81 results on '"Martí-Rodrigo A"'
Search Results
2. Impact of pharmacist-led interventions in identifying and resolving drug related problems and potentially inappropriate prescriptions among rural patients: A pilot study
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Salvador Gutiérrez-Igual, Rut Lucas-Domínguez, José Sendra-Lillo, Alberto Martí-Rodrigo, Isabel Romero Crespo, and M. Carmen Montesinos
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Medication review ,Clinical pharmacy services ,Drug-related problems ,Potentially inappropriate prescriptions ,Rural health ,Pharmacy and materia medica ,RS1-441 - Abstract
Background: Drug-related problems are a major problem that can lead to increased morbidity, mortality, and healthcare costs due to heightened medical visits, hospital readmissions, or emergency room visits. In rural areas, new tools for clinical pharmacy services, such as medication review, could decrease this problem. Objective: To analyze the prevalence of clinically relevant drug-related problems (DRPs) and potentially inappropriate prescriptions (PIPs) identified by new medication review software (Revisem®) in rural pharmacies. The effectiveness of resolving DRPs and PIPs in patients who received pharmacist-led intervention (PLI) was also evaluated. Methods: A prospective, multicenter, observational pilot study in 17 rural pharmacies from the Valencian region (Spain) was conducted over a period of 6 months. Revisem®, a type 1 medication review software, was developed and implemented to detect and resolve drug-related issues (DRPs and PIPs). The clinical history of 135 polymedicated patients was recorded, as well as the PLI conducted after the identification of incidences. The mean number of DRPs and PIPs before and after PLI were analyzed and compared. Findings: A total of 1545 drug-related issues were detected in 135 patients (86 women). 1166 were DRPs and 379 were PIPs. Interactions were the most common incidence (43.7 %), with furosemide and omeprazole being the drugs with the highest number of significant interactions. In the before-after intervention study, the mean number of incidents detected per patient by Revisem® decreased from 9.7 ± 6.9 to 8.8 ± 6.9 (p
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- 2024
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3. Impact of pharmacist-led interventions in identifying and resolving drug related problems and potentially inappropriate prescriptions among rural patients: A pilot study
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Gutiérrez-Igual, Salvador, Lucas-Domínguez, Rut, Sendra-Lillo, José, Martí-Rodrigo, Alberto, Crespo, Isabel Romero, and Montesinos, M. Carmen
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- 2024
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4. A renal clearable fluorogenic probe for in vivo β-galactosidase activity detection during aging and senolysis
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Sara Rojas-Vázquez, Beatriz Lozano-Torres, Alba García-Fernández, Irene Galiana, Ana Perez-Villalba, Pablo Martí-Rodrigo, M. José Palop, Marcia Domínguez, Mar Orzáez, Félix Sancenón, Juan F. Blandez, Isabel Fariñas, and Ramón Martínez-Máñez
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Science - Abstract
Abstract Accumulation of senescent cells with age leads to tissue dysfunction and related diseases. Their detection in vivo still constitutes a challenge in aging research. We describe the generation of a fluorogenic probe (sulfonic-Cy7Gal) based on a galactose derivative, to serve as substrate for β-galactosidase, conjugated to a Cy7 fluorophore modified with sulfonic groups to enhance its ability to diffuse. When administered to male or female mice, β-galactosidase cleaves the O-glycosidic bond, releasing the fluorophore that is ultimately excreted by the kidneys and can be measured in urine. The intensity of the recovered fluorophore reliably reflects an experimentally controlled load of cellular senescence and correlates with age-associated anxiety during aging and senolytic treatment. Interestingly, our findings with the probe indicate that the effects of senolysis are temporary if the treatment is discontinued. Our strategy may serve as a basis for developing fluorogenic platforms designed for easy longitudinal monitoring of enzymatic activities in biofluids.
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- 2024
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5. Nuevas herramientas para la revisión de la medicación: PRM en pacientes en tratamiento con inhibidores de la bomba de protones
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Salvador Gutiérrez-Igual, Rut Lucas-Domínguez, Alberto Martí Rodrigo, Isabel Romero Crespo, and M Carmen Montesinos Mezquita
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Drug Related Problem ,Community pharmacy ,Proton Pump Inhibitor ,Omeprazole ,Revisem® digital platform ,Medicine (General) ,R5-920 - Abstract
Resumen: Objetivo: Analizar mediante el programa de revisión de la medicación, Revisem®, la prevalencia de problemas relacionados con la medicación (PRM) en pacientes de la provincia de Valencia que estaban en tratamiento activo con inhibidores de la bomba de protones (IBP) en 2022. Diseño: Estudio observacional descriptivo y retrospectivo. Material y métodos: Se analizó el historial farmacoterapéutico (HFT) de 295 pacientes siguiendo los criterios propuestos por la Pharmaceutical Care Network Europe, utilizando la plataforma digital Revisem® del Muy Ilustre Colegio Oficial de Farmacéuticos de Valencia (MICOF). Resultados: La edad media de los pacientes fue 81,8 ± 11,1 años y 66,4% fueron mujeres. Se detectó al menos un PRM en 97,3% de los pacientes. De los PRM analizados, 46,9% fueron interacciones, de las cuales 29,7% implicaban un IBP, siendo el omeprazol el de mayor frecuencia. Los PRM con IBP se relacionan de forma significativa con determinadas condiciones del paciente y grupos farmacológicos, como son el sexo femenino, la edad superior a 54 años y la polifarmacia. Conclusiones: La plataforma digital Revisem®, permite la detección de una alta prevalencia de PRM a nivel provincial. La aplicación de nuevas herramientas tecnológicas para detectar la prevalencia de PRM es fundamental para optimizar los tratamientos de los pacientes. Abstract: Objective: To analyze, using the medication review program, Revisem®, the prevalence of drug-related problems (DRP) in patients in the province of Valencia who were on active treatment with proton pump inhibitors (PPI) in 2022. Design: Descriptive and retrospective observational study. Material and methods: The pharmacotherapeutic history of 295 patients was analyzed following the criteria proposed by the Pharmaceutical Care Network Europe, using the Revisem® digital platform of the Muy Ilustre Colegio Oficial de Farmacéuticos (MICOF). Results: The mean age of the patients was 81.8 ± 11.1 years and 66.4% were women. At least one DRP was detected in 97.3% of patients. 46.9% of the DRP analyzed were interactions, of which 29.7% involved a PPI, with omeprazole being the most frequent. DRPs with PPI are significantly related to certain patient conditions and pharmacological groups, such as female sex, age over 54 years and polypharmacy. Conclusions: The application of the Revisem® digital platform allows the detection of a high prevalence of DRP at the provincial level. The application of new technological tools to detect the prevalence of DRP is essential to optimize patient treatments.
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- 2024
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6. Nuevas herramientas para la revisión de la medicación: PRM en pacientes en tratamiento con inhibidores de la bomba de protones
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Gutiérrez-Igual, Salvador, Lucas-Domínguez, Rut, Martí Rodrigo, Alberto, Romero Crespo, Isabel, and Montesinos Mezquita, M Carmen
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- 2024
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7. Prolonged estrogen deprivation triggers a broad immunosuppressive phenotype in breast cancer cells
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Daniela Hühn, Pablo Martí‐Rodrigo, Silvana Mouron, Catherine Hansel, Kirsten Tschapalda, Bartlomiej Porebski, Maria Häggblad, Louise Lidemalm, Miguel Quintela‐Fandino, Jordi Carreras‐Puigvert, and Oscar Fernandez‐Capetillo
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breast cancer ,estrogen receptor ,HLA ,immunotherapy ,inflammation ,PD‐L1 ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Among others, expression levels of programmed cell death 1 ligand 1 (PD‐L1) have been explored as biomarkers of the response to immune checkpoint inhibitors in cancer therapy. Here, we present the results of a chemical screen that interrogated how medically approved drugs influence PD‐L1 expression. As expected, corticosteroids and inhibitors of Janus kinases were among the top PD‐L1 downregulators. In addition, we identified that PD‐L1 expression is induced by antiestrogenic compounds. Transcriptomic analyses indicate that chronic estrogen receptor alpha (ERα) inhibition triggers a broad immunosuppressive program in ER‐positive breast cancer cells, which is subsequent to their growth arrest and involves the activation of multiple immune checkpoints together with the silencing of the antigen‐presenting machinery. Accordingly, estrogen‐deprived MCF7 cells are resistant to T‐cell‐mediated cell killing, in a manner that is independent of PD‐L1, but which is reverted by estradiol. Our study reveals that while antiestrogen therapies efficiently limit the growth of ER‐positive breast cancer cells, they concomitantly trigger a transcriptional program that favors their immune evasion.
