-SPHY) and poly(VP-co-MPHY) also formed surfactant-free NP that were also endocyted by the assayed cells; however, these NP did not selectively reduce cell viability of cancer cells. Therefore, the chromanol ring of the vitamin E analogues has an important role in the biological activity of the copolymers. Moreover, when succinate moiety is substituted and vitamin E is directly linked to the macromolecular chain through an ester bond, the biological activity is maintained., Authors acknowledge Dr. Gema Rodriǵ uez, Lautaro Biancotto, David Goḿ ez, and Rosa Ana Ramiŕ ez for their help in AFM, SEM/TEM, and cell culture experiments. Authors also thank Dr. M.P. Murphy for providing MitoQ for the experiments. This work was funded by the Spanish Ministry of Economy and Competitiveness (MAT2010−18155), Eugenio Rodriǵ uez Pascual Foundation, CIBER BBN-ECO Foundation project, and the European University of Madrid.

Aging causes histological, electrophysiological and molecular changes in the cochlea. The free radical theory of aging, has obtained consensus, and the mitochondrion is reported to play a key role in aging as a major source of reactive oxygen species. In the last years, there has been a significant increase in the interest in polyphenols because of the antioxidant properties and their role in the prevention of various diseases associated with oxidative stress, including aging. The aim of this study was to evaluate the preventive effect of different polyphenols on ARHL with auditory-evoked potentials. 100 Healthy female Sprague–Dawley (SD) rats were used for this study. Five groups were created based on the age of the rats, in months: 3, 6, 12, 18 and 24 months old. Two additional groups were created based on the treatment received. In the control group, 50 animals were assigned to no treatment. In the treated group, 50 animals were given a vehicle mixture of polyphenols for the half of the life before euthanization. Nine frequencies were tested (0.5–16 kHz) with ASSR and tone-burst ABR, performed on all of the rats prior to sacrifice. 100-μs auditory clicks ABRs were also recorded. A significant decrease in the audition was detected with ABR and ASSR in both treated and non-treated groups, as the different groups became older. This deterioration was more accurately measured at acute frequencies. Significantly lower thresholds were observed in the treated rats in the 6, 12 and 18-month-old group in the treated rats compared with the control group. All of the thresholds elicited using the ASSR technique were lower than the thresholds obtained using the ABR, regardless of the stimulus type. The present study demonstrated the benefits of the polyphenols, which generated a significant protection against ARHL, with significantly improved ASSR and tone-burst ABR auditory thresholds in rats receiving treatment with polyphenols.

The mechanisms involved in sepsis-induced acute kidney injury (AKI) are unknown. We investigated the role of nitrosative stress in sepsis-induced AKI by studying the effects of manganese (III) tetrakis-(1-methyl-4-pyridyl) porphyrin pentachloride (MnTMPyP), a peroxynitrite decomposition catalyst, and aminoguanidine (AG), a selective nitric oxide synthase 2 (NOS2) inhibitor and peroxynitrite scavenger, on kidney function of rats subjected to cecal ligation and puncture (CLP). Sprague-Dawley rats (weighing 350 [SD, 50] g) were treated with MnTMPyP (6 mg/kg i.p.) or AG (50 mg/kg i.p.) at t = 12 and 24 h after CLP or sham procedure. At t = 36 h, mean arterial pressure and aortic blood flow were measured, and blood and urine samples were obtained for biochemical determinations, including creatinine clearance, fractional excretion of sodium, and neutrophil gelatinase-associated lipocalin concentration in the urine. Kidney tissue samples were obtained for (i) light microscopy, (ii) immunofluorescence and Western blot for 3-nitrotyrosine and NOS2, (iii) gene expression (quantitative real-time polymerase chain reaction) studies (NOS1, NOS2, NOS3, and superoxide dismutase 1), and (iv) matrix-assisted laser desorption ionization time-of-flight mass spectrometry. Mean arterial pressure was unchanged and aortic blood flow decreased 25% in CLP animals. The sepsis-induced (i) decreased urine output and creatinine clearance and increased fractional excretion of sodium and urinary neutrophil gelatinase-associated lipocalin concentration, (ii) increased protein nitration and NOS2 protein, and (iii) NOS1 and NOS2 upregulation were all significantly attenuated by treatment with MnTMPyP or AG. Nitrated proteins in renal tissue from CLP animals (matrix-assisted laser desorption ionization time-of-flight mass spectrometry) were glutamate dehydrogenase, methylmalonate-semialdehyde dehydrogenase, and aldehyde dehydrogenase, mitochondrial proteins involved in energy metabolism or antioxidant defense. Nitro-oxidative stress is involved in sepsis-induced AKI, and protein nitration seems to be one mechanism involved.

