Barajas, M. (Miguel)
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- Adenoviral gene transfer of interleukin 12 into tumors synergizes with adoptive T cell therapy both at the induction and effector level(Mary Ann Liebert, 2000) Mazzolini, G. (Guillermo); Duarte, M. (Marina); Borras-Cuesta, F. (Francisco); Qian, C. (Cheng); Barajas, M. (Miguel); Melero, I. (Ignacio); Narvaiza, I. (Íñigo); Prieto, J. (Jesús); Xie, X. (Xiaoming)Tumors infected with a recombinant defective adenovirus expressing interleukin 12 (IL-12) undergo regression, associated with a cytotoxic T lymphocyte (CTL)-mediated antitumor immune response. In the present study we generated anti-CT26 CTLs by short-term coculture of CT26 cells and lymph node cells obtained from mice harboring subcutaneous CT26 tumors injected with an adenoviral vector expressing IL-12 (AdCMVIL-12), control adenovirus (AdCMVlacZ), or saline. Regression of small intrahepatic CT26 tumors in unrelated syngeneic animals was achieved with CTLs derived from mice whose subcutaneous tumors had been injected with AdCMVIL-12 but not with CTLs from the other two control groups. The necessary and sufficient effector cell population for adoptive transfer consisted of CD8+ T cells that showed anti-CT26 specificity partly directed against the AH1 epitope presented by H-2Ld. Interestingly, treatment of a subcutaneous tumor nodule with AdCMVIL-12, combined with intravenous adoptive T cell therapy with short-term CTL cultures, had a marked synergistic effect against large, concomitant live tumors. Expression of IL-12 in the liver in the vicinity of the hepatic tumor nodules, owing to spillover of the vector into the systemic circulation, appeared to be involved in the increased in vivo antitumor activity of injected CTLs. In addition, adoptive T cell therapy improved the outcome of tumor nodules transduced with suboptimal doses of AdCMVIL-12. Our data provide evidence of a strong synergy between gene transfer of IL-12 and adoptive T cell therapy. This synergy operates both at the induction and effector phases of the CTL response, thus providing a rationale for combined therapeutic strategies for human malignancies.
- A Fermented Food Product Containing Lactic Acid Bacteria Protects ZDF Rats from the Development of Type 2 Diabetes(MDPI AG, 2019) Moreno-Aliaga, M. J. (María Jesús); Encío, I. (Ignacio); Araña, M. (Miriam); Oneca, M. (María); Cabello-Olmo, M. (Miriam); Barajas, M. (Miguel); Díaz, J.V. (Jesús Vicente); Guruceaga, E. (Elizabeth); Torre, P. (Paloma); Sainz, N. (Neira)Type 2 diabetes (T2D) is a complex metabolic disease, which involves a maintained hyperglycemia due to the development of an insulin resistance process. Among multiple risk factors, host intestinal microbiota has received increasing attention in T2D etiology and progression. In the present study, we have explored the effect of long-term supplementation with a non-dairy fermented food product (FFP) in Zucker Diabetic and Fatty (ZDF) rats T2D model. The supplementation with FFP induced an improvement in glucose homeostasis according to the results obtained from fasting blood glucose levels, glucose tolerance test, and pancreatic function. Importantly, a significantly reduced intestinal glucose absorption was found in the FFP-treated rats. Supplemented animals also showed a greater survival suggesting a better health status as a result of the FFP intake. Some dissimilarities have been observed in the gut microbiota population between control and FFP-treated rats, and interestingly a tendency for better cardiometabolic markers values was appreciated in this group. However, no significant differences were observed in body weight, body composition, or food intake between groups. These findings suggest that FFP induced gut microbiota modifications in ZDF rats that improved glucose metabolism and protected from T2D development.