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- 2022
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8. 9. Frente 3 de Fevereiro Project Description
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Martí, Rodrigo, primary
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- 2020
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9. 3. Grupo Etcétera Project Description
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Martí, Rodrigo, primary
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- 2020
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10. Macrophages Modulate Hepatic Injury Involving NLRP3 Inflammasome: The Example of Efavirenz
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Fernando Alegre, Alberto Martí-Rodrigo, Miriam Polo, Dolores Ortiz-Masiá, Celia Bañuls, Marcello Pinti, Ángeles Álvarez, Nadezda Apostolova, Juan V. Esplugues, and Ana Blas-García
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antiviral therapy ,inflammation ,fibrogenesis ,DILI ,macrophage polarization ,Biology (General) ,QH301-705.5 - Abstract
Drug-induced liver injury (DILI) constitutes a clinical challenge due to the incomplete characterization of the mechanisms involved and potential risk factors. Efavirenz, an anti-HIV drug, induces deleterious actions in hepatocytes that could underlie induction of the NLRP3 inflammasome, an important regulator of inflammatory responses during liver injury. We assessed the potential of efavirenz to modulate the inflammatory and fibrogenic responses of major liver cell types involved in DILI. The effects of efavirenz were evaluated both in vitro and in vivo. Efavirenz triggered inflammation in hepatocytes, in a process that involved NF-κB and the NLRP3 inflammasome, and activated hepatic stellate cells (HSCs), thereby enhancing expression of inflammatory and fibrogenic markers. The NLRP3 inflammasome was not altered in efavirenz-treated macrophages, but these cells polarized towards the anti-inflammatory M2 phenotype and displayed upregulated anti-inflammatory mediators. Conversely, no evidence of damage was observed in efavirenz-treated animals, except when macrophages were depleted, which resulted in the in vivo manifestation of the deleterious effects detected in hepatocytes and HSCs. Efavirenz elicits a cell-specific activation of the NLRP3 inflammasome in hepatocytes and HSCs, but macrophages appear to counteract efavirenz-induced liver injury. Our results highlight the dynamic nature of the interaction among liver cell populations and emphasize the potential of targeting macrophage polarization as a strategy to treat NLRP3 inflammasome-induced liver injury.
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- 2022
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11. Coinfección virus de inmunodeficiencia humana-virus de la Hepatitis C: hacia un nuevo escenario terapéutico
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Víctor García-Bustos, Juan Vicente Esplugues-Mota, and Alberto Martí Rodrigo
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Medicine (General) ,R5-920 ,Public aspects of medicine ,RA1-1270 - Abstract
Introducción: Las terapias contra el virus de la Hepatitis C han evolucionado vertiginosamente con el desarrollo de los antivirales de acción directa (AADs). Los nuevos regímenes han conseguido igualar las tasas de respuesta al tratamiento en los monoinfectados y los coinfectados con VIH, una población tradicionalmente difícil de tratar debido a la elevada morbimortalidad hepática y sistémica, reacciones adversas e interacciones medicamentosas. Objetivo: Analizar las opciones farmacoterapéuticas más modernas disponibles para los pacientes coinfectados con VIH y VHC, con énfasis en los nuevos antivirales de acción directa, a fin de ofrecer una herramienta útil en el abordaje terapéutico en estos pacientes. Material y métodos: Se revisaron artículos originales, ensayos clínicos y revisiones sistemáticas hasta septiembre de 2016, bases de datos internacionales de interacciones medicamentosas y Guías de Práctica Clínica actualizadas. Desarrollo: Las terapias contra el virus de la Hepatitis C (VHC) han evolucionado vertiginosamente con el desarrollo de los antivirales de acción directa (AADs). Los nuevos regímenes han conseguido igualar las tasas de respuesta al tratamiento en los monoinfectados y los coinfectados con VIH, una población tradicionalmente difícil de tratar que, además, asociaba una elevada morbimortalidad hepática y sistémica, más reacciones adversas y complejas interacciones medicamentosas. Conclusiones: En este nuevo escenario es fundamental dedicar esfuerzos a identificar el elevado porcentaje de infectados no diagnosticados, potenciales interacciones, especialmente con fármacos para patologías asociadas al envejecimiento de los pacientes, reacciones adversas a medio-largo plazos y desarrollo de resistencias, además de garantizar la cobertura universal en todos los contextos clínicos.Palabras claves: Coinfección VIH/VHC, Tratamiento VIH/VHC, Hepatitis C, VIH, Antivirales de acción directa, AAD.
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- 2017
12. PREOPERATIVE VITREORETINAL INTERFACE ABNORMALITIES ON SPECTRAL DOMAIN OPTICAL COHERENCE TOMOGRAPHY AS RISK FACTOR FOR PSEUDOPHAKIC CYSTOID MACULAR EDEMA AFTER PHACOEMULSIFICATION
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Copete, Sergio, Martí-Rodrigo, Pablo, Muñiz-Vidal, Romina, Pastor-Idoate, Salvador, Rigo, Jaume, Figueroa, Marta S., García-Arumí, JOSÉ, and Zapata, Miguel A.
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- 2019
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13. Macular optical coherence tomography for screening of pathology prior to cataract surgery: An approach based on tele-evaluation
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A. Herranz-Cabarcos, Z. Vega-López, O. Salas-Fandos, MJ Quiroz-Quiroga, P. Burgos-Fernández, P. Martí-Rodrigo, M. Castilla-Marti, V. Poposki, and AR. Martínez-Palmer
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Ophthalmology ,genetic structures ,Humans ,Epiretinal Membrane ,Cataract Extraction ,Prospective Studies ,sense organs ,General Medicine ,Cataract ,Tomography, Optical Coherence ,eye diseases - Abstract
Background To assess the benefit of macular spectral-domain optical coherence tomography (SD-OCT) as a part of the routinary preoperative study of patients undergoing cataract surgery. Methods A prospective single-center study study was performed. Consecutive patients with normal biomicroscopic funduscopy, moderate cataract and no history of ophthalmological pathologies were enrolled. All patients underwent macular SD-OCT. The obtained images were analysed by a general ophthalmologist and two retina specialists. Incidence of macular pathology and its relation to age and comorbidities were assessed. Results Eight-hundred and thirty-six eyes of 419 patients were enrolled in this study. All images were analysed telematically by a general ophthalmologist. Forty-nine eyes were excluded due to insufficient quality of the obtained images. Abnormal images were observed in 156 eyes (18.6%), including age-related macular degeneration in 68 (8.2%), epiretinal membrane (ERM) in 67 (8.0%), cystoid macular edema in 3 eyes (0.4%), among others. Diagnostics with severe impact on patient visual prognosis were observed in 16 eyes (3.82%) from 12 patients. The relationship between incidence of macular pathologies and age or comorbidities was not statistically significant. To assess accuracy of the first observer, images were subsequently analysed by two retinologists. The kappa index of concordance was 0.80 and 0.85. Conclusions Implementing a systematic macular SD-OCT as a preoperative test prior to cataract surgery would improve quality of postoperative visual prognosis information. A general ophthalmologist would be suitable to screen for pathology through macular OCT images.
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- 2022
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14. Prolonged estrogen deprivation triggers a broad immunosuppressive phenotype in breast cancer cells
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Maria Häggblad, Silvana Mouron, Bartlomiej Porebski, Catherine Hansel, Louise Lidemalm, Pablo Martí-Rodrigo, Daniela Hühn, Jordi Carreras-Puigvert, Oscar Fernandez-Capetillo, Kirsten Tschapalda, Miguel Quintela-Fandino, Karolinska Institutet, Cancerfonden Foundation, Swedish Research Council, Instituto de Salud Carlos III, Unión Europea. Comisión Europea, and Comunidad de Madrid (España)
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PD-L1 ,Cancer Research ,medicine.medical_treatment ,Estrogen receptor ,Breast Neoplasms ,B7-H1 Antigen ,Breast cancer ,Immune system ,breast cancer ,INFLAMMATION ,Cell Line, Tumor ,Genetics ,Medicine ,Humans ,IMMUNOTHERAPY ,Research Articles ,RC254-282 ,Cancer och onkologi ,business.industry ,Estrogen Antagonists ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,Estrogens ,General Medicine ,Immunotherapy ,medicine.disease ,Antiestrogen ,HLA ,Cell killing ,Phenotype ,Oncology ,inflammation ,PD‐L1 ,Cancer and Oncology ,Cancer research ,Molecular Medicine ,Female ,immunotherapy ,BREAST-CANCER PATIENTS ,business ,Janus kinase ,Estrogen receptor alpha ,Research Article ,estrogen receptor - Abstract
Among others, expression levels of programmed cell death 1 ligand 1 (PD‐L1) have been explored as biomarkers of the response to immune checkpoint inhibitors in cancer therapy. Here, we present the results of a chemical screen that interrogated how medically approved drugs influence PD‐L1 expression. As expected, corticosteroids and inhibitors of Janus kinases were among the top PD‐L1 downregulators. In addition, we identified that PD‐L1 expression is induced by antiestrogenic compounds. Transcriptomic analyses indicate that chronic estrogen receptor alpha (ERα) inhibition triggers a broad immunosuppressive program in ER‐positive breast cancer cells, which is subsequent to their growth arrest and involves the activation of multiple immune checkpoints together with the silencing of the antigen‐presenting machinery. Accordingly, estrogen‐deprived MCF7 cells are resistant to T‐cell‐mediated cell killing, in a manner that is independent of PD‐L1, but which is reverted by estradiol. Our study reveals that while antiestrogen therapies efficiently limit the growth of ER‐positive breast cancer cells, they concomitantly trigger a transcriptional program that favors their immune evasion., Under prolonged hormone therapy, ER+ breast cancer cells activate an inflammatory transcriptional program, which includes a generalized upregulation of immune checkpoint mediators together with the downregulation of the antigen‐presenting machinery. These findings reveal that, while hormone therapies efficiently arrest the growth of ER+ breast cancer cells, they also promote a phenotype switch that favors their immune evasion.
