Guillermina Baay-Guzman | Hospital Infantil de México Federico Gómez (original) (raw)

Papers by Guillermina Baay-Guzman

Revista Alergia México, 2008

El asma es una enfermedad inflamatoria crónica de las vías aéreas que inevitablemente se asocia c... more El asma es una enfermedad inflamatoria crónica de las vías aéreas que inevitablemente se asocia con remodelación pulmonar como mecanismo de reparación tisular. Los cambios estructurales por la remodelación junto con el proceso inflamatorio persistente ocasionan obstrucción del flujo de aire, lo que paradójicamente produce hipoxia en el tejido pulmonar afectado. Uno de los cambios más importantes que sufre el pulmón durante la remodelación es la angiogénesis, ésta es necesaria por el incremento en la masa pulmonar. El factor de crecimiento del endotelio vascular (VEGF) es el principal mediador de la angiogénesis y se sabe que puede ser regulado por el factor inducible en hipoxia (HIF-1), provocando un rápido incremento en la expresión de VEGF en condiciones de hipoxia. El factor de transcripción HIF-1 es un heterodímero constituido por dos subunidades: HIF-1α (inducible en hipoxia) y HIF-1β (constitutivo). HIF-1 se activa principalmente en la hipoxia y media la transcripción de genes blanco en respuesta a la disminución de oxígeno por unión a elementos que responden en hipoxia. Estudios recientes revelan la asociación de la expresión de HIF en la angiogénesis inducida por los eventos de remodelación que ocurren en los procesos de asma. Se cree que la angiogénesis puede estar modulada por el factor de transcripción HIF, como se ha descrito para otras enfermedades en donde existen eventos de hipoxia y angiogénesis. El propósito de esta revisión es mostrar un panorama general de los trabajos publicados en los últimos años acerca de los mecanismos de hipoxia y remodelación del tejido pulmonar a fin de comprender mejor la fisiopatogénesis del asma. Palabras clave: asma, remodelación de vías aéreas, VEGF, hipoxia, factor inducible en hipoxia-1 (HIF-1).

Tuberculosis, 2015

Mycobacterium tuberculosis (M. tb) is the etiological agent of pulmonary tuberculosis (TB); this ... more Mycobacterium tuberculosis (M. tb) is the etiological agent of pulmonary tuberculosis (TB); this disease remains a worldwide health problem. Yin-Yang-1 (YY1) plays a major role in the maintenance and progression of some pulmonary diseases, including pulmonary fibrosis. However, the role of YY1 in TB remains unknown. The aim of this study was to elucidate the role of YY1 in the regulation of CCL4 and its implication in TB. We determined whether YY1 regulates CCL4 using reporter plasmids, ChIP and siRNA assays. Immunohistochemistry and digital pathology were used to measure the expression of YY1 and CCL4 in a mouse model of TB. A retrospective comparison of patients with TB and control subjects was used to measure the expression of YY1 and CCL4 using tissue microarrays. Our results showed that YY1 regulates the transcription of CCL4; moreover, YY1, CCL4 and TGF-β were overexpressed in the lung tissues of mice with TB during the late stages of the disease and the tissues of TB patients. The expression of CCL4 and TGF-β correlated with YY1 expression. In conclusion, YY1 regulates CCL4 transcription; moreover, YY1 is overexpressed in experimental and human TB and is positively correlated with CCL4 and TGF-β expression. Therefore, treatments that decrease YY1 expression may be a new therapeutic strategy against TB.

