Alteración en el metabolismo de la hemoglobina y actividad antimalárica in vivo de azoles antimicóticos

Plasmodium parasites degrade host hemoglobin to obtain free amino acids, essential for protein synthesis. During this event, free toxic heme moieties crystallize spontaneously to produce a non-toxic pigment called hemozoin or ß-hematin. In this context, a group of azole antimycotics, clotrimazole (CTZ), ketoconazole (KTZ) and fluconazole (FCZ), were investigated for their abilities to inhibit ß-hematin synthesis (IßHS) and hemoglobin proteolysis (IHbP) in vitro. The ß-hematin synthesis was recorded by spectrophotometry at 405 nm and the hemoglobin proteolysis was determined by SDS-PAGE 12.5%, followed by densitometric analysis. Compounds were also assayed in vivo in a malaria murine model. CTZ and KTZ exhibited the maximal effects inhibiting both biochemical events, showing inhibition of β-hematin synthesis (IC50 values of 12.4 ± 0.9 µM and 14.4 ± 1.4 µM respectively) and inhibition of hemoglobin proteolysis (80.1 ± 2.0% and 55.3 ± 3.6%, respectively). There is a broad correlation to the in vivo results, especially CTZ, which reduced the parasitemia (%P) of infected-mice at 4th day post-infection significantly compared to non-treated controls (12.4 ± 3.0% compared to 26.6 ± 3.7%, p = 0.014) and prolonged the survival days post-infection. The results indicated that the inhibition of the hemoglobin metabolism by the azole antimycotics could be responsible for their antimalarial effect.Los parásitos del género Plasmodium degradan la hemoglobina hospedera obteniendo aminoácidos libres para su síntesis proteica. Durante este evento, unidades de hemo libre tóxicas cristalizan espontáneamente formando un pigmento no tóxico denominado ß-hematina. En este trabajo, se investigó la capacidad de un grupo de azoles antimicóticos: clotrimazol (CTZ), ketoconazol (KTZ) y fluconazol (FCZ), en inhibir la síntesis de ß-hematina y la proteólisis de la globina. La síntesis de ß-hematina se registro por espectrofotometría a 405 nm y la proteólisis de la hemoglobina se determino por SDS-PAGE 15% seguido por análisis densitométrico de las bandas de hemoglobina intactas. Los compuestos fueron también ensayados in vivo en un modelo de malaria murina. CTZ y KTZ inhibieron la síntesis de ß-hematina con CI50 entre 10 y 15 µM y bloquearon la proteólisis de la hemoglobina (80.01 ± 2.04% y 55.33 ± 3.57%, respectivamente). En relación directa con los resultados encontrados in vitro, el CTZ redujo la parasitemia de ratones infectados en forma significativa, así como prolongó lo días de sobrevivencia post-infección en comparación con animales controles no tratados. Se sugiere así que la inhibición del metabolismo de la hemoglobina por los antimicóticos azólicos pudiera ser el mecanismo responsable de su actividad antimalárica