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- 2022
15. Frente 3 de Fevereiro
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MARTÍ, RODRIGO, primary
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- 2017
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16. Grupo Etcétera
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MARTÍ, RODRIGO, primary
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- 2017
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17. Immune surveillance of neural stem cells
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Martí Rodrigo, Pablo, Fariñas Gómez, Isabel, Yáñez Boyer, Alberto, and Departament de Biologia Funcional i Antropologia Física
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antigen presentation ,immune surveillance ,UNESCO::CIENCIAS DE LA VIDA ,immune checkpoint ,t cell ,CIENCIAS DE LA VIDA [UNESCO] ,neural stem cells - Abstract
Antigen presentation through major histocompatibility complexes and the subsequent immune surveillance by cytotoxic T lymphocytes is considered a preventive mechanism against damaged or infected cells. At the same time, the central nervous system has long been considered an isolated territory where immune responses could not be fully developed. However, in the light of recent findings, these assumptions need to be revisited. On one hand, it has been demonstrated that quiescent adult stem cells down-regulate antigen exposure and evade immune surveillance in the hair follicle and the muscle. On the other hand, the identification of lymphatic routes for the drainage of brain-derived antigens have challenged the concept of brain immune privilege, and it is now assumed that the formation of neoantigens in neural cells is constantly monitored by the immune system. Specifically, the subependymal zone is the largest neurogenic niche in the adult mammalian brain and contains neural stem cells that can either be in a quiescence or in an activated state. The latter proliferate to give rise to the neurogenic lineage that generates mainly neurons for the olfactory bulb or small numbers of glial cells for the corpus callosum or the striatum. In addition, subependymal neural stem cells have been identified as the cells-of-origin of primary glioblastoma, the most aggressive form of brain tumor. However, whether adult neural stem cells undergo immune surveillance had not been studied before and we decided to explore it by using the adoptive transfer of T lymphocytes engineered to kill cells that express the green fluorescent protein in transgenic mice, in which this reporter protein is specifically expressed in the subependymal neurogenic lineage. Our results indicate that activated neural stem cells can be eliminated by T lymphocytes, while the quiescent ones evade immune surveillance. The analysis of antigen presentation and other mediators of cellular immunity reveals that the susceptibility of neural stem cells to T lymphocyte-mediated killing is determined by a finely tuned balance between activation signals, essentially major histocompatibility complexes exposure, and inhibitory mechanisms that include immune checkpoints and protective mechanisms. Also, we demonstrate that antigen presentation is subjected to post-translational regulation and depends on CD99 expression in some neural stem cells.
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- 2022
18. Macular optical coherence tomography for screening of pathology prior to cataract surgery: An approach based on tele-evaluation
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Herranz-Cabarcos, A., primary, Vega-López, Z., additional, Salas-Fandos, O., additional, Quiroz-Quiroga, MJ, additional, Burgos-Fernández, P., additional, Martí-Rodrigo, P., additional, Castilla-Marti, M., additional, Poposki, V., additional, and Martínez-Palmer, AR., additional
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- 2022
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19. Macrophages Modulate Hepatic Injury Involving NLRP3 Inflammasome: The Example of Efavirenz
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Alegre, Fernando, primary, Martí-Rodrigo, Alberto, additional, Polo, Miriam, additional, Ortiz-Masiá, Dolores, additional, Bañuls, Celia, additional, Pinti, Marcello, additional, Álvarez, Ángeles, additional, Apostolova, Nadezda, additional, Esplugues, Juan V., additional, and Blas-García, Ana, additional
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- 2022
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20. The purine analogues abacavir and didanosine increase acetaminophen-induced hepatotoxicity by enhancing mitochondrial dysfunction
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Blas-García, Ana, Martí-Rodrigo, Alberto, Víctor, Víctor M., Polo, Miriam, Alegre, Fernando, Funes, Haryes A., Apostolova, Nadezda, and Esplugues, Juan V.
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- 2016
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21. Rilpivirine attenuates liver fibrosis through selective STAT1-mediated apoptosis in hepatic stellate cells
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Pablo Martí-Rodrigo, Francisco García-García, Nadezda Apostolova, Alberto Martí-Rodrigo, Fernando Alegre, Jordi Gracia-Sancho, J Esplugues, Ángela B. Moragrega, Anabel Fernández-Iglesias, and Ana Blas-Garcia
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Liver Cirrhosis ,STAT3 Transcription Factor ,0301 basic medicine ,Apoptosis ,Risk Assessment ,Sensitivity and Specificity ,Mice ,03 medical and health sciences ,0302 clinical medicine ,Non-alcoholic Fatty Liver Disease ,Fibrosis ,Hepatic Stellate Cells ,medicine ,Animals ,Humans ,STAT1 ,610 Medicine & health ,STAT3 ,Cells, Cultured ,Liver injury ,biology ,business.industry ,Rilpivirine ,Fatty liver ,Gastroenterology ,medicine.disease ,Liver regeneration ,Liver Regeneration ,Disease Models, Animal ,STAT1 Transcription Factor ,Treatment Outcome ,030104 developmental biology ,030220 oncology & carcinogenesis ,biology.protein ,Hepatic stellate cell ,Cancer research ,business ,Janus kinase - Abstract
ObjectiveLiver fibrosis constitutes a major health problem worldwide due to its rapidly increasing prevalence and the lack of specific and effective treatments. Growing evidence suggests that signalling through cytokine-activated Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathways regulates liver fibrosis and regeneration. Rilpivirine (RPV) is a widely used anti-HIV drug not reported to produce hepatotoxicity. We aimed to describe the potential hepatoprotective effects of RPV in different models of chronic liver injury, focusing on JAK-STAT signalling regulation.DesignThe effects of RPV on hepatic steatosis, inflammation and fibrogenesis were studied in a nutritional mouse model of non-alcoholic fatty liver disease, carbon tetrachloride-induced fibrosis and bile duct ligation-induced fibrosis. Primary human hepatic stellate cells (hHSC) and human cell lines LX-2 and Hep3B were used to investigate the underlying molecular mechanisms.ResultsRPV exerted a clear anti-inflammatory and antifibrotic effect in all the in vivo models of liver injury employed, and enhanced STAT3-dependent proliferation in hepatocytes and apoptosis in HSC through selective STAT1 activation. These results were reproduced in vitro; RPV undermined STAT3 activation and triggered STAT1-mediated pathways and apoptosis in HSC. Interestingly, this selective pro-apoptotic effect completely disappeared when STAT1 was silenced. Conditioned medium experiments showed that HSC apoptosis activated STAT3 in hepatocytes in an interleukin-6-dependent mechanism.ConclusionRPV ameliorates liver fibrosis through selective STAT1-dependent induction of apoptosis in HSC, which exert paracrinal effects in hepatocytes, thus promoting liver regeneration. RPV’s actions may represent an effective strategy to treat chronic liver diseases of different aetiologies and help identify novel therapeutic targets.
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- 2020
22. Prolonged estrogen deprivation triggers a broad immunosuppressive phenotype in breast cancer cells
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Hühn, Daniela, primary, Martí‐Rodrigo, Pablo, additional, Mouron, Silvana, additional, Hansel, Catherine, additional, Tschapalda, Kirsten, additional, Porebski, Bartlomiej, additional, Häggblad, Maria, additional, Lidemalm, Louise, additional, Quintela‐Fandino, Miguel, additional, Carreras‐Puigvert, Jordi, additional, and Fernandez‐Capetillo, Oscar, additional
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- 2021
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23. Prolonged estrogen deprivation triggers a broad immunosuppressive phenotype in breast cancer cells
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Hühn, Daniela, Martí‐Rodrigo, Pablo, Mouron, Silvana, Hansel, Catherine, Tschapalda, Kirsten, Porebski, Bartlomiej, Häggblad, Maria, Lidemalm, Louise, Quintela‐Fandino, Miguel, Carreras-Puigvert, Jordi, Fernandez‐Capetillo, Oscar, Hühn, Daniela, Martí‐Rodrigo, Pablo, Mouron, Silvana, Hansel, Catherine, Tschapalda, Kirsten, Porebski, Bartlomiej, Häggblad, Maria, Lidemalm, Louise, Quintela‐Fandino, Miguel, Carreras-Puigvert, Jordi, and Fernandez‐Capetillo, Oscar
- Abstract
Among others, expression levels of programmed cell death 1 ligand 1 (PD-L1) have been explored as biomarkers of the response to immune checkpoint inhibitors in cancer therapy. Here, we present the results of a chemical screen that interrogated how medically approved drugs influence PD-L1 expression. As expected, corticosteroids and inhibitors of Janus kinases were among the top PD-L1 downregulators. In addition, we identified that PD-L1 expression is induced by antiestrogenic compounds. Transcriptomic analyses indicate that chronic estrogen receptor alpha (ER alpha) inhibition triggers a broad immunosuppressive program in ER-positive breast cancer cells, which is subsequent to their growth arrest and involves the activation of multiple immune checkpoints together with the silencing of the antigen-presenting machinery. Accordingly, estrogen-deprived MCF7 cells are resistant to T-cell-mediated cell killing, in a manner that is independent of PD-L1, but which is reverted by estradiol. Our study reveals that while antiestrogen therapies efficiently limit the growth of ER-positive breast cancer cells, they concomitantly trigger a transcriptional program that favors their immune evasion., De 2 sista författarna delar sistaförfattarskapet.