Cellular and molecular gastroenterology and hepatology, 2015

Evaluación de la expresión del factor de transcripción Yin-Yang-1 y su asociación con TGF-β en un... more Evaluación de la expresión del factor de transcripción Yin-Yang-1 y su asociación con TGF-β en un modelo murino de inflamación alérgica pulmonar con diferentes grados de severidad artículo original RESUMEN Introducción. El asma alérgica es una de las enfermedades más prevalecientes en la edad pediátrica. Los mecanismos implicados en este padecimiento no han sido esclarecidos totalmente. Se sabe que el factor de crecimiento transformante-beta (TGF-β) juega un papel muy importante en la fisiopatología de esta enfermedad y que la activación del factor de trascripción Yin-Yang-1 (YY1) induce un aumento en la expresión de esta citocina. El factor YY1 también regula la expresión de otras citocinas involucradas en el asma tales como la IL-4 y la IL-10. El objetivo de este trabajo fue evaluar la asociación entre YY1 y TGF-β en un modelo murino de inflamación alérgica pulmonar. Métodos. Se trabajó con un modelo murino de inflamación alérgica pulmonar con diferentes grados de severidad empleando ovalbúmina como alérgeno. Posteriormente se obtuvo el tejido pulmonar, que fue incluido en parafina, se construyó un microarreglo del tejido en un equipo semiautomático y, mediante inmunohistoquímica, se evaluó la expresión de YY1 y de TGF-β. La densidad de la expresión se midió de manera cuantitativa por métodos computarizados. Resultados. Se observó inflamación alérgica pulmonar diferencial acorde con el grado de severidad del modelo; se observó el mismo patrón con la producción de moco. La expresión de ambas proteínas se correlacionó de manera directa con el grado de severidad de la inflamación alérgica pulmonar. Conclusiones. Los resultados obtenidos corroboran el papel que juegan ambas proteínas en la fisiopatología de la inflamación alérgica pulmonar. Palabras clave: inflamación alérgica pulmonar, Yin-Yang-1 (YY1), TGF-β, microarreglo ABSTRACT Background. Allergic asthma is one of the most prevalent childhood diseases. This disease is characterized by airway inflammation and remodelling. The mechanisms implicated in the pathogenesis of this disease remain unclear. Several studies have shown that TGF-β plays an important role in the pathogenesis of asthma. In addition, the polymorphism of the TGF-β promoter region results in the overexpression of TGF-β via regulation of the transcription factor Yin-Yang-1 (YY1). It is has recently been demonstrated that YY1 may be involved in the pathogenesis of asthma by the regulation of IL-4 and IL-10. The aim of this study was to evaluate the association between the YY1 and TGF-β expression levels in a murine model of lung allergic inflammation. Methods. In this study we used a lung allergic inflammatory murine model with different severity degrees. Tissue microarray technology and immunohistochemistry were used to evaluate YY1 and TGF-β expression. The density expression was measured by quantitative methods using specific software. Results. Expression of both proteins correlated with the degrees of severity of lung allergic inflammation. A similar result was observed with mucus production. Conclusions. These results corroborate the role of YY1 and TGF-β in the pathogenesis of this disease.

CMGH Cellular and Molecular Gastroenterology and Hepatology, 2015

Chronic inflammation promotes development and progression of colorectal cancer (CRC). We explored... more Chronic inflammation promotes development and progression of colorectal cancer (CRC). We explored the distribution of Corticotropin-Releasing-Hormone (CRH)-family of receptors and ligands in CRC and their contribution in tumor growth and oncogenic EMT. mRNA expression of CRH-family members was analyzed in CRC (N=56) and control (N=46) samples, 7 CRC cell lines and normal NCM460 cells. Immunohistochemical detection of CRHR2 was performed in 20 CRC and 5 normal tissues. Cell proliferation, migration and invasion were compared between Urocortin-2 (Ucn2)-stimulated parental and CRHR2-overexpressing (CRHR2+) cells in absence or presence of IL-6. CRHR2/Ucn2-targeted effects on tumor growth and EMT were validated in SW620-xenograft mouse models. CRC tissues and cell lines showed decreased mRNA and protein CRHR2 expression compared to controls and NCM460, respectively. The opposite trend was shown for Ucn2. CRHR2/Ucn2 signaling inhibited cell proliferation, migration, invasion and colony formation in CRC-CRHR2+ cells. In vivo, SW620-CRHR2+ xenografts showed decreased growth, reduced expression of EMT-inducers and elevated levels of EMT-suppressors. IL-1b, IL-6 and IL-6R mRNAs where diminished in CRC-CRHR2+ cells, while CRHR2/Ucn2 signaling inhibited IL-6-mediated Stat3 activation, invasion, migration and expression of downstream targets acting as cell cycle- and EMT-inducers. Expression of cell cycle- and EMT-suppressors was augmented in IL-6/Ucn2-stimulated CRHR2+ cells. In patients, CRHR2 mRNA expression was inversely correlated with IL-6R and vimentin levels and metastasis occurrence, while positively associated with E-cadherin expression and overall survival. CRHR2 downregulation in CRC supports tumor expansion and spread through maintaining persistent inflammation and constitutive Stat3 activation. CRHR2(low) CRC phenotypes are associated with higher risk for distant metastases and poor clinical outcomes.

