Artículos (Citología e Histología Normal y Patológica)

URI permanente para esta colecciónhttps://hdl.handle.net/11441/11005

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Melatonin controls experimental autoimmune encephalomyelitis by altering the T effector/regulatory balance
(Elsevier, 2015-06-26) Álvarez Sánchez, Nuria; Cruz Chamorro, Iván; López González, Antonio; Utrilla Alcolea, José Carmelo; Fernández-Santos, José María; Martínez López, Alicia; Lardone, Patricia Judith; Guerrero Montávez, Juan Miguel; Carrillo Vico, Antonio; Bioquímica Médica y Biología Molecular e Inmunología; Citología e Histología Normal y Patológica; Bioquímica y Biología Molecular; Instituto de Salud Carlos III; Gobierno de España; Junta de Andalucía; CTS439: Sistema Neuroendocrino Difuso; CTS160: NeuroInmunoEndocrinología Molecular
Experimental autoimmune encephalomyelitis (EAE), the experimental model for multiple sclerosis (MS), is triggered by myelin-specific Th1 and Th17 cells. The immunomodulatory activities of melatonin have been shown to be beneficial under several conditions in which the immune system is exacerbated. Here, we sought to elucidate the basis of the melatonin protective effect on EAE by characterizing the T effector/regulatory responses, particularly those of the memory cell subsets. Melatonin was tested for its effect on Th1, Th17 and T regulatory (Treg) cells in the lymph nodes and CNS of immunodominant peptide of myelin oligodendrocyte glycoprotein (pMOG)-immunized and EAE mice, respectively. The capacity of melatonin to ameliorate EAE as well as modifying both T cell response and effector/regulatory balance was surveyed. T cell memory subsets and CD44, a key activation marker involved in the EAE pathogenesis, were also examined. Melatonin protected from EAE by decreasing peripheral and central Th1/Th17 responses and enhancing both the Treg frequency and IL-10 synthesis in the CNS. Melatonin reduced the T effector memory population and its pro-inflammatory response and regulated CD44 expression, which was decreased in T effector cells and increased in Tregs. The alterations in the T cell subpopulations were associated with a reduced mononuclear infiltration (CD4 and CD11b cells) of the melatonin-treated mice CNS. For the first time, we report that melatonin protects against EAE by controlling peripheral and central T effector/regulatory responses, effects that might be partially mediated by CD44. This immunomodulatory effect on EAE suggests that melatonin may represent an effective treatment option for MS.
Los cannabinoides: una perspectiva en la esclerosis múltiple
(Wanceulen Editorial S.L., 2024) Pérez Rodríguez, Marta; Barbado González, Mª Victoria; Citología e Histología Normal y Patológica; CTS1047: Fisiopatología Asociada a las Acuaporinas
El estudio del uso de los cannabinoides debido sus diferentes propiedades terapéuticas ha resultado un tema de interés en los últimos años, especialmente el uso de estos en la esclerosis múltiple. Los objetivos de este trabajo fueron revisar los conocimientos actuales del uso terapéutico de los cannabinoides en la esclerosis múltiple, así como encontrar evidencias de una mejora en la calidad de vida de los pacientes tratados con cannabinoides y conocer avances científicos en el tratamiento con cannabinoides en la esclerosis múltiple. Para ello se han consultado diferentes bases de datos, entre ellas Pubmed, Epistemonikos, Cochrane library, Scopus y Dialnet. Los resultados mostraron una eficacia limitada de los cannabinoides en la espasticidad, el dolor neuropático y la disfunción neurogénica del trato urinario inferior, además se revisa la inmunomodulación de los cannabinoides en la esclerosis múltiple. Concluyendo que estos alivian la sintomatología de la esclerosis múltiple, debido a su eficacia moderada, la necesidad más de estudios de calidad a gran escala y el posible efecto inmunomodulador de los cannabinoides en la esclerosis múltiple.
