Person: Vaquero Martín, Francisco Javier
Loading...
First Name
Francisco Javier
Last Name
Vaquero Martín
Affiliation
Universidad Complutense de Madrid
Faculty / Institute
Medicina
Department
Cirugía
Area
Traumatología y Ortopedia
Identifiers
13 results
Search Results
Now showing 1 - 10 of 13
Item Long‑term outcomes of one single‑design varus valgus constrained versus one single‑design rotating hinge in revision knee arthroplasty after over 10‑year follow‑up(Journal of Orthopaedic Surgery and Research, 2022) Sanz Ruiz, Pablo; Leon Roman, Victor Estuardo; Matas Diez, Jose Antonio; Villanueva Martinez, Manuel; Vaquero Martín, Francisco JavierBackground The appropriate degree of constraint in knee prosthetic revision is unknown, necessitating the use of the lowest possible constraint. This study aimed to compare the long-term clinical and survival results of revision with rotation hinge knee (RHK) VS constrained condylar constrained knee (CCK) implants. Methods Overall, 117 revision case were prospectively reviewed and dividing into two groups based on the degree of constraint used, using only one prosthetic model in each group (61 CCK vs 56 RHK). All implants were evaluated for a minimum of 10 years. Survival of both implants at the end of follow-up, free from revision for any cause, aseptic loosening, and septic cause was compared. Results Better results were seen with use of the RHK in joint ranges of (p = 0.023), KSCS (p = 0.015), KSFS (p = 0.043), and KOOS (p = 0.031). About 22.2% of the cases required repeat surgery (11.7% RHK vs 29.6% CCK, p = 0.023). Constrained condylar implants had a significantly lower survival rates than rotating hinge implants (p = 0.005), due to a higher aseptic loosening rate (p = 0.031). Conclusion Using a specific RHK design with less rotational constraint has better clinical and survival outcomes than implants with greater rotational constraint, such as one specific CCK.Item Neuroblastoma RAS viral oncogene homolog (N-RAS) deficiency aggravates liver injury and fibrosis(Cell Death and Disease, 2023) Kang, Zheng; Fengjie, Hao; Medrano García, Sandra; Chaobo, Chen; Morán Blanco, Laura; Peligros Gómez, María Isabel; Bañares Cañizares, Rafael; Vaquero Martín, Francisco Javier; Gómez Del Moral Martín-Consuegra, Manuel María; Regueiro González-Barros, José Ramón; Martínez Naves, Eduardo; Gallego Durán, Rocío; Maya, Douglas; Ampuero, Javier; Romero Gómez, Manuel; Gilbert Ramos, Albert; Guixé Muntet, Sergi; Fernández Iglesias, Anabel; Gracia Sancho, Jordi; Coll, Mar; Graupera, Isabel; Ginès, Pere; Pericàs, Juan M.; Ramos Molina, Bruno; Herranz, José María; Ávila, Matías A.; Nevzorova, Yulia; Fernández Malavé, Edgar Gonzalo; Cubero Palero, Francisco JavierProgressive hepatic damage and fibrosis are major features of chronic liver diseases of different etiology, yet the underlying molecular mechanisms remain to be fully defined. N-RAS, a member of the RAS family of small guanine nucleotide-binding proteins also encompassing the highly homologous H-RAS and K-RAS isoforms, was previously reported to modulate cell death and renal fibrosis; however, its role in liver damage and fibrogenesis remains unknown. Here, we approached this question by using N-RAS deficient (N-RAS-/-) mice and two experimental models of liver injury and fibrosis, namely carbon tetrachloride (CCl4) intoxication and bile duct ligation (BDL). In wild-type (N-RAS+/+) mice both hepatotoxic procedures augmented N-RAS expression in the liver. Compared to N-RAS+/+ counterparts, N-RAS-/- mice subjected to either CCl4 or BDL showed exacerbated liver injury and fibrosis, which was associated with enhanced hepatic stellate cell (HSC) activation and leukocyte infiltration in the damaged liver. At the molecular level, after CCl4 or BDL, N-RAS-/- livers