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- 2021
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24. Role of p62/SQSTM1 beyond autophagy: a lesson learned from drug-induced toxicity in vitro
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J Esplugues, Nadezda Apostolova, Miriam Polo, Fernando Alegre, Ángela B. Moragrega, Ana Blas-Garcia, and Alberto Martí-Rodrigo
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0301 basic medicine ,Pharmacology ,Mitochondrial ROS ,Scaffold protein ,Autophagy ,ATG5 ,Inflammasome ,Mitochondrion ,Biology ,Cell biology ,03 medical and health sciences ,030104 developmental biology ,medicine ,Gene silencing ,Viability assay ,medicine.drug - Abstract
Background and Purpose SQSTM1/p62 is a multifunctional, stress-induced, scaffold protein involved in multiple cellular processes including autophagic clearance, regulation of inflammatory responses and redox homeostasis. Its altered function has been associated with different human pathologies, such as neurodegenerative, metabolic and bone diseases (down-regulation), and cancerogenesis (up-regulation). However, its role in the off-target effects of clinically used drugs is still not understood. Experimental Approach We evaluated the expression of p62 in cultured Hep3B cells and their derived ρ° cells (lacking mitochondria), along with markers of autophagy and mitochondrial dysfunction. The effects of efavirenz were compared with those of known pharmacological stressors, rotenone, thapsigargin and CCCP, and we also used transient silencing with siRNA and p62 overexpression. Western blotting, quantRT-PCR and fluorescence microscopy were used to assay these effects and their underlying mechanisms. Key Results In Hep3B cells, efavirenz augmented p62 protein content, an effect not observed in the corresponding ρ° cells. p62 up-regulation followed enhanced SQSTM1 expression mediated through the transcription factor CHOP/DDIT3, while other well-known regulators (NF-kB and Nrf2) were not involved. Inhibition of autophagy with 3MA or with transient silencing of Atg5 did not affect SQSTM1 expression in efavirenz-treated cells while p62 overexpression ameliorated the deleterious effect of efavirenz on cell viability. Conclusion and Implications In our model, p62 exerted a specific, autophagy-independent role and protected against efavirenz-induced mitochondrial ROS generation and activation of the NLRP3 inflammasome. These findings add to the multifunctional nature of p62 and may help to understand the off-target effects of clinically useful drugs.
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- 2018
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25. Rilpivirine attenuates liver fibrosis through selective STAT1-mediated apoptosis in hepatic stellate cells
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Martí-Rodrigo, Alberto, primary, Alegre, Fernando, additional, Moragrega, Ángela B, additional, García-García, Francisco, additional, Martí-Rodrigo, Pablo, additional, Fernández-Iglesias, Anabel, additional, Gracia-Sancho, Jordi, additional, Apostolova, Nadezda, additional, Esplugues, Juan V, additional, and Blas-García, Ana, additional
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- 2019
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26. The antiretroviral rilpivirine induces hepatic regeneration in liver fibrosis and cirrhosis by modulating the STAT3/STAT1 balance
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Nadezda Apostolova, Juan V. Esplugues, Ana Blas-Garcia, Alberto Martí-Rodrigo, D. Castelli, Ángela B. Moragrega, and P. Martí-Rodrigo
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medicine.medical_specialty ,Cirrhosis ,Hepatology ,biology ,business.industry ,Regeneration (biology) ,Liver fibrosis ,medicine.disease ,Gastroenterology ,chemistry.chemical_compound ,chemistry ,Internal medicine ,Rilpivirine ,medicine ,biology.protein ,STAT1 ,business ,STAT3 ,Balance (ability) - Published
- 2018
27. Rilpivirine attenuates liver fibrosis through selective STAT1-mediated apoptosis in hepatic stellate cells.
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Martí-Rodrigo, Alberto, Alegre, Fernando, Moragrega, Ángela B., García-García, Francisco, Martí-Rodrigo, Pablo, Fernández-Iglesias, Anabel, Gracia-Sancho, Jordi, Apostolova, Nadezda, Esplugues, Juan V., and Blas-García, Ana
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LIVER cells ,FIBROSIS ,ALANINE aminotransferase ,EMTRICITABINE ,LIVER ,TRANSFORMING growth factors-beta - Published
- 2020
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28. Lon protease: a novel mitochondrial matrix protein in the interconnection between drug-induced mitochondrial dysfunction and endoplasmic reticulum stress
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J Esplugues, Ana Blas-Garcia, Nadezda Apostolova, Alberto Martí-Rodrigo, Lara Gibellini, Miriam Polo, Fernando Alegre, and Ángela B. Moragrega
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0301 basic medicine ,Pharmacology ,Mitochondrial DNA ,Chemistry ,Endoplasmic reticulum ,Mitochondrion ,medicine.disease ,Carbonyl cyanide m-chlorophenyl hydrazone ,Cell biology ,03 medical and health sciences ,Mitofusin-2 ,chemistry.chemical_compound ,030104 developmental biology ,0302 clinical medicine ,Mitochondrial matrix ,Unfolded protein response ,medicine ,Optic Atrophy 1 ,030217 neurology & neurosurgery - Abstract
Background and Purpose Mitochondria-associated membranes (MAMs) are specific endoplasmic reticulum (ER) domains that enable it to interact directly with mitochondria and mediate metabolic flow and Ca2+ transfer. A growing list of proteins have been identified as MAMs components, but how they are recruited and function during complex cell stress situations is still not understood, while the participation of mitochondrial matrix proteins is largely unrecognized. Experimental Approach This work compares mitochondrial/ER contact during combined ER stress/mitochondrial dysfunction using a model of human hepatoma cells (Hep3B cell line) treated for 24 h with classic pharmacological inducers of ER stress (thapsigargin), mitochondrial dysfunction (carbonyl cyanide m-chlorophenyl hydrazone or rotenone) or both (the antiretroviral drug efavirenz used at clinically relevant concentrations). Key Results Markers of mitochondrial dynamics (dynamin-related protein 1, optic atrophy 1 and mitofusin 2) were expressed differently with these stimuli, pointing to a specificity of combined ER/mitochondrial stress. Lon, a matrix protease involved in protein and mtDNA quality control, was up-regulated at mRNA and protein levels under all conditions. However, only efavirenz decreased the mitochondrial content of Lon while increasing its extramitochondrial presence and its localization to MAMs. This latter effect resulted in an enhanced mitochondria/ER interaction, as shown by co-immunoprecipitation experiments of MAMs protein partners and confocal microscopy imaging. Conclusion and Implications A specific dual drug-induced mitochondria-ER effect enhances the MAMs content of Lon and its extramitochondrial expression. This is the first report of this phenomenon and suggests a novel MAMs-linked function of Lon protease.
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- 2017
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29. Prolonged estrogen deprivation triggers a broad immunosuppressive phenotype in breast cancer cells.