Oleocanthal Supplemented Diet Improves Renal Damage And Endothelial Dysfunction In Pristane-Induced Systemic Lupus Erythematosus In Mice
(Elsevier, 2023) Montoya García, Tatiana; Sánchez Hidalgo, Marina; Castejón Martínez, María Luisa; Vázquez Román, María Victoria; Álvarez de Sotomayor Paz, María; Ortega Vidal, Juan; González Rodríguez, María Luisa; Alarcón de la Lastra Romero, Catalina; Farmacología; Citología e Histología Normal y Patológica; Farmacia y Tecnología Farmacéutica; Ministerio de Economía y Competitividad (MINECO). España; Junta de Andalucía
Systemic lupus erythematosus (SLE) is a multiorgan disorder with a deregulated immune-inflammatory response. Nutritional therapy has been considered a promising approach to SLE management. Oleocanthal (OLE), the main extra virgin olive oil (EVOO)-derived secoiridoid, has shown to regulate the immune-inflammatory response in various disease contexts; however, its possible beneficial effects on SLE remain unclear. This study sought to evaluate the effects of OLE enriched diet on renal damage and aortic endothelial dysfunction in murine pristane-induced SLE, focusing on the action mechanisms and signaling pathways involved. BALB/c mice were injected with pristane and fed with OLE supplemented diet (0.01 % (w/w)) for six months. Levels of cytokines were measured by ELISA in lipopolysaccharide (LPS)-stimulated peritoneal macrophages and splenocytes. Presence of IgG and IgM immune complexes was examined by immunofluorescence and immunohistochemistry. Thoracic aortas were used to evaluate endothelial dysfunction. Western blotting was employed to detect signaling pathways and oxidative-inflammatory-related mediators. Dietary OLE supplementation reduced Th1/Th17 pro-inflammatory cytokines production and alleviated renal damage by decreasing immunoglobulin complexes deposition, and inflammation-mediating enzymes expression. The mechanisms underlying these protective effects could be related to the regulation of nuclear factor erythroid 2-related factor 2/Haem oxygenase 1 (Nrf-2/HO-1), mitogen-activated protein kinases (MAPKs), signal transducer and transcription activator of transcription (STAT-3), inflammasome and, nuclear factor kappa B (NF-B) signaling pathways. Also, dietary OLE improved aortic endothelial dysfunction and vascular reactivity, normalizing endothelial nitric oxide synthase (eNOS) uncoupling, and NADPH oxidase-1 (NOX-1) overexpression. This study shows the immunomodulatory effects of OLE in an in vivo model of SLE by improving renal damage and regulating aortic endothelial dysfunction. These preliminary results provide OLE as a new therapeutic strategy in SLE management.
EWS::FLI1-DHX9 interaction promotes Ewing sarcoma sensitivity to DNA topoisomerase 1 poisons by altering R-loop metabolism
(Springer Nature, 2025-07-28) Olmedo Pelayo, Joaquín; Granado Calle, Esperanza; Delgado Bellido, Daniel; Lobo Selma, Laura; García-Domínguez, Daniel J.; Gómez Herreros, Fernando; Álava Casado, Enrique de; Bioquímica Médica y Biología Molecular e Inmunología; Citología e Histología Normal y Patológica; Genética; Junta de Andalucía; Universidad de Sevilla; Instituto de Salud Carlos III; Asociación Pablo Ugarte; Asociación Candela Riera; Asociación Todos Somos Iván; Fundación Sonrisa de Alex; Deutsche Forschungsgemeinschaft / German Research Foundation (DFG); German Cancer Aid; Ministerio de Ciencia e Innovación (MICIN). España; Junta de Andalucía
Drug resistance is an ill-defined cause of dismal outcomes in cancer. Ewing sarcoma (EwS), a pediatric cancer characterized by high therapy failure rates, is driven by a single oncogenic event generating EWSR1::ETS gene fusions (primarily EWSR1::FLI1) in a silent genomic background. This provides a straightforward model to study the impact of gene fusions on drug responses. Here, we describe a novel mechanism of sensitivity to DNA topoisomerase 1 poisons in EwS. We discovered that EWS::FLI1 prevents the resolution of R-loops induced by these drugs via sequestering DHX9 helicase, ultimately resulting in R-loop accumulation, replication stress, and genome instability. In turn, excessive DHX9 or reduced EWS::FLI1 levels render EwS cells resistant to the active metabolite of irinotecan (SN-38) independent of proliferation and global transcription rates. This resistance helps explain how elevated DHX9 levels predict worse clinical outcomes. Overall, our research demonstrates the impact of a dominant mutation on cancer drug sensitivity, highlighting its significant clinical implications.