exhibited augmented expression of necroptotic death markers along with JNK1/2 hyperactivation. In line with this, N-RAS ablation in a human hepatocytic cell line resulted in enhanced activation of JNK and necroptosis mediators in response to cell death stimuli. Of note, loss of hepatic N-RAS expression was characteristic of chronic liver disease patients with fibrosis. Collectively, our study unveils a novel role for N-RAS as a negative controller of the progression of liver injury and fibrogenesis, by critically downregulating signaling pathways leading to hepatocyte necroptosis. Furthermore, it suggests that N-RAS may be of potential clinical value as prognostic biomarker of progressive fibrotic liver damage, or as a novel therapeutic target for the treatment of chronic liver disease.Item Neuroblastoma RAS viral oncogene homolog (N-RAS) deficiency aggravates liver injury and fibrosis(Cell death diseases, 2023) Kang, Zheng; Fengjie, Hao; Medrano García, Sandra; Chaobo, Chen; Morán Blanco, Laura; Peligros Gómez, María Isabel; Vaquero Martín, Francisco Javier; Bañares Cañizares, Rafael; Gómez Del Moral Martín-Consuegra, Manuel María; Regueiro González-Barros, José Ramón; Martínez Naves, Eduardo; Nevzorova, Yulia; Fernández Malavé, Edgar Gonzalo; Cubero Palero, Francisco JavierProgressive hepatic damage and fibrosis are major features of chronic liver diseases of different etiology, yet the underlying molecular mechanisms remain to be fully defined. N-RAS, a member of the RAS family of small guanine nucleotide-binding proteins also encompassing the highly homologous H-RAS and K-RAS isoforms, was previously reported to modulate cell death and renal fibrosis; however, its role in liver damage and fibrogenesis remains unknown. Here, we approached this question by using N-RAS deficient (N-RAS−/−) mice and two experimental models of liver injury and fibrosis, namely carbon tetrachloride (CCl4) intoxication and bile duct ligation (BDL). In wild-type (N-RAS+/+) mice both hepatotoxic procedures augmented N-RAS expression in the liver. Compared to N-RAS+/+ counterparts, N-RAS−/− mice subjected to either CCl4 or BDL showed exacerbated liver injury and fibrosis, which was associated with enhanced hepatic stellate cell (HSC) activation and leukocyte infiltration in the damaged liver. At the molecular level, after CCl4 or BDL, N-RAS−/− livers exhibited augmented expression of necroptotic death markers along with JNK1/2 hyperactivation. In line with this, N-RAS ablation in a human hepatocytic cell line resulted in enhanced activation of JNK and necroptosis mediators in response to cell death stimuli. Of note, loss of hepatic N-RAS expression was characteristic of chronic liver disease patients with fibrosis. Collectively, our study unveils a novel role for N-RAS as a negative controller of the progression of liver injury and fibrogenesis, by critically downregulating signaling pathways leading to hepatocyte necroptosis. Furthermore, it suggests that N-RAS may be of potential clinical value as prognostic biomarker of progressive fibrotic liver damage, or as a novel therapeutic target for the treatment of chronic liver disease.Item Preconditioning by portal vein embolization modulates hepatic hemodynamics and improves liver function in pigs with extended hepatectomy(Surgery, 2016) Asencio Pascual, José Manuel; García Sabrido, José Luis; López Baena, José Ángel; Peligros Gómez, María Isabel; Sola Vendrell, Emma; Bañares Cañizares, Rafael; Vaquero Martín, Francisco Javier; Olmedilla, Luis; Lozano, Pablo; Morales-Taboada, Alvaro; Fernandez-Mena, Carolina; Steiner, Miguel Angel; Perez-Peña, Jose Maria; Herrero, Miriam; Laso, Juan; Lisbona, Cristina; Casanova, JavierBackground. Portal vein embolization is performed weeks before extended hepatic