Modulation of the oxidative stress in malaria infection by clotrimazole

Antimycotic clotrimazole (CTZ) has demonstrated remarkable activity against Plasmodium falciparum in vitro and in vivo. Hemoglobin degradation by Plasmodium parasites makes amino acids available for protein synthesis, inducing oxidative stress in infected cells and producing free heme. These events represent biochemical targets for potential antimalarials. In this study, we have tested the ability of CTZ to modify the oxidative status in Plasmodium berghei-infected erythrocytes. After hemolysis, activities of superoxide dismutase (SOD), catalase (CAT), glutathione cycle and NADPH+H+-producing dehydrogenases were investigated using UV-visible spectrophotometry. Thiobarbituric acid reactive substances (TBARS) were evaluated as a marker of lipid damage. Results showed that CTZ significantly decreased the overall activity of 6-phosphagluconate dehydrogenase (6PGD) compared to infected and non-treated cells; consequently, the glutathione cycle was inhibited, leaving the parasite vulnerable to the oxidative stress originating from hemoglobin degradation. As a compensatory response, CTZ prevented some loss of SOD and CAT activities in infected cells. The infection triggered lipid peroxidation in erythrocytes, which was decreased by CTZ. These results suggest the presence of a redox unbalance in cells treated with CTZ, discussing a possible effect of this compound disturbing the oxidative status in a Plasmodium berghei-infection.O antifúngico clotrimazol (CTZ) tem demonstrado notável atividade contra Plasmodium falciparum. A degradação da hemoglobina por Plasmodium para a obtenção dos aminoácidos necessários à síntese protéica induz estresse oxidativo em eritrócitos devido à liberação de hemos oxidantes. Estes eventos representam alvos bioquímicos para a produção de antimaláricos potenciais. Neste estudo, testamos a capacidade do CTZ para modificar o estado oxidativo em eritrócitos infectados com Plasmodium berghei. Depois da hemólise, as atividades da superóxido dismutase (SOD), catalase (CAT), desidrogenases produtoras de NADPH+H+ e do ciclo de glutationa (GSH) foram investigados. A produção das espécies reativas ao ácido tiobarbitúrico (TBARS) foi avaliada como marcador de dano lipídico. Os resultados mostraram que o CTZ diminuiu a atividade da 6-fosfogliconato desidrogenase (6PGD), em comparação com eritrócitos infectados e não tratados. Consequentemente, o ciclo da GSH foi inibido, tornando os parasitas vulneráveis ao estresse oxidativo resultante da degradação da hemoglobina. Como resposta compensatória, CTZ impediu a perda de atividade da SOD e CAT nas células infectadas. A infecção induz peroxidação lipídica nos eritrócitos, sendo esta diminuída pelo CTZ. Estes resultados sugerem a existência de desequilíbrio redox nas células tratadas com CTZ, interferindo, assim, com o estado oxidativo verificado durante a infecção malárica

Análisis de la estimulación psicomotora en las clases de Educación Física de segundo ciclo en dos jardines infantiles de la Región Metropolitana

Tesis (Profesor de Educación Física, Licenciado en Educación)La investigación tuvo como propósito evaluar y ver cómo inciden las clases de educación física en los niños y las niñas de colegios y jardines infantiles, dado que en la actualidad, vemos que el desarrollo de los niños/as ha ido cambiando ya sea por la estimulación que tienen en sus casa o por la clara educación que han tenido en los colegios por parte de los educadores. La metodología usada fue una investigación de campo que constaba de dos test, con una muestra total de 142 niños/as en el test de patrones motores de David L. Gallahue y 133 niños/as en el test motor de Ozeretski. Para esto igualmente quisimos enfocarnos en realizar observaciones a ambos establecimientos, uno es un colegio particular que tiene profesores de educación física para los preescolares, y el otro es un jardín JUNJI, que trabaja solamente con Educadoras de párvulo y sus respectivas técnicos, con esto quisimos demostrar cuán importante es que el párvulo reciba, la educación apropiada para su edad, y estas están a cargo de realizar todas las clases que tienen los niños/as del establecimiento. Como resultados pudimos obtener que en el colegio particular se encontraron mucho mejor en todo lo que respecta al desarrollo motor grueso, particularmente en los patrones motores, como salto, carrera y lanzamiento, sin embargo demostraron muy deficientes en lo que es desarrollo motor fino y resolución de problema. En cuanto al jardín JUNJI se demostró que se encuentran con desarrollo motor fino mucho más amplio, pero deficiente en el desarrollo motor grueso. Con lo anterior podemos demostrar que el trabajo de los educadores o profesores es lo que interviene en el desarrollo de los menores.The purpose of the research was to evaluate and see how physical education classes affect children in kindergartens and preschools, since today we see that the development of children has been changing either by stimulation That they have in their homes or by the clear education they have had in the schools by the educators. The methodology used was a field investigation that consisted of two tests, with a total sample of 142 children in the motor pattern test of David L. Gallahue and 133 children in the Ozeretski motor test. For this we also wanted to focus on making observations to both establishments, one is a private school that has physical education teachers for preschoolers, and the other is a JUNJI garden, which works only with nursery school teachers and their respective technicians, who with this We wanted to show how important it is that the child receives, education appropriate to his age. So in charge of performing all the classes that have the children of the establishment. As results we could obtain that in private school they found much better in everything concerning the gross motor development, particularly in the motor patterns, like jump, race and launch, nevertheless they demonstrated very deficient in what is fine motor development and resolution of problem. As for the JUNJI garden it was shown that they are found with much more extensive fine motor development, but deficient in gross motor development. With the above we can demonstrate that the work of educators or teachers is what is involved in the development of children