Cancer Immunology, Immunotherapy, 2015

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Revista alergia Mexico (Tecamachalco, Puebla, Mexico : 1993)

Asthma is a chronic airway inflammatory disease that is associated with pulmonary remodelling of ... more Asthma is a chronic airway inflammatory disease that is associated with pulmonary remodelling of respiratory tissue. During asthma, lung structure changes due to persistent inflammation and causes obstruction of the air flow, which leads to a paradoxical hypoxic condition in the affected pulmonary tissue. Angiogenesis, which is one of the main components of the remodelling process, is mainly regulated by the vascular endothelial growth factor (VEGF), although other less influential factors are also involved. It is known that VEGF is up-regulated by hypoxia inducible factor 1 (HIF-1) during hypoxia. The transcription factor HIF-1 is a dimeric protein composed of two subunits: HIF-1alpha (inducible by hypoxia) and HIF-1beta (constitutive). HIF-1 activates the transcription of genes during hypoxia by translocating to the nucleus and binding to hypoxia response elements (HREs) on the promoter regions of target genes. Recently the expression of HIF has been documented during angiogenesis...

C37. EXERCISE, AEROSOLS AND AIRWAY DYNAMICS, 2011

Nitric Oxide, 2007

Interest in elucidating the mechanisms of action of various classes of anticancer agents and expl... more Interest in elucidating the mechanisms of action of various classes of anticancer agents and exploring the pathways of induced nitric oxide (NO) release provides an impetus to conceive better designed approach to locally detect NO in tumors in vivo. We report here on the use of an electrochemical sensor that allows the in vivo detection of NO in tumorbearing mice. First, we performed the electrochemical characterization of a stable electroactive probe, directly injected into the liquid micro-environment especially created around the electrode in the tumor. Second, the ability of the inserted electrode system to detect the presence of NO itself in the tumoral tissue was achieved by using three NO donors: two diazeniumdiolates, namely diethylammonium (Z)-1-(N,N-diethylamino)-diazen-1-ium-1,2-diolate (DEA-NONOate) and (Z)-1-[N-(2-aminoepropyl)-N-(2-ammoniopropyl)amino]-diazen-1-ium-1,2-diolate (PAPA-NONOate), and trinitrine. These NO donors allowed proving the electrochemical detection of intratumoral NO by (i) direct injection of exogenous NO solution into the tumor, upon DEA-NONOate decomposition and (ii) biomimetically induced endogenous release of NO in the tumoral tissue upon intratumoral injection of PAPA-NONOate or intra-peritoneal injection of trinitrine. This approach allows us to detect NO in vivo locally and in a real-time manner. This method could be applied to the in vivo study of anticancer drug candidates acting on NO pathways.

Respiratory Research, 2012

Background: The pathogenesis of allergic airway inflammation in asthmatic patients is complex and... more Background: The pathogenesis of allergic airway inflammation in asthmatic patients is complex and characterized by cellular infiltrates and activity of many cytokines and chemokines. Both the transcription factor hypoxia inducible factor-1 (HIF-1) and chemokine CCL2 have been shown to play pivotal roles in allergic airway inflammation. The interrelationship between these two factors is not known. We hypothesized that the expression of HIF-1 and CCL2 may be correlated and that the expression of CCL2 may be under the regulation of HIF-1. Several lines of evidence are presented to support this hypothesis.