resections to increase the future liver remnant and prevent posthepatectomy liver failure. Portal vein embolization performed closer to the operation also could be protective, but worsening of portal hyper-perfusion is a major concern. We determined the hepatic hemodynamic effects of a portal vein embolization performed 24 hours prior to hepatic operation. Methods. An extended (90%) hepatectomy was performed in swine undergoing (portal vein embolization) or not undergoing (control) a portal vein embolization 24 hours earlier (n = 10/group). Blood tests, hepatic and systemic hemodynamics, hepatic function (plasma disappearance rate of indocyanine green), liver histology, and volumetry (computed tomographic scanning) were assessed before and after the hepatectomy. Hepatocyte proliferating cell nuclear antigen expression and hepatic gene expression also were evaluated. Results. Swine in the control and portal vein embolization groups maintained stable systemic hemodynamics and developed similar increases of portal blood flow (302 ± 72% vs 486 ± 92%, P = .13). Portal pressure drastically increased in Controls (from 9.4 ± 1.3 mm Hg to 20.9 ± 1.4 mm Hg, P < .001), while being markedly attenuated in the portal vein embolization group (from 11.4 ± 1.5 mm Hg to 16.1 ± 1.3 mm Hg, P = .061). The procedure also improved the preservation of the hepatic artery blood flow, liver function, and periportal edema. These effects occurred in the absence of hepatocyte proliferation or hepatic growth and were associated with the induction of the vasoprotective gene Klf2. Conclusion. Portal vein embolization preconditioning represents a potential hepato-protective strategy for extended hepatic resections. Further preclinical studies should assess its medium-term effects, including survival. Our study also supports the relevance of hepatic hemodynamics as the main pathogenetic factor of post-hepatectomy liver failure.Item Activation of the Unfolded Protein Response (UPR) Is Associated with Cholangiocellular Injury, Fibrosis and Carcinogenesis in an Experimental Model of Fibropolycystic Liver Disease(Cancers, 2021) Chaobo, Chen; Hanghang, Wu; Hui, Ye; Tortajada Alonso, Agustín; Peligros Gómez, María Isabel; Kang, Zheng; Vaquero Martín, Francisco Javier; Bañares Cañizares, Rafael; Martínez Naves, Eduardo; Nevzorova, Yulia; Cubero Palero, Francisco JavierFibropolycystic liver disease is characterized by hyperproliferation of the biliary epithelium and the formation of multiple dilated cysts, a process associated with unfolded protein response (UPR). In the present study, we aimed to understand the mechanisms of cyst formation and UPR activation in hepatocytic c-Jun N-terminal kinase 1/2 (Jnk1/2) knockout mice. Floxed JNK1/2 (Jnkf/f) and Jnk∆hepa animals were sacrificed at different time points during progression of liver disease. Histological examination of specimens evidenced the presence of collagen fiber deposition, increased α-smooth muscle actin (αSMA), infiltration of CD45, CD11b and F4/80 cells and proinflammatory cytokines (Tnf, Tgfβ1) and liver injury (e.g., ALT, apoptosis and Ki67-positive cells) in Jnk∆hepa compared with Jnkf/f livers from 32 weeks of age. This was associated with activation of effectors of the UPR, including BiP/GRP78, CHOP and spliced XBP1. Tunicamycin (TM) challenge strongly induced ER stress and fibrosis in Jnk∆hepa animals compared with Jnkf/f littermates. Finally, thioacetamide (TAA) administration to Jnk∆hepa mice induced UPR activation, peribiliary fibrosis, liver injury and markers of biliary proliferation and cholangiocarcinoma (CCA). Orthoallografts of DEN/CCl4-treated Jnk∆hepa liver tissue triggered malignant CCA. Altogether, these results suggest that activation of the UPR in conjunction with fibrogenesis