Synthesis and antimalarial activity of novel chiral and achiral benzenesulfonamides bearing 1, 3, 4-oxadiazole moieties.

A series of new benzenesulfonamides, most of which are chiral, incorporating 1, 3, 4-oxadiazole and amino acid moieties have been synthesized. Some of these compounds were screened for antimalarial activity and also evaluated for their ability to inhibit hem polymerization. The electrophoretic analysis indicated that one compound was effective in inhibiting the degradation of hemoglobin. The synthesized compounds were tested in mice infected with Plasmodium berghei. These derivatives have the potential for the development of novel antimalarial lead compounds

Synthesis, Characterization, Crystal Structure and Antimalarial Activity of (2E)-2-(1-{4-[(7-chloroquinolin-4-yl)amino]phenyl} ethylidene)hydrazine Carbothioamide

A simple synthesis and study by UV-vis, IR, NMR, ESI-CID-MS2 and X-ray diffraction of ((2E)-2-(1-{4-[(7-chloroquinolin-4-yl)amino]phenyl}ethylidene)hydrazinecarbothioamide is reported. It was tested in vitro against chloroquine-resistant strain (W2) of Plasmodium falciparum, hemozoin (β-hematin) formation and cysteine protease falcipain-2. In general, it was found to possess a proved activity in its inhibitory power on the parasite but less active on the formation of hemozoin (β-hematin) and falcipain-2. Also, the X-ray analysis presented an unexpected electronic density that can be assigned like S(2). This electronic density can be attributed to autocondensation of thiosemicarbazide, generating H2S as a subproduct. DOI: http://dx.doi.org/10.17807/orbital.v9i4.100

Synthesis, antimalarial activity, structure–activity relationship analysis of thieno-[3,2-b]benzothiazine S,S-dioxide analogs

An improved procedure for the synthesis of 3-amino-9-arylsubstituted-thieno[3,2-b]benzothiazine S,S-dioxide 2-decarboxylated is reported. Thieno-[3,2-b]benzothiazine S,S-dioxide derivatives were investigated for their abilities to inhibit β-hematin formation, hemoglobin hydrolysis and in vivo for their efficacy in rodent Plasmodium berghei. Compounds 5j-o were the most promising as inhibitors of hemoglobin hydrolysis, however, the compounds are not as efficient as chloroquine. A structure-activity relationship (SAR) study was carried out in this series. Our results allow us to determine the minimal structural requirements to produce the biological response.Fil: Barazarte, Arthur. Universidad Central de Venezuela; VenezuelaFil: Camacho, José. Universidad Central de Venezuela; VenezuelaFil: Domínguez, José. Universidad Central de Venezuela; VenezuelaFil: Lobo, Gricela. Universidad Central de Venezuela; VenezuelaFil: Gamboa, Neira. Universidad Central de Venezuela; VenezuelaFil: Rodrigues, Juan. Universidad Central de Venezuela; VenezuelaFil: Capparelli, Mario V.. Universidad Central de Venezuela; VenezuelaFil: Álvarez Larena, Ángel. Universitat Autònoma de Barcelona; EspañaFil: Andujar, Sebastian Antonio. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - San Luis. Instituto Multidisciplinario de Investigaciones Biológicas de San Luis. Universidad Nacional de San Luis. Facultad de Ciencias Físico Matemáticas y Naturales. Instituto Multidisciplinario de Investigaciones Biológicas de San Luis; ArgentinaFil: Enriz, Ricardo Daniel. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - San Luis. Instituto Multidisciplinario de Investigaciones Biológicas de San Luis. Universidad Nacional de San Luis. Facultad de Ciencias Físico Matemáticas y Naturales. Instituto Multidisciplinario de Investigaciones Biológicas de San Luis; ArgentinaFil: Charris, Jaime. Universidad Central de Venezuela; Venezuel