Targeting iysosomal acidification to restore microglial homeostasis and mitigate memory decline during male brain ageing
(Elsevier science; Elsevier BV, 2025-11-04) Barrella, Lorenzo; Ramírez-Ponce, María Pilar; Vázquez Román, María Victoria; Millán-Huang, Marta San; Maldonado y Aibar, María Dolores; Flores Cordero, Juan Antonio; Alés González de la Higuera, Eva María; Citología e Histología Normal y Patológica; Bioquímica Médica y Biología Molecular e Inmunología; Fisiología Médica y Biofísica; CTS439: Sistema Neuroendocrino Difuso; CTS160: Neuroinmunoendocrinología Molecular; CTS151: Bioquímica Medica; BIO236: Biofísica Celular
Lysosomal dysfunction lies at the nexus of inflammaging, microglial dystrophy and synaptic fragility, making it an attractive target for brain rejuvenation. Here we demonstrate that a five-month oral course of ketotifen, an approved H1-antihistamine and mast-cell stabiliser, re-acidifies lysosomes in aged C57BL/6J male mice, restoring the quinacrine signal of peripheral macrophages and SIM-A9 microglia. This proton rebound is coupled to broad anti-cytokine effects: ketotifen attenuates lipopolysaccharide-evoked release of TNF-α, IL-1β and IL-10 in vitro and ex vivo. In the brain, the drug restores a highly ramified, homeostatic microglial morphology throughout the cortex and hippocampus. Ketotifen robustly elevates cortical synaptophysin and PSD-95 above age-matched levels. Behaviourally, ketotifen enhances spatial learning and object-location memory without altering locomotor activity or anxiety-like behaviour. Collectively, these findings identify lysosomal re-acidification as the initiating trigger of a multifaceted rejuvenation cascade that dampens multi-cytokine signalling, restores microglial morphology and preserves synaptic integrity. Because ketotifen is inexpensive, brain-permeable and already licensed for human use, our work unveils an immediately actionable geroprotective strategy to forestall early cognitive decline.
The role of the primary cilium in thyroid function and dysfunction with implications for thyroid disease
(Springer Science and Business Media LLC, 2025-11-06) Martín Lacave, Inés María; Vázquez Román, María Victoria; Pérez-Fernández, B.; Fernández-Santos, José María; Citología e Histología Normal y Patológica; Consejería de Economía, Innovación, Ciencia y Empleo, Junta de Andalucía; VII PPIT, CITIUS, Universidad de Sevilla /JMF; CTS439: Sistema Neuroendocrino Difuso
The thyroid gland is a unique endocrine organ, composed of morpho-functional units called thyroid follicles, which are responsible for thyroid hormone (TH) biosynthesis, an iodination process demanding a highly oxidative yet protected environment. Despite primary cilium (PC) being observed in the thyroid gland more than a century ago, its precise role in thyroid activity remains rather unexplored. Given its strategic position at the apical surface of follicular epithelium, projecting into the lumen, PCs are crucial for the regulation of TH biosynthetic processes. Consequently, changes in thyroid function, either physiological or pathological, are reflected in PC characteristics. Similarly, defects in ciliogenesis are expected to lead to different pathological thyroid alterations. This review summarizes the current understanding of PC’s involvement in regulating normal thyroid activity and its modifications in functional and neoplastic thyroid diseases. Particular focus will be given to the notable loss of PCs in certain types of thyroid cancer and the promising potential of their restoration as a tumor suppressor strategy in thyroid tumorigenesis.
Ketotifen reacidifies secretory lysosomes and normalises ageing phenotypes in mast cells
(Academic press inc jnl-comp subscriptions; Academic press inc elsevier science; Elsevier, 2025-10-29) Barrella, Lorenzo; Ramírez-Ponce, María Pilar; Vázquez Román, María Victoria; San Millán-Huang, Marta; Flores Cordero, Juan Antonio; Alés González de la Higuera, Eva María; Citología e Histología Normal y Patológica; Bioquímica Médica y Biología Molecular e Inmunología; Fisiología Médica y Biofísica; CTS439: Sistema Neuroendocrino Difuso; CTS151: Bioquímica Medica; BIO236: Biofísica Celular
Mast-cell (MC) granules are secretory lysosomes whose function depends on a highly acidic lumen. We asked whether lysosomal pH drifts with age and whether this alteration is reversible. Lysosomal acidification was assessed by quinacrine imaging of peritoneal MCs, which revealed very low fluorescence in MCs from 2-month-old mice, consistent with immature granules. As MCs matured, quinacrine signal increased, reflecting expansion of the secretory lysosome pool; however, from 15 to 17 months, fluorescence progressively declined, indicating gradual deacidification. Chronic ketotifen treatment restored and amplified the quinacrine signal, enlarged granules, and reduced late-life MC expansion. Acute pharmacological assays revealed that ketotifen's effect requires V-ATPase activity and dynamin-dependent endocytosis. FM1-43 uptake confirmed enhanced endocytic activity with ketotifen. In the brain, ageing led to hypertrophy of toluidine blue–positive MCs without major changes in cell number; five months of ketotifen treatment reversed these morphometric alterations toward a youthful profile. These findings identify lysosomal deacidification as a hallmark of ageing MCs and demonstrate that ketotifen reacidifies secretory lysosomes via V-ATPase and endocytosis-dependent mechanisms, highlighting lysosomal pH control as a tractable strategy to mitigate MC-driven components of inflammaging.