might trigger hepatic cystogenesis and early stages of CCA.Item An Experimental DUAL Model of Advanced Liver Damage(Hepatology Communications, 2021) Benede Ubieto, Raquel; Estévez Vázquez, Olga; Guo, Feifei; Chen, Chaobo; Gómez Del Moral Martín-Consuegra, Manuel María; Lamas Paz, Aranzazu; Morán, Laura; López Alcántara, Nuria; S. Mazariegos, Marina; Zheng, Kang; Juárez Martín-Delgado, Ignacio; Martín Villa, José Manuel; Asensio, Iris; Vaquero Martín, Francisco Javier; Peligros Gómez, María Isabel; Romero Gómez, Manuel; Bañares Cañizares, Rafael; Cubero Palero, Francisco Javier; Nevzorova, YuliaIndividuals exhibiting an intermediate alcohol drinking pattern in conjunction with signs of metabolic risk present clinical features of both alcohol-associated and metabolic-associated fatty liver diseases. However, such combination remains an unexplored area of great interest, given the increasing number of patients affected. In the present study, we aimed to develop a preclinical DUAL (alcohol-associated liver disease plus metabolic-associated fatty liver disease) model in mice. C57BL/6 mice received 10% vol/vol alcohol in sweetened drinking water in combination with a Western diet for 10, 23, and 52 weeks (DUAL model). Animals fed with DUAL diet elicited a significant increase in body mass index accompanied by a pronounced hypertrophy of adipocytes, hypercholesterolemia, and hyperglycemia. Significant liver damage was characterized by elevated plasma alanine aminotransferase and lactate dehydrogenase levels, extensive hepatomegaly, hepatocyte enlargement, ballooning, steatosis, hepatic cell death, and compensatory proliferation. Notably, DUAL animals developed lobular inflammation and advanced hepatic fibrosis. Sequentially, bridging cirrhotic changes were frequently observed after 12 months. Bulk RNA-sequencing analysis indicated that dysregulated molecular pathways in DUAL mice were similar to those of patients with steatohepatitis. Conclusion: Our DUAL model is characterized by obesity, glucose intolerance, liver damage, prominent steatohepatitis and fibrosis, as well as inflammation and fibrosis in white adipose tissue. Altogether, the DUAL model mimics all histological, metabolic, and transcriptomic gene signatures of human advanced steatohepatitis, and therefore serves as a preclinical tool for the development of therapeutic targets.Item Intestinal Epithelial Cell-Derived Extracellular Vesicles Modulate Hepatic Injury via the Gut-Liver Axis During Acute Alcohol Injury(Frontiers in Pharmacology, 2020) Lamas Paz, Arantza; Morán, Laura; Salinas Rodríguez, Beatriz; López Alcántara, Nuria; Asensio, Iris; Fengjie, Hao; Kang, Zheng; Martín Adrados, Beatriz; Moreno Gutiérrez, Laura; Cogolludo Torralba, Ángel Luis; Gómez Del Moral Martín-Consuegra, Manuel María; Martínez Naves, Eduardo; Vaquero Martín, Francisco Javier; Bañares Cañizares, Rafael; Nevzorova, Yulia; Cubero Palero, Francisco JavierBinge drinking, i.e., heavy episodic drinking in a short time, has recently become an alarming societal problem with negative health impact. However, the harmful effects of acute alcohol injury in the gut-liver axis remain elusive. Hence, we focused on the physiological and pathological changes and the underlying mechanisms of experimental binge drinking in the context of the gut-liver axis. Eight-week-old mice with a C57BL/6 background received a single dose (p.o.) of ethanol (EtOH) [6 g/kg b.w.] as a preclinical model of acute alcohol injury. Controls received a single dose of PBS. Mice were sacrificed 8 h later. In parallel, HepaRGs and Caco-2 cells, human cell lines of differentiated hepatocytes and intestinal epithelial cells intestinal epithelial cells (IECs), respectively, were challenged in the presence or absence of EtOH [0-100 mM]. Extracellular