16α‐Bromoepiandrosterone as a new candidate for experimental diabetes‐tuberculosis comorbidity treatment

Tuberculosis (TB) is the leading cause of death from a single bacterial infectious agent and is one of the most relevant issues of public health. Another pandemic disease is type II diabetes mellitus (T2D) that is estimated to affect half a billion people in the world. T2D is directly associated with obesity and a sedentary lifestyle and is frequently associated with immunosuppression. Immune dysfunction induced by hyperglycemia increases infection frequency and severity. Thus, in developing countries the T2D/TB co-morbidity is frequent and represents one of the most significant challenges for the health-care systems. Several immunoendocrine abnormalities are occurring during the chronic phase of both diseases, such as high extra-adrenal production of active glucocorticoids (GCs) by the activity of 11-β-hydroxysteroid dehydrogenase type 1 (11-βHSD1). 11-βHSD1 catalyzes the conversion of inactive cortisone to active cortisol or corticosterone in lungs and liver, while 11-β-hydroxysteroid dehydrogenase type 2 (11-βHSD2) has the opposite effect. Active GCs have been related to insulin resistance and suppression of Th1 responses, which are deleterious factors in both T2D and TB. The anabolic adrenal hormone dehydroepiandrosterone (DHEA) exerts antagonistic effects on GC signaling in immune cells and metabolic tissues; however, its anabolic effects prohibit its use to treat immunoendocrine diseases. 16α-bromoepiandrosterone (BEA) is a water miscible synthetic sterol related to DHEA that lacks an anabolic effect while amplifying the immune and metabolic properties with important potential therapeutic uses. In this work, we compared the expression of 11-βHSD1 and the therapeutic efficacy of BEA in diabetic mice infected with tuberculosis (TB) (T2D/TB) with respect to non-diabetic TB-infected mice (TB). T2D was induced by feeding mice with a high-fat diet and administering a single low-dose of streptozotocin. After 4 weeks of T2D establishment, mice were infected intratracheally with a high-dose of Mycobacterium tuberculosis strain H37Rv. Then, mice were treated with BEA three times a week by subcutaneous and intratracheal routes. Infection with TB increased the expression of 11-βHSD1 and corticosterone in the lungs and liver of both T2D/TB and TB mice; however, T2D/TB mice developed a more severe lung disease than TB mice. In comparison with untreated animals, BEA decreased GC and 11-βHSD1 expression while increasing 11-βHSD2 expression. These molecular effects of BEA were associated with a reduction in hyperglycemia and liver steatosis, lower lung bacillary loads and pneumonia. These results uphold BEA as a promising effective therapy for the T2D/TB co-morbidity.Fil: López Torres, Manuel Othoniel. Instituto Nacional de la Nutrición Salvador Zubiran; MéxicoFil: Marquina Castillo, Brenda. Instittuto de Ciencias Médicas y Nutrición; MéxicoFil: Ramos Espinosa, Octavio. Instittuto de Ciencias Médicas y Nutrición; MéxicoFil: Mata Espinosa, Dulce. Instittuto de Ciencias Médicas y Nutrición; MéxicoFil: Barrios Payan, Jorge A.. Instittuto de Ciencias Médicas y Nutrición; MéxicoFil: Baay Guzman, Guillermina. Instittuto de Ciencias Médicas y Nutrición; MéxicoFil: Huerta Yepez, Sara. Instittuto de Ciencias Médicas y Nutrición; MéxicoFil: Bini, Estela Isabel. Instittuto de Ciencias Médicas y Nutrición; MéxicoFil: Torre Villalvazo, Ivan. Instittuto de Ciencias Médicas y Nutrición; MéxicoFil: Torres, Nimbe. Instittuto de Ciencias Médicas y Nutrición; MéxicoFil: Tovar, Armando. Instittuto de Ciencias Médicas y Nutrición; MéxicoFil: Chamberlin, William. No especifíca;Fil: Ge, Yu. No especifíca;Fil: Carranza, Maria Andrea. Consejo Nacional de Investigaciones Cientificas y Tecnicas. Oficina de Coordinacion Administrativa Houssay. Instituto Alberto C. Taquini de Investigaciones En Medicina Traslacional. - Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Cardiologicas "prof. Dr. Alberto C. Taquini". Instituto Alberto C. Taquini de Investigaciones En Medicina Traslacional.; ArgentinaFil: Hernández Pando, Rogelio. Instituto Nacional de Ciencias Medicas y Nutricion; Méxic