- Nutritional Interventions with Bacillus coagulans Improved Glucose Metabolism and Hyperinsulinemia in Mice with Acute Intermittent Porphyria(2023) Riezu-Boj, J.I. (José Ignacio); Di-Pierro, E. (Elena); Collantes, M. (María); Moreno-Aliaga, M. J. (María Jesús); Peñuelas-Sanchez, I. (Ivan); Solares, I. (Isabel); Avila, M.A. (Matías Antonio); Córdoba-Quiñones, K. M. (Karol Marcela); Milagro-Yoldi, F.I. (Fermín Ignacio); Barajas, M. (Miguel); Dongiovanni, P. (Paola); Urtasun, R. (Raquel); Fontanellas-Romá, A. (Antonio); Longo, M. (Miriam); Sampedro, A. (Ana); Jericó-Asenjo, D. (Daniel)Acute intermittent porphyria (AIP) is a metabolic disorder caused by mutations in the porphobilinogen deaminase (PBGD) gene, encoding the third enzyme of the heme synthesis pathway. Although AIP is characterized by low clinical penetrance (~1% of PBGD mutation carriers), patients with clinically stable disease report chronic symptoms and frequently show insulin resistance. This study aimed to evaluate the beneficial impact of nutritional interventions on correct carbohydrate dysfunctions in a mouse model of AIP that reproduces insulin resistance and altered glucose metabolism. The addition of spores of Bacillus coagulans in drinking water for 12 weeks modified the gut microbiome composition in AIP mice, ameliorated glucose tolerance and hyperinsulinemia, and stimulated fat disposal in adipose tissue. Lipid breakdown may be mediated by muscles burning energy and heat dissipation by brown adipose tissue, resulting in a loss of fatty tissue and improved lean/fat tissue ratio. Probiotic supplementation also improved muscle glucose uptake, as measured using Positron Emission Tomography (PET) analysis. In conclusion, these data provide a proof of concept that probiotics, as a dietary intervention in AIP, induce relevant changes in intestinal bacteria composition and improve glucose uptake and muscular energy utilization. Probiotics may offer a safe, efficient, and cost-effective option to manage people with insulin resistance associated with AIP.
- Nuevas estrategias terapéuticas en diabetes mellitus tipo 1(Gobierno de Navarra, Departamento de Salud., 2008) Barajas, M. (Miguel); Salvador, J. (Javier); Escalada, J. (Javier); Prosper-Cardoso, F. (Felipe); Príncipe, R.M. (R.M.)El principal determinante del riesgo de complicaciones derivadas de la diabetes mellitus tipo 1 se debe a los altos niveles de glucosa en sangre mantenidos durante largo tiempo. Para conseguir un beneficio terapéutico en pacientes con diabetes mellitus es necesario desarrollar tratamientos que permitan de manera segura, efectiva y estable mantener la normoglucemia. Lamentablemente, el tratamiento de la diabetes mellitus tipo 1 mediante el aporte exógeno de insulina no es capaz de conseguir niveles estables de glucosa en sangre, de manera que con frecuencia se producen casos de severa hipoglucemia o hiperglucemia. Hasta la fecha la única solución para reestablecer de manera permanente la normoglucemia se consigue mediante el trasplante de páncreas o de islotes pancreáticos. Sin embargo, a medida que se incrementa el número de centros especializados en el trasplante de islotes, mayor es la necesidad de islotes para su trasplante. Así pues, el estudio de nuevas fuentes de células productoras de insulina así como de nuevos tratamientos que permitan preservar o incluso aumentar la masa de células beta en los pacientes con diabetes mellitus representa un objetivo de primera necesidad en este campo. En este sentido, en la última década ha habido un avance significativo en el campo de la biología de las células madre. Sin embargo, la identificación de células apropiadas para la generación de nuevas células beta, además del desarrollo de técnicas para la caracterización de estas células, así como de ensayos y modelos animales apropiados para probar su capacidad de diferenciación tanto in vitro como in vivo son de vital importancia para la puesta en marcha de nuevas estrategias terapéuticas basadas en la aplicación de las células madre para el tratamiento de la diabetes mellitus tipo 1.