vesicles (EVs) isolated by ultracentrifugation from culture media of IECs were added to hepatocyte cell cultures. Increased intestinal permeability, loss of zonula occludens-1 (ZO-1) and MUCIN-2 expression, and alterations in microbiota-increased Lactobacillus and decreased Lachnospiraceae species-were found in the large intestine of mice exposed to EtOH. Increased TUNEL-positive cells, infiltration of CD11b-positive immune cells, pro-inflammatory cytokines (e.g., tlr4, tnf, il1β), and markers of lipid accumulation (Oil Red O, srbep1) were evident in livers of mice exposed to EtOH, particularly in females. In vitro experiments indicated that EVs released by IECs in response to ethanol exerted a deleterious effect on hepatocyte viability and lipid accumulation. Overall, our data identified a novel mechanism responsible for driving hepatic injury in the gut-liver axis, opening novel avenues for therapyItem Comprehensive Characterization of a Porcine Model of The “Small-for-Flow” Syndrome(Journal of Gastrointestinal Surgery, 2019) Orue-Echebarria, Maitane I.; Vaquero Martín, Francisco Javier; Lisbona, Cristina J.; Lozano, Pablo; Steiner, Miguel A.; Morales, Álvaro; López Baena, José Ángel; Laso, Juan; Hernández, Inmaculada; Olmedilla, Luis; García Sabrido, José Luis; Peligros Gómez, María Isabel; Sola Vendrell, Emma; Fernández Carballal, Carlos; Vara Ameigeiras, Elena María; Asencio Pascual, José ManuelMethods We performed subtotal (90%) hepatectomies in 10 female MiniPigs using a simplified transection technique with a tourniquet. Blood tests, hepatic and systemic hemodynamics, and hepatic function and histology were assessed before (Bas), 15 min (t-15 min) and 24 h (t-24 h) after the operation. Some pigs underwent computed tomography (CT) scans for hepatic volumetry (n = 4) and intracranial pressure (ICP) monitoring (n = 3). Postoperative care was performed in an intensive care unit environment. Results All hepatectomies were successfully performed, and hepatic volumetry confirmed liver remnant volumes of 9.2% [6.2–11.2]. The hepatectomy resulted in characteristic hepatic hemodynamic alterations, including portal hyperperfusion, relative decrease of hepatic arterial blood flow, and increased portal pressure (PP) and portal-systemic pressure gradient. The model reproduced major diagnostic features including the development of cholestasis, coagulopathy, encephalopathy with increased ICP, ascites, and renal failure, hyperdynamic circulation, and hyperlactatemia. Two animals (20%) died before t-24 h. Histological liver damage was observed at t-15 min and at t-24 h. The degree of histological damage at t-24 h correlated with intraoperative PP (r = 0.689, p = 0.028), hepatic arterial blood flow (r = 0.655, p = 0.040), and hepatic arterial pulsatility index (r = 0.724, p = 0.066). All animals with intraoperative PP > 20 mmHg presented liver damage at t-24 h. Conclusion The present 90% hepatectomy porcine experimental model is a feasible and reproducible model for investigating the “Small-for-Flow” syndrome.Item Lack of Cyclin E1 in hepatocytes aggravates ethanol-induced liver injury and hepatic steatosis in experimental murine model of acute and chronic alcohol-associated liver disease(BBA - Molecular Basis of Disease, 2023) Ramadori, Pierluigi; Woitok, Marius Maximilian; Estévez Vázquez, Olga; Benede Ubieto, Raquel; Leal Lassalle, Héctor; Lamas Paz, Arantza; Guo, Feifei; Fabre, Jeanne; Otto, Julia; Verwaayen, Anna; Reissing, Johanna; Bruns, Tony; Erschfeld, Stephanie; Haas, Ute; Paffen, Daniela; Nelson, Leonard J.; Vaquero Martín, Francisco Javier; Bañares Cañizares, Rafael; Trautwein, Christian; Cubero Palero, Francisco Javier; Liedtke, Christian; Nevzorova, YuliaBackground: Cyclin E1 is the regulatory subunit of cyclin-dependent