Las emociones en los procesos pedagógicos y artísticos

Este cuarto volumen de la Colección Emociones e Interdisciplina orienta la mirada hacia dos dimensiones centrales, en las cuales la afectividad se analiza tanto a partir de los procesos pedagógicos, como del arte y del registro de lo estético. Esta mirada se adentra en el estudio del sujeto que siente, piensa y reflexiona y es justo, a partir de este punto, donde es posible acotar, teórica y metodológicamente, las emociones y sus expresiones como objeto de estudio sociológico.ITESO. A.C

The Role of High Mobility Group Box 1 Protein (HMGB1) in the Immunopathology of Experimental Pulmonary Tuberculosis

Background The high mobility group box 1 (HMGB1) is the prototype of alarmin protein released by stressed or dying cells. The redox state of this protein confers different functions in the regulation of inflammation and immune response. Aim Determine the kinetics, cellular sources and function of HMGB1 in experimental tuberculosis. Methods BALB/c mice were infected with Mycobacterium tuberculosis strain H37Rv. At different time points, HMGB1 was quantified in bronchial lavage fluid (BALF) and in lungs was determined its cellular sources by immunohistochemistry. HMGB1 was blocked with specific antibodies or recombinant HMGB1 was administered during early or late infection. Bacilli burdens, inflammation and cytokines expression were determined. Results The maximal concentration of HMGB1 in BALF was at day one of infection. Bronchial epithelium and macrophages were the most important sources. At day 7 to 21 the oxidized HMGB1 was predominant, while during late infection only the reduced form was seen. Blocking HMGB1 during early infection produced significant decrease of bacilli burdens and high production of pro-inflammatory cytokines, while the opposite was seen when HMGB1 was administered. Blocking HMGB1 activity or administrated it in high amounts during late infection worsening the disease. Conclusions HMGB1 is liberated during experimental tuberculosis and promotes or suppress the immune response and inflammation depending on the redox state.Fil: Bottasso, Oscar. Institute of Experimental and Clinic Immunology, Rosario, IDICER, CONICET, School of Medical Sciences. UNR. Rosario; ArgentinaFil: Bini, Estela Isabel. Institute of Experimental and Clinic Immunology, Rosario, IDICER, CONICET, School of Medical Sciences. UNR. Rosario; Argentin

The Therapeutic Effect of Intranasal Administration of Dexamethasone in Neuroinflammation Induced by Experimental Pulmonary Tuberculosis

Tuberculosis (TB) is an important infectious disease and a public health problem. The organs most frequently affected by TB are the lungs; despite this, it has been reported that TB patients suffer from depression and anxiety, which have been attributed to social factors. In previous experimental work, we observed that the extensive pulmonary inflammation characteristic of TB with high cytokine production induces neuroinflammation, neuronal death and behavioral abnormalities in the absence of brain infection. The objective of the present work was to reduce this neuroinflammation and avoid the psycho-affective disorders showed during pulmonary TB. Glucocorticoids (GCs) are the first-line treatment for neuroinflammation; however, their systemic administration generates various side effects, mostly aggravating pulmonary TB due to immunosuppression of cellular immunity. Intranasal administration is a route that allows drugs to be released directly in the brain through the olfactory nerve, reducing their doses and side effects. In the present work, dexamethasone’s (DEX) intranasal administration was evaluated in TB BALB /c mice comparing three different doses (0.05, 0.25 and 2.5 mg/kg BW) on lung disease evolution, neuroinflammation and behavioral alterations. Low doses of dexamethasone significantly decreased neuroinflammation, improving behavioral status without aggravating lung disease

Performance of a highly successful outbreak strain of Mycobacterium tuberculosis in a multifaceted approach to bacterial fitness assessment