- Intrahepatic injection of adenovirus reduces inflammation and increases gene transfer and therapeutic effect in mice(Wiley-Blackwell, 2006) Berraondo, P. (Pedro); González-Aseguinolaza, G. (Gloria); Rooijen, N. (Nico) van; Qian, C. (Cheng); Kochanek, S. (Stefan); Barajas, M. (Miguel); Shankar, V. (Vijay); Ochoa, L. (Laura); Crettaz, J. (Julien); Prieto, J. (Jesús); Hernandez-Alcoceba, R. (Rubén); Mauleon, I. (Itsaso)Recombinant adenoviruses (Ad) are among the most extensively used vectors for liver gene transfer. One of the major limitations for the clinical application of these vectors is the inflammatory immune response associated with systemic administration of high dose of virus. We evaluated the effect of Ad administration route on the inflammatory immune response and liver transgene expression. We compared direct intrahepatic injection (IH) with the systemic administration via tail vein (IV). IH injection of Ad resulted in a lower inflammatory response and a higher transgene expression. When a relatively low dose of virus was used, IV administration resulted in no detectable protein expression but production of proinflammatory cytokines. In contrast, IH administration induced high levels of transgene expression and no inflammation, although we detected a transient hypertransaminemia, which fully resolved within days. Furthermore, IH injection resulted in a faster protein expression being more intense at the site of injection, whereas IV administration caused slower but diffuse liver expression. IH injection also reduced the spreading of the virus to other organs. Independently of the route, depletion of Kupffer cells significantly enhanced the transduction efficiency of Ad. This effect was stronger when using IV injection, indicating that IH injection partially overcomes Kupffer cell phagocytic activity. Moreover, the antitumor efficacy of high-capacity-Ad encoding murine interleukin-12 (IL-12) was significantly greater when the vector was administered by IH injection than when given IV. In conclusion, IH injection of adenovirus represents a safe and efficient administration route for clinical applications of gene therapy targeting the liver.
- Gene therapy of orthotopic hepatocellular carcinoma in rats using adenovirus coding for interleukin 12(Wiley Blackwell, 2001) Mazzolini, G. (Guillermo); Genove, G. (Guillem); Qian, C. (Cheng); Sangro, B. (Bruno); Barajas, M. (Miguel); Bilbao, R. (Roberto); Melero, I. (Ignacio); Narvaiza, I. (Íñigo); Prieto, J. (Jesús); Schmitz, V. (Volker)The use of gene therapy to enhance antitumor immunity has emerged as a promising procedure to fight cancer. In this study we have tested the ability of an adenovirus carrying interleukin 12 (IL-12) gene (AdCMVIL-12) to eliminate tumoral lesions in 3 animal models of orthotopic hepatocellular carcinoma (HCC). Intratumoral injection of AdCMVIL-12 in animals with a single big tumor nodule implanted in the liver resulted in significant inhibition of tumor growth in a dose-dependent manner. Fifty percent of animals that received a dose of 5 x 10(9) plaque-forming units, showed complete regression of the tumor 2 weeks after treatment. In animals with 2 independent tumor nodules in the left liver lobe, injection in only one of them of 5 x 10(9) pfu AdCMVIL-12 induced, 15 days after therapy, complete regression of 50% of treated tumors and also of 50% of untreated lesions, with 60% long-term survival. Rats that were tumor free after therapy with AdCMVIL-12 showed protection against tumor rechallenge. A group of rats received the carcinogen diethylnitrosamine and developed multiple hepatic dysplasic nodules of 1 to 5 mm in diameter. These animals were treated by intrahepatic artery injection of either AdCMVIL-12 (5 x 10(9) pfu) or control vector. In this model AdCMVIL-12 induced complete tumor regression in 20% of treated rats and inhibited tumor growth in 60% of cases with an increase in rat survival. Activation of natural killer (NK) cells and inhibition of angiogenesis were found to be antitumor mechanisms set in motion by AdCMVIL-12. Our data indicate that experimental HCC can be efficiently treated by intratumoral or intravascular injection of adenovirus expressing IL-12.
- Reversal of hyperglycemia by insulin-secreting rat bone marrow- and blastocyst-derived hypoblast stem cell-like cells(Public Library of Science, 2013) Esguerra, C. (Camila); Hering, B. (Bernhard); Lo-Nigro, A. (Antonio); Heremans, Y. (Y.); Kumar, A. (Anujith); Mathieu, C. (Chantal); Cai, Q. (Qing); Barajas, M. (Miguel); Porciuncula, A. (Angelo); Nelson-Holte, M. (Molly); Gysemans, C. (Conny); Heimberg, H. (Harry); Prosper-Cardoso, F. (Felipe); Jimenez-Gonzalez, M. (María); Verfaillie, C.M. (Catherine M.); Binas, B. (Bert)β-cell replacement may efficiently cure type 1 diabetic (T1D) patients whose insulin-secreting β-cells have been selectively destroyed by autoantigen-reactive T cells. To generate insulin-secreting cells we used two cell sources: rat multipotent adult progenitor cells (rMAPC) and the highly similar rat extra-embryonic endoderm precursor (rXEN-P) cells isolated under rMAPC conditions from blastocysts (rHypoSC). rMAPC/rHypoSC were sequentially committed to definitive endoderm, pancreatic endoderm, and β-cell like cells. On day 21, 20% of rMAPC/rHypoSC progeny expressed Pdx1 and C-peptide. rMAPCr/HypoSC progeny secreted C-peptide under the stimulus of insulin agonist carbachol, and was inhibited by the L-type voltage-dependent calcium channel blocker nifedipine. When rMAPC or rHypoSC differentiated d21 progeny were grafted under the kidney capsule of streptozotocin-induced diabetic nude mice, hyperglycemia reversed after 4 weeks in 6/10 rMAPC- and 5/10 rHypoSC-transplanted mice. Hyperglycemia recurred within 24 hours of graft removal and the histological analysis of the retrieved grafts revealed presence of Pdx1-, Nkx6.1- and C-peptide-positive cells. The ability of both rMAPC and HypoSC to differentiate to functional β-cell like cells may serve to gain insight into signals that govern β-cell differentiation and aid in developing culture systems to commit other (pluripotent) stem cells to clinically useful β-cells for cell therapy of T1D.