Nitric Oxide, 2009

Tumor cells develop mechanisms that dysregulate apoptotic pathways resulting in resistance to cyt... more Tumor cells develop mechanisms that dysregulate apoptotic pathways resulting in resistance to cytotoxic stimuli. Primary SW480 and metastatic SW620 colon cancer cells are resistant to CDDP-induced apoptosis. Apoptosis-inducing factor (AIF) was significantly downregulated in SW620 compared to SW480 cells; while apoptotic mediators such as Bax, Bcl-2, and Bcl XL were not altered in these cell lines. Examination of tumor tissues from patients with colon cancer demonstrated a significant downregulation of AIF in patients with advanced disease. The role of AIF expression in resistance was examined. Several lines of evidence suggest the involvement of AIF expression level in the sensitivity of SW620 to CDDP-induced apoptosis: (1) sensitization of SW620 by the NO donor DETANONOate to CDDP-induced apoptosis correlated with the induction of AIF as assessed by RT-PCR and Western blot analysis, (2) treatment of SW620 cells with siRNA AIF, but not with control siRNAs, inhibited DETANONOate-induced sensitization to CDDP apoptosis, (3) sensitization by DETANONOate observed in vitro was corroborated in vivo in nude mice bearing SW620 tumor xenografts and treated with the combination of DETANONOate and CDDP, and (4) tumor tissues derived from the SW620 xenografts revealed significant upregulation of AIF and increased apoptosis by DETANONOate and CDDP combination treatment. Altogether, these findings underscore the potential therapeutic application of NO donors and subtoxic chemotherapeutic drugs in the treatment of advanced colon cancer resistant to conventional chemotherapeutic agents.

Nitric Oxide, 2013

Nitric oxide (NO) donors have been shown to activate or inhibit constitutively-activated survival... more Nitric oxide (NO) donors have been shown to activate or inhibit constitutively-activated survival/antiapoptotic pathways, such as NF-jB, in cancer cells. We report here that treatment of drug-resistant human prostate carcinoma cell lines with high levels (500-1000 lM) of the NO-donor DETANONOate sensitized the resistant tumor cells to apoptosis by CDDP and the combination was synergistic. We hypothesized that DETANONOate inhibits previously identified NF-jB-regulated resistant factors such as Yin Yang 1 (YY1) and Bcl-2/Bcl XL . Lysates from tumor cells treated with DETANONOate showed inhibition of YY1 and Bcl XL expressions. Transfection with either YY1 or Bcl XL siRNA resulted in the inhibition of both YY1 and Bcl XL expressions and sensitized the cells to CDDP apoptosis. Mice bearing PC-3 tumor xenografts and treated with the combination of DETANONOate and CDDP resulted in significant inhibition of tumor growth; treatment with single agent alone did not have any effect on tumor growth. Analysis of patients TMA tissues with prostatic cancer revealed higher expression of both YY1 and Bcl XL as a function of tumor grades and their levels were directly correlated. Thus, both YY1 and Bcl XL are potential prognostic biomarkers. Overall, the above findings suggest that one mechanism of DETANONOateinduced sensitization of resistant tumor cells to CDDP correlated with the inhibition of NF-jB and its targets YY1 and Bcl XL . The examination of the combination of NO donors and cytotoxic therapy in the treatment of resistant prostate cancer may be warranted.

Infection and Immunity, 2013

The genus Mycobacterium comprises more than 150 species, including important pathogens for humans... more The genus Mycobacterium comprises more than 150 species, including important pathogens for humans which cause major public health problems. The vast majority of efforts to understand the genus have been addressed in studies with Mycobacterium tuberculosis. The biological differentiation between M. tuberculosis and nontuberculous mycobacteria (NTM) is important because there are distinctions in the sources of infection, treatments, and the course of disease. Likewise, the importance of studying NTM is not only due to its clinical significance but also due to the mechanisms by which some species are pathogenic while others are not. Mycobacterium avium complex (MAC) is the most important group of NTM opportunistic pathogens, since it is the second largest medical complex in the genus after the M. tuberculosis complex. Here, we evaluated the virulence and immune response of M. avium subsp. avium and Mycobacterium colombiense, using experimental models of progressive pulmonary tuberculosis and subcutaneous infection in BALB/c mice. Mice infected intratracheally with a high dose of MAC strains showed high expression of tumor necrosis factor alpha (TNF-α) and inducible nitric oxide synthase with rapid bacillus elimination and numerous granulomas, but without lung consolidation during late infection in coexistence with high expression of anti-inflammatory cytokines. In contrast, subcutaneous infection showed high production of the proinflammatory cytokines TNF-α and gamma interferon with relatively low production of anti-inflammatory cytokines such as interleukin-10 (IL-10) or IL-4, which efficiently eliminate the bacilli but maintain extensive inflammation and fibrosis. Thus, MAC infection evokes different immune and inflammatory responses depending on the MAC species and affected tissue.