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Hühn, Daniela, Martí‐Rodrigo, Pablo, Mouron, Silvana, Hansel, Catherine, Tschapalda, Kirsten, Porebski, Bartlomiej, Häggblad, Maria, Lidemalm, Louise, Quintela‐Fandino, Miguel, Carreras‐Puigvert, Jordi, and Fernandez‐Capetillo, Oscar
- Abstract
Among others, expression levels of programmed cell death 1 ligand 1 (PD‐L1) have been explored as biomarkers of the response to immune checkpoint inhibitors in cancer therapy. Here, we present the results of a chemical screen that interrogated how medically approved drugs influence PD‐L1 expression. As expected, corticosteroids and inhibitors of Janus kinases were among the top PD‐L1 downregulators. In addition, we identified that PD‐L1 expression is induced by antiestrogenic compounds. Transcriptomic analyses indicate that chronic estrogen receptor alpha (ERα) inhibition triggers a broad immunosuppressive program in ER‐positive breast cancer cells, which is subsequent to their growth arrest and involves the activation of multiple immune checkpoints together with the silencing of the antigen‐presenting machinery. Accordingly, estrogen‐deprived MCF7 cells are resistant to T‐cell‐mediated cell killing, in a manner that is independent of PD‐L1, but which is reverted by estradiol. Our study reveals that while antiestrogen therapies efficiently limit the growth of ER‐positive breast cancer cells, they concomitantly trigger a transcriptional program that favors their immune evasion. [ABSTRACT FROM AUTHOR]
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- 2022
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30. Estrogen deprivation triggers an immunosuppressive phenotype in breast cancer cells
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Daniela Hühn, Pablo Martí-Rodrigo, Silvana Mouron, Catherine S. Hansel, Kirsten Tschapalda, Bartlomiej Porebski, Maria Häggblad, Louise Lidemalm, Miguel A. Quintela-Fandino, Jordi Carreras-Puigvert, and Oscar Fernandez-Capetillo
- Subjects
0303 health sciences ,medicine.drug_class ,business.industry ,Estrogen receptor ,Antiestrogen ,medicine.disease ,3. Good health ,Metastasis ,03 medical and health sciences ,0302 clinical medicine ,Immune system ,Cell killing ,Breast cancer ,Estrogen ,030220 oncology & carcinogenesis ,Cancer research ,medicine ,Hormonal therapy ,business ,skin and connective tissue diseases ,hormones, hormone substitutes, and hormone antagonists ,030304 developmental biology - Abstract
Estrogen receptor (ER)-positive breast tumors are routinely treated with estrogen-depriving therapies. Despite their effectiveness, patients often progress into a more aggressive form of the disease. Through a chemical screen oriented to identify chemicals capable of inducing the expression of the immune-checkpoint ligand PD-L1, we found antiestrogens as hits. Subsequent validations confirmed that estrogen deprivation or ERα depletion induces PD-L1 expression in ER-positive breast cancer cells, both in vitro and in vivo. Likewise, PD-L1 expression is increased in metastasis arising from breast cancer patients receiving adjuvant hormonal therapy for their local disease. Transcriptome analyses indicate that estrogen deprivation triggers a broad immunosuppressive program, not restricted to PD-L1. Accordingly, estrogen deprived MCF7 cells are resistant to T-cell mediated cell killing, in a manner that can be reverted by estradiol. Our study reveals that while antiestrogen therapies effectively limit tumor growth in ER-positive breast cancers, they also trigger a transcriptional program that favors immune evasion.
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- 2019
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31. Antiretroviral therapy and its role in the progression of acute and chronic liver injury
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Martí Rodrigo, Alberto, Esplugues Mota, Juan Vicente, Blas García, Ana, and Departament de Farmacologia
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Hepatología ,Farmacología Experimental ,Biología Molecular ,Fibrosis Hepática ,Gastroenterología - Abstract
Durante las últimas décadas, la utilización de terapias antirretrovirales combinadas para combatir la infección por el virus de la inmunodeficiencia humana (VIH) ha convertido esta enfermedad en una patología crónica. Por ello, en la actualidad, la morbimortalidad asociada a los pacientes infectados por VIH está fundamentalmente relacionada con el envejecimiento, ciertamente acelerado en comparación con la población general, y con el efecto tóxico crónico tanto de la propia infección vírica como de la terapia antiviral. Así pues, el principal criterio clínico para la elección de unos fármacos antirretrovirales u otros es su seguridad en terapias administradas de por vida. En la presente tesis doctoral se estudió la implicación de ciertos fármacos anti- VIH en la evolución de la enfermedad hepática aguda y crónica, así como los mecanismos celulares y moleculares responsables. En primer lugar, se estudiaron, a través de modelos in vitro, los mecanismos moleculares subyacentes a la toxicidad mitocondrial que presentan diversos fármacos de la familia de inhibidores de transcriptasa inversa análogos de nucleósidos (ITIAN), especialmente Abacavir (ABC) y Didanosina (ddI), en hepatocitos. De esta manera, describimos por primera vez como estos fármacos, a dosis clínicas, son capaces de reducir la actividad de los complejos I y III de la cadena de transporte de electrones mitocondrial y el consumo de oxígeno celular sin llegar a alterar significativamente su viabilidad. Sin embargo, cuando ABC y ddI se administraron en combinación con dosis clínicas de paracetamol, otro conocido fármaco hepatotóxico cuyo mecanismo también implica afectación mitocondrial, se observó una clara disminución de la viabilidad celular de los hepatocitos, con un significativo aumento de los niveles de especies reactivas de oxígeno y disminución de los niveles endógenos de glutatión. Cabe destacar que la combinación de estos ITIAN con otros fármacos cuya hepatotoxicidad no implica tan directamente a la mitocondria no produjo estos efectos citotóxicos. El objetivo principal de la segunda parte de esta tesis fue estudiar la implicación de la terapia anti-VIH en la iniciación y progresión de la enfermedad hepática crónica. Para ello, en primer lugar, se llevaron a cabo un modelo nutricional de enfermedad de hígado graso no alcohólico (EHGNA) y diversas variantes del modelo clásico de fibrosis hepática inducida por tetracloruro de carbono en ratón. Durante la duración de los distintos modelos, distintos grupos experimentales fueron tratados diariamente, por vía oral, con dosis clínicas de distintos fármacos antirretrovirales. Paralelamente a los modelos in vivo, se llevaron a cabo cultivos in vitro de hepatocitos y células estrelladas hepáticas, que fueron tratadas con nuestros fármacos a dosis clínicamente relevantes. Como resumen de los datos obtenidos, podemos afirmar que, de entre los fármacos testados, Efavirenz (EFV) y Rilpivirina (RPV), pertenecientes a la familia de los inhibidores de la transcriptasa inversa no análogos de nucleósidos, ejercieron un inesperado e intenso efecto antiadipogénico, antiinflamatorio y antifibrogénico en nuestros modelos de EHGNA. Si bien el efecto antiadipogénico no queda completamente caracterizado en este estudio, sí que observamos una clara regulación de PPARγ y LXRβ en respuesta tanto a EFV como a RPV, que se traduce en una profunda reducción de la infiltración grasa en hígado. Además, el efecto antiinflamatorio de ambos fármacos parece estar claramente mediado por una inactivación de NF- 𝜅��𝜅��B y del inflamasoma NLRP3 así como a una disminución de la infiltración hepática de neutrófilos y macrófagos, ambas células directamente implicadas en la respuesta inmune innata. El efecto ejercido por RPV se reprodujo también en diversos modelos de fibrosis hepática inducida por CCl4, en los cuales fue capaz de disminuir la progresión del daño crónico y, además, contrarrestar dicha progresión cuando se administró en animales con fibrosis ya establecida. Podemos afirmar en este punto que el efecto hepatoprotector de RPV es independiente del tipo de daño producido en el hígado y se basa, fundamentalmente, en su capacidad para inducir selectivamente apoptosis en células estrelladas hepáticas a través de la activación directa del factor de transcripción STAT1. Además, RPV induce una respuesta regenerativa en hepatocitos, mediada por la activación de STAT3 inducida por el secretoma de las células estrelladas apoptóticas en respuesta a RPV, pero no por otros estímulos proapoptóticos independientes de STAT1. Cabe destacar que el efecto de RPV in vitro desapareció al silenciar STAT1 y que, además, este efecto se reprodujo en células estrelladas hepáticas primarias humanas. Considerando la enorme incidencia de enfermedad hepática crónica en la sociedad actual y la ausencia de fármacos capaces de combatirla, defendemos, a través de este estudio, la posible utilización terapéutica de RPV como fármaco hepatoprotector y antifibrótico. Puesto que su seguridad a largo plazo viene dada por su uso clínico como antirretroviral, su posicionamiento clínico requeriría únicamente de estudios confirmatorios en pacientes con enfermedad hepática crónica. De confirmarse este efecto terapéutico, supondría no solo un gran avance clínico, sino un nuevo enfoque en el desarrollo de estrategias antifibróticas cuya aplicabilidad iría más allá de la fibrosis hepática, pudiendo extenderse su estudio a trastornos fibróticos en otros órganos como riñón, pulmón, corazón o páncreas, entre otros. In the last decades, the use of combined antiretroviral therapies (cART) has become human immunodeficiency virus (HIV) infection in a chronic disease. Thus, current clinical criteria to select the best antiviral combinations mainly rely on the safety of each drug in for life-therapeutic regimens. In this doctoral thesis, the involvement of several antiretrovirals in the progression of both acute and chronic liver damage was studied. First of all, we assessed the mitochondrial disturbances which lead to the clinical toxicity of the nucleosideanalogue reverse transcriptase inhibitors Abacavir (ABC) and Didanosine (ddI) in hepatocytes. We described how these molecules, at clinical doses, undermined the mitochondrial function by inhibiting complexes I and III of the electron transport chain without affecting cellular viability. However, these drugs became cytotoxic in hepatocytes when they were combined with clinical doses of acetaminophen, whose hepatotoxicity also involves the mitochondria. The second part of this study was aimed to describe the implication of the anti- HIV therapy in the onset and progression of chronic liver disease. After testing several drugs in a mouse model of non-alcoholic fatty liver disease (NAFLD), we focused on Efavirenz (EFV) and Rilpivirine (RPV), both non-nucleoside analogue reverse transcriptase inhibitors (NNRTI), because they exerted an unexpected and surprising anti-adipogenic, anti-inflammatory and anti-fibrogenic effect in the liver. To further analyse this effect, we performed both mouse models of CCl4- induced liver fibrosis and in vitro studies with hepatocytes and hepatic stellate cells (HSC). In this case, we were able to reproduce the RPV-induced hepatoprotective effects observed in the rest of animal models, confirming that this drug exerts a striking anti-inflammatory and anti-fibrotic role in the liver. Additionally, we described that this effect is directly mediated by a selective induction of apoptosis in HSC, which depends on the activation of the transcription factor STAT1 in these cells. At the same time, the secretome of RPV-induced apoptotic HSC activates an intense regenerative response in the liver mediated by STAT3 activation in hepatocytes. Considering that there is no cure for either NALFD or liver fibrosis, the relevance and the clinical applicability of this study is evident. We defend the utilization of RPV in all those HIV-infected patients with special susceptibility to liver disease. Furthermore, we also propose RPV as a potential anti-fibrotic drug, whose effectivity should be tested in patients with chronic liver disease in the next future. Finally, we encourage the scientific community to deeply explore the role of JAKSTAT1 and 3 in the different cell subsets within the liver, as well as in other organs, as key targets to therapeutically manage different fibrotic disorders.