- In vitro and in vivo comparative study of chimeric liver-specific promoters(Nature Publishing Group, 2003) Berraondo, P. (Pedro); Qian, C. (Cheng); Rodrigo, M. (Manuel); Wu, C. (Catherine); Barajas, M. (Miguel); Kramer, M.G. (María Gabriela); Prieto, J. (Jesús); Razquin, N. (Nerea); Fortes, P. (Puri)Targeting therapeutic genes to the liver is essential to improve gene therapy protocols of hepatic diseases and of some hereditary disorders. Transcriptional targeting can be achieved using liver-specific promoters. In this study we have made chimeric constructs combining promoter and enhancer regions of the albumin, alpha 1-antitrypsin, hepatitis B virus core protein, and hemopexin genes. Tissue specificity, activity, and length of gene expression driven from these chimeric regulatory sequences have been analyzed in cultured cells from hepatic and nonhepatic origin as well as in mice livers and other organs. We have identified a collection of liver-specific promoters whose activities range from twofold to less than 1% of the CMV promoter in human hepatoma cells. We found that the best liver specificity was attained when both enhancer and promoter sequences of hepatic genes were combined. In vivo studies were performed to analyze promoter function during a period of 50 days after gene transfer to the mouse liver. We found that among the various chimeric constructs tested in this work, the alpha1-antitrypsin promoter alone or linked to the albumin or hepatitis B enhancers is the most potent in directing stable gene expression in liver cells.
- Multipotent Adult Progenitor Cells (MAPC) contribute to hepatocarcinoma neovasculature(Elsevier, 2007) Riezu-Boj, J.I. (José Ignacio); Berasain, C. (Carmen); Guitart, A. (Anunciata); Garate, L. (Leire); Franchi, F. (F.); Gutierrez-Perez, M. (María); Barajas, M. (Miguel); Kramer, M.G. (María Gabriela); Narvaiza, I. (Íñigo); Prieto, J. (Jesús); Clavel, C. (C.); Prosper-Cardoso, F. (Felipe); Merino, J. (Juana); Abizanda-Sarasa, G. (Gloria); Aranguren, X.L. (Xabier L.); Moreno, C. (Cristina)The use of stem cells as a vehicle of therapeutic genes is an attractive approach for the development of new antitumoral strategies based on gene therapy. The aim of our study was to assess the potential of bone marrow-derived Multipotent Adult Progenitor Cells (rMAPCs) to differentiate in vitro and in vivo into endothelial cells and to be recruited to areas of tumor vasculogenesis. In vitro, rMAPCs obtained from Buffalo rats differentiated into cells expressing endothelial markers and demonstrated functional endothelial capacity. Intravenous injection of undifferentiated rMAPC transduced with a lentivirus expressing GFP in an orthotopic rat model of hepatocellular carcinoma, resulted in tumor recruitment of the injected cells and in vivo differentiation into endothelial cells in the tumor area with contribution to vasculogenesis. In summary, our results suggest that rMAPCs can be efficiently recruited by vascularized tumors and differentiate to endothelium and thus may represent a useful vehicle for delivery of therapeutic genes to sites of active tumor neovascularization.
- Gene therapy of primary and metastatic liver tumors(Medical Science International Publishing, 2001) Mazzolini, G. (Guillermo); Qian, C. (Cheng); Sangro, B. (Bruno); Barajas, M. (Miguel); Melero, I. (Ignacio); Narvaiza, I. (Íñigo); Prieto, J. (Jesús)