Dietary freeze-dried beer prevents inflammation in DSS-induced chronic ulcerative colitis in mice
(Royal Society of Chemistry, 2025-07-01) Paredes Sánchez, María; Muñoz García, Rocío; Ávila Román, Francisco Javier; Lobo Prieto, Ana; Orta Cuevas, María del Mar; García González, Diego L.; Vázquez Román, María Victoria; Talero Barrientos, Elena Mª; Sánchez Hidalgo, Marina; Farmacología; Química Analítica; Citología e Histología Normal y Patológica
Inflammatory bowel disease (IBD) is a complex condition that is influenced by numerous factors, including genetic, immune and environmental factors. In the search for new therapies, nutritional interventions including dietary polyphenols are becoming increasingly important in the management of IBD. The present study aimed to investigate the antioxidant and anti-inflammatory effects of commercial freeze-dried beer, an interesting product resulting from the fermentation of cereals, rich in polyphenols, in (I) an in vitro model of inflammation using lipopolysaccharide (LPS)-stimulated THP-1 human derived macrophages and (II) a murine dextran sodium sulfate (DSS)-induced chronic colitis model, for elucidating the action mechanism involved. According to the results, commercial freeze-dried beer exhibits antioxidant, anti-inflammatory and immunomodulatory properties in LPS-stimulated THP-1 human macrophages by reducing reactive oxygen species (ROS), tumor necrosis factor (TNF)-α and interleukin (IL)-6 levels. Moreover, in vivo results showed that preventive treatment with dietary freeze-dried beer improved murine DSS-induced chronic colitis by attenuation of the clinical and histological signs of colonic damage. Colonic cytokine levels in animals fed with commercial freeze-dried beer reached values near basal levels. In addition, pro-inflammatory cyclooxygenase (COX)-2 and microsomal prostaglandin E synthase (mPGES)-1 protein expressions were significantly downregulated via inhibition of nuclear transcription factor kappa B (NF-κB) translocation. This inhibition may be mediated by an induction of the antioxidant nuclear factor (erythroid-derived 2)-like 2 (Nrf2)/heme oxygenase-1 (HO-1) signaling pathway and a reduction of signal transducer and activator of transcription (STAT)-3 phosphorylation orchestrating its potent anti-inflammatory and immunomodulatory effects. Overall, our results suggest that dealcoholized beer may be effective in the management of immune-mediated inflammatory diseases in which macrophages are crucial, including IBD, providing clues for developing useful dietary interventions against inflammation-associated pathologies.
The PAD4 inhibitor GSK484 diminishes neutrophil extracellular trap in the colon mucosa but fails to improve inflammatory biomarkers in experimental colitis
(Portland Press, 2025-06-11) Xie, Kangzhe; Hunter, Jordan; Lee, Aaron; Ahmad, Gulfam; Witting, Paul K.; Ortiz Cerda, Tamara Andrea; Citología e Histología Normal y Patológica; Gobierno de España
Inflammatory bowel disease (IBD) is a gastrointestinal disorder characterised by elevated colonic neutrophil extracellular traps (NETs), which are associated with disease severity. Formation of NETs is primarily driven by peptidyl arginine deaminase IV (PAD4) and other enzymes including myeloperoxidase (MPO) and neutrophil elastase. The present study evaluated the effect of MPO and PAD4 inhibition in dextran sodium sulfate (DSS)-induced colitis. Experimental colitis was induced in male C57BL/6 mice by 2% w/v DSS in drinking water ad libitum. Treatment groups received daily oral administration of MPO inhibitor (AZD3241; 30 mg/kg) and/or intraperitoneal injection of PAD4 inhibitor (GSK484; 4 mg/kg) 4 times over 9 days. Inhibition of PAD4 significantly diminished NET density in the colonic mucosa of mice insulted with DSS, reaching levels similar to that detected in control mice. Both inhibitors offered limited improvement in disease-activity-index, a scoring system that considers the extent of weight loss, stool consistency and rectal bleeding. Histology showed that MPO and/or PAD4 inhibition did not recover DSS-induced colon histoarchitectural damage whilst Alcian blue staining demonstrated that PAD4 failed to reduce goblet cell loss. The selected dosage of PAD4 inhibition also yielded no effect on inflammatory markers and antioxidant protein levels. These data sets suggest that other mechanisms may be involved in the pathogenesis of IBD, and the appropriate dosage of GSK484 requires thorough investigation.