- Published
- 2019
32. The antiretroviral rilpivirine induces hepatic regeneration in liver fibrosis and cirrhosis by modulating the STAT3/STAT1 balance
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Martí-Rodrigo, A., primary, Moragrega, Ángela B., additional, Martí-Rodrigo, P., additional, Castelli, D., additional, Apostolova, N., additional, Esplugues, Juan V., additional, and Blas-García, A., additional
- Published
- 2018
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33. PREOPERATIVE VITREORETINAL INTERFACE ABNORMALITIES ON SPECTRAL DOMAIN OPTICAL COHERENCE TOMOGRAPHY AS RISK FACTOR FOR PSEUDOPHAKIC CYSTOID MACULAR EDEMA AFTER PHACOEMULSIFICATION
- Author
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Pablo Martí-Rodrigo, Romina Muñiz-Vidal, Sergio Copete, Salvador Pastor-Idoate, Miguel A Zapata, Jaume Rigo, Marta S. Figueroa, and José García-Arumí
- Subjects
Male ,medicine.medical_specialty ,genetic structures ,Pseudophakia ,Fundus Oculi ,medicine.medical_treatment ,Spectral domain ,Macular Edema ,03 medical and health sciences ,0302 clinical medicine ,Optical coherence tomography ,Risk Factors ,Ophthalmology ,Medicine ,Humans ,Macula Lutea ,Prospective Studies ,Risk factor ,Fluorescein Angiography ,Prospective cohort study ,Macular edema ,Aged ,Phacoemulsification ,medicine.diagnostic_test ,business.industry ,General Medicine ,Cataract surgery ,Fluorescein angiography ,medicine.disease ,eye diseases ,Preoperative Period ,030221 ophthalmology & optometry ,Female ,sense organs ,business ,030217 neurology & neurosurgery ,Tomography, Optical Coherence - Abstract
We assessed the role of vitreoretinal interface status in the development of pseudophakic cystoid macular edema (PCME) after cataract surgery.Prospective cohort study in which 112 patients (112 eyes) scheduled for cataract surgery were selected at random to undergo spectral domain optical coherence tomography (OCT) within 1 week preoperatively and at 1 and 3 months postoperatively. Spectral domain OCT macular images included no vitreoretinal contact, focal and diffuse vitreomacular adhesion, focal and diffuse vitreomacular traction, epiretinal membrane, macular hole, and macular edema.The incidence of PCME was 11.6% (13 eyes), all of them being diagnosed at 1 month, and 7 eyes resolved at 3 months. The only risk factor for PCME was detection of nonsurgical epiretinal membrane by spectral domain OCT before phacoemulsification, being developed in 5 of 16 eyes (χ = 0.08, odds ratio 4.53, 95% confidence interval 1.28-16.13). Other variables such as posterior vitreous detachment, subfoveal choroidal thickness, diabetes, or hypertension were not significantly associated with PCME.In this cohort, preoperative detection of epiretinal membrane by spectral domain OCT was a risk factor for PCME after cataract extraction. It is recommended to perform a spectral domain OCT before cataract surgery because the presence of an epiretinal membrane may be passed unnoticed by fundus examination.
- Published
- 2018
34. Shikonin Prevents Early Phase Inflammation Associated with Azoxymethane/Dextran Sulfate Sodium-Induced Colon Cancer and Induces Apoptosis in Human Colon Cancer Cells
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María del Carmen Recio, Rosa M. Giner, José Luis Ríos, Isabel Andújar, and Alberto Martí-Rodrigo
- Subjects
0301 basic medicine ,Farmacología ,Anti-Inflammatory Agents ,Azoxymethane ,Pharmaceutical Science ,Caspase 3 ,Apoptosis ,Pharmacology ,Plant Roots ,Analytical Chemistry ,Proinflammatory cytokine ,03 medical and health sciences ,chemistry.chemical_compound ,In vivo ,Drug Discovery ,medicine ,Animals ,Humans ,Colitis ,Medicine, Chinese Traditional ,Inflammation ,Mice, Inbred BALB C ,Wound Healing ,biology ,Chemistry ,Lithospermum ,Organic Chemistry ,Dextran Sulfate ,medicine.disease ,Inflammatory Bowel Diseases ,Nitric oxide synthase ,Disease Models, Animal ,030104 developmental biology ,Complementary and alternative medicine ,Caco-2 ,Colonic Neoplasms ,biology.protein ,Molecular Medicine ,Colitis, Ulcerative ,Female ,Caco-2 Cells ,Naphthoquinones - Abstract
Shikonin is the main active principle in the root of Lithospermum erythrorhizon, widely used in traditional Chinese medicine for its anti-inflammatory and wound healing properties. Recent research highlights shikonin's antitumor properties and capacity to prevent acute ulcerative colitis. The aim of the present study was to evaluate the ability of shikonin to prevent, in vivo, the early phases of colorectal cancer development, with special focus on its cytotoxic mechanism in vitro. We employed the azoxymethane/dextran sulfate sodium model of colitis in Balb/C mice. Body weight and drinking were monitored throughout the experiment, and length of colon and lesions of the colon were recorded on termination of the experiment in all of the experimental groups. Colons underwent histological evaluation and biochemical analyses [myeloperoxidase activity assay, measurement of interleukin-6, evaluation of proinflammatory enzymes (cyclooxygenase-2 and inducible nitric oxide synthase), and nuclear factor-κB activation by Western blot]. Caco-2 cells were used to evaluate, in vitro, the effect of shikonin on proliferation, cytotoxicity, cell cycle, and apoptosis. Our results reveal that shikonin significantly protected the intestinal tissue of our animals by preventing the shortening of the colorectum and ulcer formation in a dose-dependent manner. Shikonin attenuated the expression of cyclooxygenase-2 and inducible nitric oxide synthase, and myeloperoxidase activity, and inhibited the production of interleukin-6 and activation of nuclear factor-κB. It induced Bcl-2 and inhibited caspase 3. In conclusion, shikonin acts as a chemopreventive agent in the azoxymethane/dextran sulfate sodium model through inhibition of the proinflammatory milieu generated during the disease, an important risk factor in cancer development. Ministerio de Ciencia e Innovación (SAF2009-130593-C03-01) Universitat de València (UV-INV-AE13-139455) 2.746 JCR (2018) Q1, 56/228 Plant Sciences, 5/27 Integrative & Complementary Medicine; Q2, 29/61 Chemistry, Medicinal, 121/267 Pharmacology & Pharmacy 0.559 SJR (2018) Q1, 21/109 Complementary and Alternative Medicine; Q2, 50/125 Analytical Chemistry, 79/170 Drug Discovery, 66/218 Pharmaceutical Science, 88/185 Organic Chemistry; Q3, 172/335 Pharmacology, 120/177 Molecular Medicine No data IDR 2018 UEV
- Published
- 2018
35. Shikonin Prevents Early Phase Inflammation Associated with Azoxymethane/Dextran Sulfate Sodium-Induced Colon Cancer and Induces Apoptosis in Human Colon Cancer Cells
- Author
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Andújar I, Martí-Rodrigo A, Giner RM, Ríos JL, and Recio MC
- Subjects
shikonin ,in vivo ,inflammatory bowel disease ,Lithospermum erythrorhizon ,Boraginaceae ,ulcerative colitis - Abstract
Shikonin is the main active principle in the root of Lithospermum erythrorhizon , widely used in traditional Chinese medicine for its anti-inflammatory and wound healing properties. Recent research highlights shikonins antitumor properties and capacity to prevent acute ulcerative colitis. The aim of the present study was to evaluate the ability of shikonin to prevent, in vivo , the early phases of colorectal cancer development, with special focus on its cytotoxic mechanism in vitro . We employed the azoxymethane/dextran sulfate sodium model of colitis in Balb/C mice. Body weight and drinking were monitored throughout the experiment, and length of colon and lesions of the colon were recorded on termination of the experiment in all of the experimental groups. Colons underwent histological evaluation and biochemical analyses [myeloperoxidase activity assay, measurement of interleukin-6, evaluation of proinflammatory enzymes (cyclooxygenase-2 and inducible nitric oxide synthase), and nuclear factor- B activation by Western blot]. Caco-2 cells were used to evaluate, in vitro , the effect of shikonin on proliferation, cytotoxicity, cell cycle, and apoptosis. Our results reveal that shikonin significantly protected the intestinal tissue of our animals by preventing the shortening of the colorectum and ulcer formation in a dose-dependent manner. Shikonin attenuated the expression of cyclooxygenase-2 and inducible nitric oxide synthase, and myeloperoxidase activity, and inhibited the production of interleukin-6 and activation of nuclear factor- B. It induced Bcl-2 and inhibited caspase 3. In conclusion, shikonin acts as a chemopreventive agent in the azoxymethane/dextran sulfate sodium model through inhibition of the proinflammatory milieu generated during the disease, an important risk factor in cancer development.