To demonstrate that increased formation of reactive oxygen (ROS) and nitrogen species (RNS) is involved in VILI-induced vascular dysfunction.Male Sprague-Dawley anesthetized rats were ventilated for 60 min using low V(T) ventilation [V(T) 9 ml/kg, positive end-expiratory pressure (PEEP) 5 cmH(2)O, n = 18], and high V(T) ventilation (V(T) 35 ml/kg, zero PEEP, n = 18). Arterial pressure and respiratory system mechanics were monitored. Blood samples for the determination of arterial blood gases and lactate concentration were drawn. Vascular rings from the thoracic aortae were mounted in organ baths for isometric tension recording. We studied endothelium-dependent relaxation in norepinephrine-precontracted rings (acetylcholine, 10 nM-10 microM) and contraction induced by norepinephrine (1 nM-10 microM) in resting vessels. Vascular rings were preincubated for 30 min with Zn-Mn-SOD (100 u/ml) or tempol (10(-4) M) (extracellular and intracellular superoxide scavengers, respectively) or MnTMPyP (10(-5) M) (a superoxide and peroxynitrite scavenger). The presence of superoxide and nitrotyrosine in aortic rings was evaluated by immunofluorescence.High V(T) ventilation induced hypotension, systemic acidosis, hypoxemia and hyperlactatemia, as well as impairment in acetylcholine and norepinephrine-induced responses in vitro. Responses to acetylcholine were improved by tempol (P = 0.004) and completely corrected (P0.001) by MnTMPyP. Responses to norepinephrine were also improved by treatment with tempol (P0.001) and MnTMPyP (P0.001). However, Zn-Mn-SOD did not improve acetylcholine- or norepinephrine-induced responses. Immunostaining for both superoxide and nitrotyrosine was increased in aortic rings from the high V(T) group.Our data support a role for intracellular ROS and peroxynitrite in the high V(T) ventilation-induced vascular dysfunction.

This is an open-access article distributed under the terms of the Creative Commons Attribution License.-- et al., A hallmark feature of Williams-Beuren Syndrome (WBS) is a generalized arteriopathy due to elastin deficiency, presenting as stenoses of medium and large arteries and leading to hypertension and other cardiovascular complications. Deletion of a functional NCF1 gene copy has been shown to protect a proportion of WBS patients against hypertension, likely through reduced NADPH-oxidase (NOX)-mediated oxidative stress. DD mice, carrying a 0.67 Mb heterozygous deletion including the Eln gene, presented with a generalized arteriopathy, hypertension, and cardiac hypertrophy, associated with elevated angiotensin II (angII), oxidative stress parameters, and Ncf1 expression. Genetic (by crossing with Ncf1 mutant) and/or pharmacological (with ang II type 1 receptor blocker, losartan, or NOX inhibitor apocynin) reduction of NOX activity controlled hormonal and biochemical parameters in DD mice, resulting in normalized blood pressure and improved cardiovascular histology. We provide strong evidence for implication of the redox system in the pathophysiology of the cardiovascular disease in a mouse model of WBS. The phenotype of these mice can be ameliorated by either genetic or pharmacological intervention reducing NOX activity, likely through reduced angII-mediated oxidative stress. Therefore, anti-NOX therapy merits evaluation to prevent the potentially serious cardiovascular complications of WBS, as well as in other cardiovascular disorders mediated by similar pathogenic mechanism., This work was supported by grants from the Spanish Ministry of Science and Innovation of Health (FIS 07/0059 to VC, FIS 10/2512 to LAP-J, RD06/0020/0001 to XRB) and the VI Framework Programme of the European Union (LSHG-CT-2006-037627 to LAP-J). VC is a Miguel Servet FIS Investigator (CP04/00068). MS-P is supported by a CIBERER Fellowship. MM-M is supported by the CSIC JAE-Doc program.