The combination of epigenetic drugs SAHA and HCI-2509 synergistically inhibits EWS-FLI1 and tumor growth in Ewing sarcoma
(Impact Journals Llc, 2018-07-31) García-Domínguez, Daniel J.; Hontecillas-Prieto, Lourdes; Rodríguez-Núñez, Pablo; Pascual-Pasto, Guillem; Vila-Ubach, Monica; García-Mejías, Rosa; Robles, María José; Tirado, Oscar M.; Mora, Jaume; Carcaboso, Angel M.; Álava Casado, Enrique de; Bioquímica Médica y Biología Molecular e Inmunología; Citología e Histología Normal y Patológica; CTS1035: Patología Molecular del Cáncer Sólido
Purpose: Epigenetic regulation is crucial in mammalian development and maintenance of tissue-cell specific functions. Perturbation of epigenetic balance may lead to alterations in gene expression, resulting in cellular transformation and malignancy. Previous studies in Ewing sarcoma (ES) have shown that the Nucleosome Remodeling Deacetylase (NuRD) complex binds directly to EWS-FLI1 oncoprotein and modulates its transcriptional activity. The role of EWS-FLI1 as a driver of proliferation and transformation in ES is widely known, but the effect of epigenetic drugs on fusion activity remains poorly described. The present study evaluated the combination effects of the histone deacetylases inhibitor suberoylanilide hydroxamic acid (SAHA) and Lysine-specific demethylase1 inhibitor (HCI-2509) on different biological functions in ES and in comparison to monotherapy treatments. Results: The study of proliferation and cell viability showed a synergistic effect in most ES cell lines analyzed. An enhanced effect was also observed in the induction of apoptosis, together with accumulation of cells in G1 phase and a blockage of the migratory capacity of ES cell lines. Treatment, either in monotherapy or in combination, caused a significant decrease of EWS-FLI1 mRNA and protein levels and this effect is mediated in part by fusion gene promoter regulation. The anti-tumor effect of this combination was confirmed in patient-derived xenograft mouse models, in which only the combination treatment led to a statistically significant decrease in tumor volume. Conclusions: The combination of SAHA and HCI-2509 is proposed as a novel treatment strategy for ES patients to inhibit the essential driver of this sarcoma and tumor growth.
Advanced sporadic renal epithelioid angiomyolipoma: Case report of an extraordinary response to sirolimus linked to TSC2 mutation
(Springer Nature, 2018-05-15) Espinosa, Marta; Roldán-Romero, Juan María; Durán, Ignacio; Álava Casado, Enrique de; Apellaniz-Ruiz, María; Cascón, Alberto; Garrigós, Carmen; Robledo, Mercedes; Rodríguez-Antona, Cristina; Citología e Histología Normal y Patológica; Farmacología; Ministerio de Economia, Industria y Competitividad (MINECO). España
Background: Renal epithelioid angiomyolipomas (EAML) are rare tumors with aggressive behavior. EAML can be sporadic or develop within the tuberous sclerosis complex syndrome, where mutations of TSC1 or TSC2 genes (critical negative regulators of mTOR Complex 1) result in an increased activation of mTOR pathway. Optimal EAML treatment, including mTOR inhibitors, remains undetermined. Case presentation: Here we present the case of a young adult with a renal EAML that after radical nephrectomy developed metastases, first in liver and then in lumbar vertebrae. After complete surgical resection of these lesions, liver recurrence was detected, this time with incomplete surgical resection. After finding a new liver lesion, systemic treatment with sirolimus started. The patient exhibited a complete and durable response to this drug, being disease free at the time of publication, after 36 months of treatment. Targeted next generation sequencing (NGS) of MTOR, TSC1 and TSC2 genes in the primary tumor, metastasis and blood of the patient, revealed one inactivating TSC2 mutation (c.2739dup; p.K914*) in the tumor cells. Immunohistochemistry revealed decreased TSC2 protein content and increased phospho-S6 in the tumor cells, demonstrating mTOR pathway activation. Conclusion: NGS on an EAML patient with an extraordinary response to sirolimus uncovered TSC2 inactivation as the mechanism for the response. This study supports NGS as a useful tool to identify patients sensitive to mTOR inhibitors and supports the treatment of malignant EAML with these drugs.