kinase 2 (Cdk2) and one of the central players in cell cycle progression. We recently showed its crucial role for initiation of liver fibrosis and hepatocarcinogenesis. In the present study, we investigated the role of Cyclin E1 in the development of alcohol-associated liver disease (ALD). Methods: Mice with constitutive (E1-/-), hepatocyte-specific (Cyclin E1Δhepa), or intestinal-epithelial-cell-specific (Cyclin E1ΔIEC) inactivation of Cyclin E1 and corresponding wild type littermate controls (WT) were administered either a Lieber-DeCarli ethanol diet (LDE) for 3 weeks or acute ethanol binges (6 g/kg) through oral gavage. Serum parameters of liver functionality were measured; hepatic tissues were collected for biochemical and histological analyses. Results: The administration of acute EtOH binge and chronic LDE diet to E1-/- mice enhanced hepatic steatosis, worsened liver damage and triggered body weight loss. Similarly, in the acute EtOH binge model, Cyclin E1Δhepa mice revealed a significantly worsened liver phenotype. In contrast, inactivation of Cyclin E1 only in intestinal epithelial cell (IECs)did not lead to any significant changes in comparison to WT mice after acute EtOH challenge. Remarkably, both acute and chronic EtOH administration in E1-/- animals resulted in increased levels of ADH and decreased expression of ALDH1/2. The additional application of a pan-Cdk inhibitor (S-CR8) further promoted liver damage in EtOH-treated WT mice. Conclusion: Our data point to a novel unexpected role of Cyclin E1 in hepatocytes for alcohol metabolism, which seems to be independent of the canonical Cyclin E1/Cdk2 function as a cell cycle regulator.Item Curcumin encapsulated in milk small extracellular vesicles as a nanotherapeutic alternative in experimental chronic liver disease(Biomedicine & Pharmacotherapy, 2024) Albadalejo-García, Virginia; Morán, Laura; Santos-Coquillat, Ana; González, María I.; Ye, Hui; Vázquez Ogando, Elena; Salinas, Beatriz; Vaquero Martín, Francisco Javier; Cubero Palero, Francisco JavierCurcumin is a natural molecule widely tested in preclinical and clinical studies due to its antioxidant and anti-inflammatory activity. Nevertheless, its high hydrophobicity and low bioavailability limit in vivo applications. To overcome curcumin´s drawbacks, small extracellular vesicles (sEVs) have emerged as potential drug delivery systems due to their non-immunogenicity, nanometric size and amphiphilic composition. This work presents curcumin cargo into milk sEV structure and further in vitro and in vivo evaluation as a therapeutic nanoplatform. The encapsulation of curcumin into sEV was performed by two methodologies under physiological conditions: a passive incorporation and active cargo employing saponin. Loaded sEVs (sEVCurPas and sEVCurAc) were fully characterized by physicochemical techniques, confirming that neither methodology affects the morphology or size of the nanoparticles (sEV: 113.3±5.1 nm, sEVCurPas: 127.0±4.5 nm and sEVCurAc: 98.5±3.6 nm). Through the active approach with saponin (sEVCurAc), a three-fold higher cargo was obtained (433.5 µg/mL) in comparison with the passive approach (129.1 µg/mL). These sEVCurAc were further evaluated in vitro by metabolic activity assay (MTT), confocal microscopy, and flow cytometry, showing a higher cytotoxic effect in the tumoral cells RAW264.7 and HepG2 than in primary hepatocytes, specially at high doses of sEVCurAc (4%, 15% and 30% of viability). In vivo evaluation in an experimental model of liver fibrosis confirmed sEVCurAc therapeutic effects, leading to a significant decrease of serum markers of liver damage (ALT) (557 U/L to 338 U/L with sEVCurAc therapy) and a tendency towards decreased liver fibrogenesis and extracellular matrix (ECM) deposition.