- Published
- 2018
36. PS-094-Selective activation of JAK-STATl-mediated apoptosis in hepatic stellate cells as a new therapeutic option for liver fibrosis: Role of rilpivirine
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Aleksandra Gruevska, Anabel Fernández-Iglesias, Nadezda Apostolova, Juan V. Esplugues, Alberto Martí-Rodrigo, Ángela B. Moragrega, Jordi Gracia-Sancho, and Ana Blas-Garcia
- Subjects
chemistry.chemical_compound ,Hepatology ,chemistry ,business.industry ,Apoptosis ,Rilpivirine ,Liver fibrosis ,Cancer research ,Hepatic stellate cell ,Medicine ,business - Published
- 2019
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37. Estrogen deprivation triggers an immunosuppressive phenotype in breast cancer cells
- Author
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Hühn, Daniela, primary, Martí-Rodrigo, Pablo, additional, Mouron, Silvana, additional, Hansel, Catherine S., additional, Tschapalda, Kirsten, additional, Porebski, Bartlomiej, additional, Häggblad, Maria, additional, Lidemalm, Louise, additional, Quintela-Fandino, Miguel A., additional, Carreras-Puigvert, Jordi, additional, and Fernandez-Capetillo, Oscar, additional
- Published
- 2019
- Full Text
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38. PS-094-Selective activation of JAK-STATl-mediated apoptosis in hepatic stellate cells as a new therapeutic option for liver fibrosis: Role of rilpivirine
- Author
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Martí-Rodrigo, Alberto, primary, Moragrega, Ángela B., additional, Gruevska, Aleksandra, additional, Fernández-Iglesias, Anabel, additional, Gracia-Sancho, Jordi, additional, Esplugues, Juan V., additional, Apostolova, Nadezda, additional, and Blas-García, Ana, additional
- Published
- 2019
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39. FRI-089 - The antiretroviral rilpivirine induces hepatic regeneration in liver fibrosis and cirrhosis by modulating the STAT3/STAT1 balance
- Author
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Martí-Rodrigo, A., Moragrega, Ángela B., Martí-Rodrigo, P., Castelli, D., Apostolova, N., Esplugues, Juan V., and Blas-García, A.
- Published
- 2018
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40. Coinfección virus de inmunodeficiencia humana-virus de la Hepatitis C: hacia un nuevo escenario terapéutico
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García Bustos, Víctor, Esplugues Mota, Juan V., Martí Rodrigo, Alberto, García Bustos, Víctor, Esplugues Mota, Juan V., and Martí Rodrigo, Alberto
- Abstract
Introduction:Therapies for hepatitis C virus (HCV) have rapidly evolved with the development of direct-acting antiviral agents. New regimens, achieve an equate response rates to treatment in cases of HCV mono-infected and HIV/HCV co-infected; a population traditionally difficult to treat due to a high hepatic and systemic morbidity-mortality, adverse reactions and drug interactions. Objective: To analyse the current Pharma-therapeutic options available for co-infected HIV-HCV patients, with emphasis I the new direct-acting antiviral agents, in order to offer a useful tool for the therapeutic approach in these patients. Material and Methods: Original articles, clinical studies and systematic reviews until September 2016 were carried out, as well as international drug interactions databases and updated Practical Guidelines. Development: Therapies for hepatitis C virus (HCV) have rapidly evolved with the development of direct-acting antiviral agents. New regimens achieve an equate response rates to treatment in HCV mono-infected and HIV/HCV co-infected; a population traditionally difficult to treat, which also associate a high hepatic and systemic morbidity-mortality, adverse reactions and complex drug interactions. Conclusions: In this new scenario efforts must be addressed to identify the high percentage of undiagnosed patients; potential interactions, especially with drugs related with patient’s aging; medium and long-term adverse reactions and development of drug resistances, as well as to guarantee universal coverage in all clinical contexts. Keywords: HIV/HCV coinfection, HIV/HCV treatment, Hepatitis C, HIV, Direct-acting antiviral agents, DAA., Introducción: Las terapias contra el virus de la Hepatitis C han evolucionado vertiginosamente con el desarrollo de los antivirales de acción directa (AADs). Los nuevos regímenes han conseguido igualar las tasas de respuesta al tratamiento en los monoinfectados y los coinfectados con VIH, una población tradicionalmente difícil de tratar debido a la elevada morbimortalidad hepática y sistémica, reacciones adversas e interacciones medicamentosas. Objetivo: Analizar las opciones farmacoterapéuticas más modernas disponibles para los pacientes coinfectados con VIH y VHC, con énfasis en los nuevos antivirales de acción directa, a fin de ofrecer una herramienta útil en el abordaje terapéutico en estos pacientes. Material y métodos: Se revisaron artículos originales, ensayos clínicos y revisiones sistemáticas hasta septiembre de 2016, bases de datos internacionales de interacciones medicamentosas y Guías de Práctica Clínica actualizadas. Desarrollo: Las terapias contra el virus de la Hepatitis C (VHC) han evolucionado vertiginosamente con el desarrollo de los antivirales de acción directa (AADs). Los nuevos regímenes han conseguido igualar las tasas de respuesta al tratamiento en los monoinfectados y los coinfectados con VIH, una población tradicionalmente difícil de tratar que, además, asociaba una elevada morbimortalidad hepática y sistémica, más reacciones adversas y complejas interacciones medicamentosas. Conclusiones: En este nuevo escenario es fundamental dedicar esfuerzos a identificar el elevado porcentaje de infectados no diagnosticados, potenciales interacciones, especialmente con fármacos para patologías asociadas al envejecimiento de los pacientes, reacciones adversas a medio-largo plazos y desarrollo de resistencias, además de garantizar la cobertura universal en todos los contextos clínicos.Palabras claves: Coinfección VIH/VHC, Tratamiento VIH/VHC, Hepatitis C, VIH, Antivirales de acción directa, AAD.