Dietary supplementation of male mice with inorganic, organic or nanoparticle selenium preparations: evidence supporting a putative gut-thyroid-male fertility axis
(Informa UK Limited, 2025) Mojadadi, Albaraa; Au, Aaron; Ortiz Cerda, Tamara Andrea; Shao, Yu‐Hsuan Joni; O’Neil, Thomas A.; Bell‐Anderson, Kim; Andersen, J. W.; Webb, J.; Witting, Paul K.; Citología e Histología Normal y Patológica
Selenium (Se) is linked to physiological homeostasis. Male mice (n = 8/group) were fed control (AIN93G) or diets enriched in sodium selenite (NaSe, 5.6 ppm), methylselenocysteine (Met, 4.7 ppm), diphenyl diselenide (DPDS, 14.2 ppm), or nanoselenium (NanoSe, 2.7 ppm); dietary Se ascertained by inductively-coupled plasma mass spectrometry. At 4 weeks testes, sperm, thyroids, blood and stool were collected to assess histoarchitecture, circulating hormones (thyroxine, T4; triiodothyronine, T3; thyroid stimulating hormone, TSH) and gut microbiome (16S rRNAV3-V4 amplicon sequencing). Supplemented NaSe, Met, and NanoSe increased plasma testosterone and testis glutathione peroxidases (GPx-1/4) while testicular superoxide dismutase and catalase increased slightly in the NanoSe group indicating a selective antioxidant response. Overall, NanoSe and NaSe enhanced male reproductive factors. All thyroids isolated from Se-supplemented mice contained marginal vacuoles and a lower follicle area vs control. Nano-Se enhanced thyroidiodothyronine deiodinase-1 (DIO1) expression however, thyroid GPx-1/4 remained unchanged. Supplemented NaSe and DPDSl increased plasma T3/T4 ratio, while plasma TSH was unchanged. Microbiome analyses showed that NanoSe was most efficacious in altering composition (judged by α-diversity, Shannon index and taxon richness) while the NaSe diet showed the greatest overall change in α-diversity. Dietary Se supplementation, particularly encapsulated NanoSe, may improve male fertility factors by enhancing the gut-thyroid-fertility axis.
The PARP inhibitor olaparib enhances the sensitivity of Ewing sarcoma to trabectedin
(Impact Journals LLC, 2017-05-27) Ordóñez, José Luis; Amaral, Ana Teresa; Carcaboso, Ángel M.; Herrero-Martin, David; García-Macías, María del Carmen; Sevillano, Vicky; Álava Casado, Enrique de; Citología e Histología Normal y Patológica; Gobierno de España; European Commission (EC). Fondo Europeo de Desarrollo Regional (FEDER); Instituto de Salud Carlos III; CTS1035: Patología Molecular del Cáncer Sólido
Recent preclinical evidence has suggested that Ewing Sarcoma (ES) bearing EWSR1-ETS fusions could be particularly sensitive to PARP inhibitors (PARPinh) in combination with DNA damage repair (DDR) agents. Trabectedin is an antitumoral agent that modulates EWSR1-FLI1 transcriptional functions, causing DNA damage. Interestingly, PARP1 is also a transcriptional regulator of EWSR1-FLI1, and PARPinh disrupts the DDR machinery. Thus, given the impact and apparent specificity of both agents with regard to the DNA damage/DDR system and EWSR1-FLI1 activity in ES, we decided to explore the activity of combining PARPinh and Trabectedin in in vitro and in vivo experiments. The combination of Olaparib and Trabectedin was found to be highly synergistic, inhibiting cell proliferation, inducing apoptosis, and the accumulation of G2/M. The drug combination also enhanced γH2AX intranuclear accumulation as a result of DNA damage induction, DNA fragmentation and global DDR deregulation, while EWSR1-FLI1 target expression remained unaffected. The effect of the drug combination was corroborated in a mouse xenograft model of ES and, more importantly, in two ES patient-derived xenograft (PDX) models in which the tumors showed complete regression. In conclusion, the combination of the two agents leads to a biologically significant deregulation of the DDR machinery that elicits relevant antitumor activity in preclinical models and might represent a promising therapeutic tool that should be further explored for translation to the clinical setting.
Evaluating the anti-inflammatory and antioxidant efficacy of complementary andalternative medicines (CAM) used for management of inflammatory bowel disease:a comprehensive review
(Taylor & Francis, 2025-03-08) Shin, Sia; Xie, Kangzhe; Duhun, Suehad Abou; Ortiz Cerda, Tamara Andrea; Citología e Histología Normal y Patológica
beenfullyelucidated,andcurrenttreatmentsarenotdefinitiveandoftencarryseveralsideeffects. The Complementary andAlternativeMedicine (CAM) offers a newapproach to conventional medicine.However, theirclinicalapplicationandmechanismsremainlimited. Objective:Theaimof thisreviewistoevaluatetheanti-inflammatory, impactonmicrobiotaand antioxidantefficacyofcurrentlyavailableCAMfor IBD. Methods:TheliteraturecollectionwasobtainedfromGoogleScholar,MEDLINE,PubMedandWebof Science(WOS).Studiesinbothhumanandanimalmodels,publishedinEnglishlanguagebetween 2018 and 2024, were selected. Sixty-seven studieswere included in the current reviewafter inclusionandexclusionscreeningprocesses. Results:Mostly,studiesshowedsignificantanti-inflammatory,gutmicrobiotarestoring,antioxidant effectsofpolyphenols,polysaccharides, emodin, short-chainfattyacids (SCFA; includingbutyrate, propionateandacetate), andprobiotics althoughsomecontrasting resultswerenoted. Current evidence shows that polyphenols exhibit the most consistent result in alleviating IBD pathophysiology,primarilyduetotheirsignificantSCFA-elevatingeffect. Discussion:Futurestudiesmayfocusonhumanstudies,narrowingdownonindividualfactorswhich maychangenatural product’smetabolism. Further researchstudies arealsoessential toobtain therapeuticrecommendations.