Determining bacterial fitness represents a major challenge and no single parameter can accurately predict the ability of a certain pathogen to succeed. The M strain of Mycobacterium tuberculosis managed to spread and establish in the community and caused the largest multidrug-resistant tuberculosis outbreak in Latin America. We have previously shown that the M strain can manipulate the host immune response, but we still have no direct evidence, other than epidemiology, that can account for the enhanced fitness of the M strain. Our objective was to further characterize the performance of the outbreak strain M in different fitness assays. Two main aspects were evaluated: (1) molecular characterization of selected isolates from the M outbreak and related strains and (2) comparative fitness and in vivo performance of representative M strain isolates vs. the non-prosperous M strain variant 410. Our approach confirmed the multifaceted nature of fitness. Altogether, we conclude that the epidemiologically abortive strain 410 was vulnerable to drug-driven pressure, a weak competitor, and a stronger inductor of protective response in vivo. Conversely, the isolate 6548, representative of the M outbreak peak, had a growth disadvantage but performed very well in competition and induced lung damage at advanced stages in spite of reaching relatively low CFU counts. Integration of these observations supports the idea that the M strain managed to find a unique path to success.Fil: Yokobori, Noemí. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; ArgentinaFil: López, Beatriz. Dirección Nacional de Institutos de Investigación. Administración Nacional de Laboratorios e Institutos de Salud. Instituto Nacional de Enfermedades Infecciosas; ArgentinaFil: Monteserin, Johana. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Dirección Nacional de Institutos de Investigación. Administración Nacional de Laboratorios e Institutos de Salud. Instituto Nacional de Enfermedades Infecciosas; ArgentinaFil: Paul, Roxana. Dirección Nacional de Institutos de Investigación. Administración Nacional de Laboratorios e Institutos de Salud. Instituto Nacional de Enfermedades Infecciosas; ArgentinaFil: Von Groll, Andrea. Universidade Federal do Rio Grande do Sul; BrasilFil: Martin, Anandi. Université Catholique de Louvain; Bélgica. University of Ghent; BélgicaFil: Marquina Castillo, Brenda. Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán; MéxicoFil: Palomino, Juan Carlos. University of Ghent; BélgicaFil: Hernández Pando, Rogelio. Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán; MéxicoFil: Sasiain, María del Carmen. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; ArgentinaFil: Ritacco, Gloria Viviana. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Dirección Nacional de Institutos de Investigación. Administración Nacional de Laboratorios e Institutos de Salud. Instituto Nacional de Enfermedades Infecciosas; Argentin

The influence of sex steroid hormones in the immunopathology of experimental pulmonary tuberculosis.

The relation between men and women suffering pulmonary tuberculosis is 7/3 in favor to males. Sex hormones could be a significant factor for this difference, considering that testosterone impairs macrophage activation and pro-inflammatory cytokines production, while estrogens are proinflammatory mediator's inducer. The aim of this work was to compare the evolution of tuberculosis in male and female mice using a model of progressive disease. BALB/c mice, male and female were randomized into two groups: castrated or sham-operated, and infected by the intratracheal route with a high dose of Mycobacterium tuberculosis strain H37Rv. Mice were euthanized at different time points and in their lungs were determined bacilli loads, inflammation, cytokines expression, survival and testosterone levels in serum. Non-castrated male mice showed significant higher mortality and bacilli burdens during late disease than female and castrated male animals. Compared to males, females and castrated males exhibited significant higher inflammation in all lung compartments, earlier formation of granulomas and pneumonia, while between castrated and non-castrated females there were not significant differences. Females and castrated males expressed significant higher TNF-α, IFN γ, IL12, iNOS and IL17 than non-castrated males during the first month of infection. Serum Testosterone of males showed higher concentration during late infection. Orchidectomy at day 60 post-infection produced a significant decrease of bacilli burdens in coexistence with higher expression of TNFα, IL-12 and IFNγ. Thus, male mice are more susceptible to tuberculosis than females and this was prevented by castration suggesting that testosterone could be a tuberculosis susceptibility factor

Cellular sources of HMGB1 determined by immunohistochemistry.

<p>(A) Lung section from a mouse after one day of infection, there is strong HMGB1 immunostaining in the cytoplasm of bronchial epithelial cells. (B) After 60 days of infection, the bronchial epithelium show scarce immunereactivity (asterisk), while macrophages in the pneumonic areas show strong immunostaining (arrows). (C) The morphometric study shows a progressive increase of macrophages with HMGB1 immunostaining. (D) Immunoelectronmicroscopy micrograph from a bronchial epithelial cell after one day of infection, there are several submembranal vesicles (V) with HMGB1 detected with antibodies labeled with colloidal gold (arrows). (E) An apoptotic macrophage from day seven of infection shows many black dots that correspond to HMGB1 detected with specific antibodies labelled with colloidal gold (arrows).</p