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- 2017
41. The purine analogues abacavir and didanosine increase acetaminophen-induced hepatotoxicity by enhancing mitochondrial dysfunction
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Haryes A. Funes, Miriam Polo, Juan V. Esplugues, Ana Blas-Garcia, Victor M. Victor, Alberto Martí-Rodrigo, Nadezda Apostolova, and Fernando Alegre
- Subjects
0301 basic medicine ,Microbiology (medical) ,Mitochondrial Diseases ,stavudine ,Anti-HIV Agents ,antiretroviral therapy ,Purine analogue ,Context (language use) ,Mitochondria, Liver ,Mitochondrion ,Pharmacology ,medicine.disease_cause ,acute liver-failure ,Cell Line ,03 medical and health sciences ,Oxygen Consumption ,medicine ,Humans ,Pharmacology (medical) ,Reverse-transcriptase inhibitors ,Acetaminophen ,chemistry.chemical_classification ,mechanisms ,Reactive oxygen species ,business.industry ,association ,toxicity ,Analgesics, Non-Narcotic ,medicine.disease ,Glutathione ,Reactive Nitrogen Species ,Dideoxynucleosides ,hep3b cells ,Mitochondrial toxicity ,Didanosine ,030104 developmental biology ,Infectious Diseases ,chemistry ,Electron Transport Chain Complex Proteins ,Toxicity ,hypersensitivity ,Chemical and Drug Induced Liver Injury ,business ,hepatic cells ,Oxidative stress ,medicine.drug - Abstract
Background NRTIs are essential components of HIV therapy with well-documented, long-term mitochondrial toxicity in hepatic cells, but whose acute effects on mitochondria are unclear. As acetaminophen-induced hepatotoxicity also involves mitochondrial interference, we hypothesized that it would be exacerbated in the context of ART. Methods We evaluated the acute effects of clinically relevant concentrations of the most widely used NRTIs, alone or combined with acetaminophen, on mitochondrial function and cellular viability. Results The purine analogues abacavir and didanosine produced an immediate and concentration-dependent inhibition of oxygen consumption and complex I and III activity. This inhibition was accompanied by an undermining of mitochondrial function, with increased production of reactive oxygen species and reduction of mitochondrial membrane potential and intracellular ATP levels. However, this interference did not compromise cell survival. Co-administration with concentrations of acetaminophen below those considered hepatotoxic exacerbated the deleterious effects of both compounds on mitochondrial function and compromised cellular viability, showing a clear correlation with diminished glutathione levels. Conclusions The simultaneous presence of purine analogues and low concentrations of acetaminophen significantly potentiates mitochondrial dysfunction, increasing the risk of liver injury. This new mechanism is relevant given the liver's susceptibility to mitochondrial dysfunction-related toxicity and the tendency of the HIV infection to increase oxidative stress. This work was supported by the Instituto de Salud Carlos III, Ministerio de Economía y Competitividad [grants PI11/00327, PI13/1025, PI14/00312 and CIBER CB06/04/0071], and postgraduate research grant FI12/00198 awarded to F.A.; the Conselleria d'Educació, Formació i Ocupació, Generalitat Valenciana [grants PROMETEO/2010/060, PROMETEOII/2014/035, ACOMP/2013/236 and GVA/2014/118] and postgraduate research grant ACIF/2013/136 awarded to M.P.; the Universitat Jaume I [grant P1.1B-2014/15]; the Ministerio of Economía y Competitividad [Juan de la Cierva contract JCI-2012–15124 to A.B.-G.]; the Ministerio de Sanidad and Generalitat Valenciana [contract CES10/030 to V.M.V]; and the Ministerio de Educación, Cultura y deporte [postgraduate research grant FPU13/00151 to A.M.-R.].
- Published
- 2016
42. p62/sqstm1 in a drug-induced model of hepatotoxicity: a novel role beyond autophagy
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Ana Blas-Garcia, Juan V. Esplugues, Fernando Alegre, Alberto Martí-Rodrigo, Miriam Polo, Ángela B. Moragrega, and Nadezda Apostolova
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Drug ,Hepatology ,business.industry ,media_common.quotation_subject ,Autophagy ,Cancer research ,Medicine ,business ,media_common - Published
- 2017
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43. The anti-human immunodeficiency virus drug rilpivirine decreases hepatic injury in a nutritional model of non-alcoholic fatty liver disease through activation of the IL6/IL22-STAT3-p53 axis
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Martí-Rodrigo, A., primary, Alegre, F., additional, Polo, M., additional, Moragrega, Á.B., additional, Apostolova, N., additional, Esplugues, J.V., additional, and Blas-García, A., additional
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- 2017
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44. Coinfección virus de inmunodeficiencia humana-virus de la Hepatitis C: hacia un nuevo escenario terapéutico
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Víctor García-Bustos, Juan Vicente Esplugues-Mota, and Alberto Martí-Rodrigo
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Coinfección VIH/VHC ,Tratamiento VIH/VHC ,Hepatitis C ,VIH ,Antivirales de acción directa ,AAD ,Medicine (General) ,R5-920 ,Public aspects of medicine ,RA1-1270 - Abstract
Introducción: Las terapias contra el virus de la Hepatitis C han evolucionado vertiginosamente con el desarrollo de los antivirales de acción directa (AADs). Los nuevos regímenes han conseguido igualar las tasas de respuesta al tratamiento en los monoinfectados y los coinfectados con VIH, una población tradicionalmente difícil de tratar debido a la elevada morbimortalidad hepática y sistémica, reacciones adversas e interacciones medicamentosas. Objetivo: Analizar las opciones farmacoterapéuticas más modernas disponibles para los pacientes coinfectados con VIH y VHC, con énfasis en los nuevos antivirales de acción directa, a fin de ofrecer una herramienta útil en el abordaje terapéutico en estos pacientes. Material y métodos: Se revisaron artículos originales, ensayos clínicos y revisiones sistemáticas hasta septiembre de 2016, bases de datos internacionales de interacciones medicamentosas y Guías de Práctica Clínica actualizadas. Desarrollo: Las terapias contra el virus de la Hepatitis C (VHC) han evolucionado vertiginosamente con el desarrollo de los antivirales de acción directa (AADs). Los nuevos regímenes han conseguido igualar las tasas de respuesta al tratamiento en los monoinfectados y los coinfectados con VIH, una población tradicionalmente difícil de tratar que, además, asociaba una elevada morbimortalidad hepática y sistémica, más reacciones adversas y complejas interacciones medicamentosas. Conclusiones: En este nuevo escenario es fundamental dedicar esfuerzos a identificar el elevado porcentaje de infectados no diagnosticados, potenciales interacciones, especialmente con fármacos para patologías asociadas al envejecimiento de los pacientes, reacciones adversas a medio-largo plazos y desarrollo de resistencias, además de garantizar la cobertura universal en todos los contextos clínicos.
45. Novel Function of Mitochondrial Lon Protease (LONP) in a Drug-Induced Dual Model of Er-Stress and Mitochondrial Dysfunction in Hepatic Cells
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Ana Blas-Garcia, Fernando Alegre, Nadezda Apostolova, Juan V. Esplugues, Alberto Martí-Rodrigo, and Miriam Polo
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Drug ,Hepatology ,Dual model ,Chemistry ,Lon Protease ,media_common.quotation_subject ,Hepatic stellate cell ,Unfolded protein response ,Function (biology) ,media_common ,Cell biology - Published
- 2016
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46. Régimen jurídico y metodología de investigación de siniestros marítimos
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Martí Rodrigo, Carlos, Rodrigo de Larrucea, Jaime, and Universitat Politècnica de Catalunya. Departament de Ciència i Enginyeria Nàutiques
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Nàutica::Dret marítim i administratiu [Àrees temàtiques de la UPC] ,Nàutica::Seguretat marítima::Accidents marítims [Àrees temàtiques de la UPC] ,Vaixells -- Accidents ,Maritime law ,derecho marítimo ,Marine accidents ,Dret marítim -- Responsabilitat ,accidentes marítimos - Abstract
El trabajo tiene dos partes diferenciadas, pero absolutamente complementarias: el régimen jurídico de la investigación de los siniestros marítimos y la metodología y análisis de los mismos El trabajo tiene dos partes diferenciadas, pero absolutamente complementarias: el régimen jurídico de la investigación de los siniestros marítimos y la metodología y análisis de los mismos
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- 2008
47. FRI-440 - p62/sqstm1 in a drug-induced model of hepatotoxicity: a novel role beyond autophagy
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Alegre, F., Polo, M., Marti-Rodrigo, A., Moragrega, A.B., Esplugues, J.V., Blas-Garcia, A., and Apostolova, N.
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- 2017
- Full Text
- View/download PDF
48. THU-368 - The anti-human immunodeficiency virus drug rilpivirine decreases hepatic injury in a nutritional model of non-alcoholic fatty liver disease through activation of the IL6/IL22-STAT3-p53 axis
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Martí-Rodrigo, A., Alegre, F., Polo, M., Moragrega, Á.B., Apostolova, N., Esplugues, J.V., and Blas-García, A.
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- 2017
- Full Text
- View/download PDF
49. THU-304 - Novel Function of Mitochondrial Lon Protease (LONP) in a Drug-Induced Dual Model of Er-Stress and Mitochondrial Dysfunction in Hepatic Cells
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Polo, M., Alegre, F., Marti-Rodrigo, A., Blas-Garcia, A., Esplugues, J.V., and Apostolova, N.
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- 2016
- Full Text
- View/download PDF
50. Régimen jurídico y metodología de investigación de siniestros marítimos
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Universitat Politècnica de Catalunya. Departament de Ciència i Enginyeria Nàutiques, Rodrigo de Larrucea, Jaime, Martí Rodrigo, Carlos, Universitat Politècnica de Catalunya. Departament de Ciència i Enginyeria Nàutiques, Rodrigo de Larrucea, Jaime, and Martí Rodrigo, Carlos
- Abstract
El trabajo tiene dos partes diferenciadas, pero absolutamente complementarias: el régimen jurídico de la investigación de los siniestros marítimos y la metodología y análisis de los mismos, El trabajo tiene dos partes diferenciadas, pero absolutamente complementarias: el régimen jurídico de la investigación de los siniestros marítimos y la metodología y análisis de los mismos
- Published
- 2008
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