Carcinoma de células basales queloideo
(Aula Médica Ediciones, 2015) Torres Gómez, Francisco Javier; Torres Olivera, Francisco Javier; Torres Gómez, Amelia; Citología e Histología Normal y Patológica; CTS949: Biopatología y Estrés Oxidativo
El carcinoma de células basales es la neoplasia maligna más frecuente en humanos. Se han descrito múltiples variantes morfológicas con distintas implicaciones pronósticas. La variante queloidea ha sido referida en la literatura en contadas ocasiones. La intensa reacción fibrosa estromal de tipo queloideo obliga a plantear diagnósticos diferenciales con procesos cicatriciales. La seriación sistemática de la lesión y la identificación del componente neoplásico tipo carcinoma serán claves para establecer el diagnóstico.
Alpha-catenin-dependent recruitment of the centrosomal protein cap350 to adherens junctions allows epithelial cells to acquire a columnar shape
(Public Library Science, 2015-03-12) Gavilán Dorronzoro, María de la Paz; Arjona, Marina; Zurbano, Ángel; Formstecher, Etienne; Martinez-Morales, Juan R.; Bornens, Michel; Rios, Rosa M.; Citología e Histología Normal y Patológica; Junta de Andalucía; Gobierno de España
Abstract Epithelial morphogenesis involves a dramatic reorganisation of the microtubule cytoskele ton. How this complex process is controlled at the molecular level is still largely unknown. Here, wereport that the centrosomal microtubule (MT)-binding protein CAP350 localises at adherens junctions in epithelial cells. By two-hybrid screening, we identified a direct interaction of AP350with the adhesion protein α-catenin that was further confirmed by co-immunoprecipitation experiments. Block of epithelial cadherin (E-cadherin)-mediated cell-cell adhesion or α-catenin depletion prevented CAP350 localisation at cell-cell junctions. Knocking downjunction-located CAP350 inhibited the establishment of an apico-basal array of microtubules and impaired the acquisition of columnar shape in Madin-Darby canine kidney II (MDCKII) cells grown as polarised epithelia. Furthermore, MDCKII cystogenesis was also defective in junctional CAP350-depleted cells. CAP350-depleted MDCKII cysts were smaller and contained either multiple lumens or no lumen. Membrane polarity wasnotaffected, but cortical microtubule bundles did not properly form. Our results indicate that CAP350mayactasanadaptorbetweenadherensjunctions and microtubules, thus regulating epithelial differentiation and contributing to the definition of cell architecture. We also uncover a central role of α-catenin in global cytoskeleton remodelling, in which it acts not only on actin but also on MT reorganisation during epithelial morphogenesis.
Proteomic profiling of ewing sarcoma reveals a role for traf6 in proliferation and ribonucleoproteins/rna processing
(Omics Publishing Group, 2016) Madoz-Gúrpide, Juan; Herrero Martín, David; Gómez López, Gonzalo; Hontecillas Prieto, Lourdes; Biscuola, Michele; Chamizo, Cristina; García Domínguez, Daniel José; Marcilla, David; Amaral, Ana Teresa; Ordoñez, José Luis; Álava Casado, Enrique de; Citología e Histología Normal y Patológica; CTS1035: Patología Molecular del Cáncer Sólido
Notwithstanding advances over the last decade in the comprehension of the molecular biology of Ewing sarcoma (ES), we still lack an understanding of critical issues, especially those regarding its genesis. In particular, little effort has been devoted to characterization of the proteic component of the mechanisms and pathways deployed by the activation of the fusion protein resulting from chromosomal translocation. We decided to investigate the proteic alterations of an ES cell line bearing a representative fusion protein. The combination of RNA interference of EWS FLI1 in the ES cell line TC-71, a proteomic analysis by 2-D electrophoresis and subsequent mass-spectrometry identification, and a global overrepresentation study detected changes in more than 500 spots. Forty-three proteins were identified as being significantly differentially abundant. As expected, we found and validated changes in proteins linked to nucleotide processing, transcription regulation, ribonucleoproteins, helicases, cell-cycle control and proliferation, and metabolic processes. Additionally, TNF receptor-associated factor 6 was revealed as a hub node. Our strategy showed the potential to reveal the protein interplay associated with the known functions of the fusion protein: binding to DNA and RNA in order to act as aberrant transcription factors or potent repressors, or by altering RNA processing.
Hibernoma de cavidad oral. Una entidad infrecuente
(Ediciones Ergon S.A; Sociedad Española de Cirugía Oral y Maxilofacial, 2015-01-19) Torres Gómez, Francisco Javier; Torres Gómez, Amelia; Torres Olivera, Francisco Javier; Citología e Histología Normal y Patológica; CTS949: Biopatología y Estrés Oxidativo
El hibernoma es un tumor adiposo benigno que morfológicamente rememora la grasa fetal. Su presencia a nivel oral es excepcional. Presentamos un caso de hibernoma de cavidad oral, revisamos la entidad y mostramos los distintos diagnósticos diferenciales.
Characterization of Human Mesenchymal Stem Cells from Ewing Sarcoma Patients. Pathogenetic Implications
(Public Library of Science, 2014-02-03) Amaral, Ana Teresa; Manara, María Cristina; Berghuis, Dagmar; Ordoñez, José Luis; Biscuola, Michele; Lóez García, María Ángeles; Osuna, Daniel; Lucarelli, Enrico; Alviano, Francesco; Lankester, Arjan; Scotlandi, Katia; Álava Casado, Enrique de; Citología e Histología Normal y Patológica; Italian Association for cancer research; Red Temática de Investigación del Cáncer
Background Ewing Sarcoma (EWS) is a mesenchymal-derived tumor that generally arises in bone and soft tissue. Intensive research regarding the pathogenesis of EWS has been insufficient to pinpoint the early events of Ewing sarcomagenesis. However, the Mesenchymal Stem Cell (MSC) is currently accepted as the most probable cell of origin. Materials and Methods In an initial study regarding a deep characterization of MSC obtained specifically from EWS patients (MSC-P), we compared them with MSC derived from healthy donors (MSC-HD) and EWS cell lines. We evaluated the presence of the EWS-FLI1 gene fusion and EWSR1 gene rearrangements in MSC-P. The presence of the EWS transcript was confirmed by q-RT-PCR. In order to determine early events possibly involved in malignant transformation, we used a multiparameter quantitative strategy that included both MSC immunophenotypic negative/positive markers, and EWS intrinsic phenotypical features. Markers CD105, CD90, CD34 and CD45 were confirmed in EWS samples. Results We determined that MSC-P lack the most prevalent gene fusion, EWSR1-FLI1 as well as EWSR1 gene rearrangements. Our study also revealed that MSC-P are more alike to MSC-HD than to EWS cells. Nonetheless, we also observed that EWS cells had a few overlapping features with MSC. As a relevant example, also MSC showed CD99 expression, hallmark of EWS diagnosis. However, we observed that, in contrast to EWS cells, MSC were not sensitive to the inhibition of CD99. Conclusions In conclusion, our results suggest that MSC from EWS patients behave like MSC-HD and are phenotypically different from EWS cells, thus raising important questions regarding MSC role in sarcomagenesis.
Clathrin-Mediated Endocytosis Is Impaired in Type A–B Niemann–Pick Disease Model Cells and Can Be Restored by ICAM-1-Mediated Enzyme Replacement
(American Chemical Society, 2014-06-20) Rappaport, Jeff; Garnacho Montero, Carmen; Muro, Silvia; Citología e Histología Normal y Patológica; NIH; National Science Foundation (NSF). United States; University of Maryland
Drugs often use endocytosis to achieve intracellular delivery, either by passive uptake from the extracellular fluid or by active targeting of cell surface features such as endocytic receptors. An example is enzyme replacement therapy, a clinically practiced treatment for several lysosomal storage diseases where glycosylated recombinant enzymes naturally target the mannose-6-phosphate receptor and are internalized by clathrin mediated endocytosis (CME). However, lysosomal substrate accumulation, a hallmark of these diseases, has been indirectly linked to aberrant endocytic activity. These effects are poorly understood, creating an obstacle to therapeutic efficiency. Here we explored endocytic activity in fibroblasts from patients with type A Niemann–Pick disease, a lysosomal storage disease characterized by acid sphingomyelinase (ASM) deficiency. The uptake of fluid phase markers and clathrin-associated ligands, formation of endocytic structures, and recruitment of intracellular clathrin to ligand binding sites were all altered, demonstrating aberrant CME in these cells. Model polymer nanocarriers targeted to intercellular adhesion molecule-1 (ICAM-1), which are internalized by a clathrin-independent route, enhanced the intracellular delivery of recombinant ASM more than 10-fold compared to free enzyme. This strategy reduced substrate accumulation and restored clathrin endocytic activity to wild-type levels. There appears to be a relationship between lysosomal storage and diminished CME, and bypassing this pathway by targeting ICAM-1 may enhance future therapies for lysosomal storage diseases.

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