Modulation of the oxidative stress in malaria infection by clotrimazole

Antimycotic clotrimazole (CTZ) has demonstrated remarkable activity against Plasmodium falciparum in vitro and in vivo. Hemoglobin degradation by Plasmodium parasites makes amino acids available for protein synthesis, inducing oxidative stress in infected cells and producing free heme. These events represent biochemical targets for potential antimalarials. In this study, we have tested the ability of CTZ to modify the oxidative status in Plasmodium berghei-infected erythrocytes. After hemolysis, activities of superoxide dismutase (SOD), catalase (CAT), glutathione cycle and NADPH+H+-producing dehydrogenases were investigated using UV-visible spectrophotometry. Thiobarbituric acid reactive substances (TBARS) were evaluated as a marker of lipid damage. Results showed that CTZ significantly decreased the overall activity of 6-phosphagluconate dehydrogenase (6PGD) compared to infected and non-treated cells; consequently, the glutathione cycle was inhibited, leaving the parasite vulnerable to the oxidative stress originating from hemoglobin degradation. As a compensatory response, CTZ prevented some loss of SOD and CAT activities in infected cells. The infection triggered lipid peroxidation in erythrocytes, which was decreased by CTZ. These results suggest the presence of a redox unbalance in cells treated with CTZ, discussing a possible effect of this compound disturbing the oxidative status in a Plasmodium berghei-infection.O antifúngico clotrimazol (CTZ) tem demonstrado notável atividade contra Plasmodium falciparum. A degradação da hemoglobina por Plasmodium para a obtenção dos aminoácidos necessários à síntese protéica induz estresse oxidativo em eritrócitos devido à liberação de hemos oxidantes. Estes eventos representam alvos bioquímicos para a produção de antimaláricos potenciais. Neste estudo, testamos a capacidade do CTZ para modificar o estado oxidativo em eritrócitos infectados com Plasmodium berghei. Depois da hemólise, as atividades da superóxido dismutase (SOD), catalase (CAT), desidrogenases produtoras de NADPH+H+ e do ciclo de glutationa (GSH) foram investigados. A produção das espécies reativas ao ácido tiobarbitúrico (TBARS) foi avaliada como marcador de dano lipídico. Os resultados mostraram que o CTZ diminuiu a atividade da 6-fosfogliconato desidrogenase (6PGD), em comparação com eritrócitos infectados e não tratados. Consequentemente, o ciclo da GSH foi inibido, tornando os parasitas vulneráveis ao estresse oxidativo resultante da degradação da hemoglobina. Como resposta compensatória, CTZ impediu a perda de atividade da SOD e CAT nas células infectadas. A infecção induz peroxidação lipídica nos eritrócitos, sendo esta diminuída pelo CTZ. Estes resultados sugerem a existência de desequilíbrio redox nas células tratadas com CTZ, interferindo, assim, com o estado oxidativo verificado durante a infecção malárica

The Caldera. No. 25 Special Edition 2022. 70 years

Especial: Instituto Caldas, 70 años de historia En las siguientes páginas, los estudiantes rinden homenaje a nuestra querida Institución, a través, especialmente, de la Palabra. Mi eterna gratitud a cada uno de ellos, jóvenes lectores, escritores, dibujantes pero, sobre todo, Caldistas de CORAZÓN: Laura Camila Herrera, Victoria Chacón Gil, María Paula Méndez, Steven Gómez Guerrero, Constanza Narváez Solano, Yatana Zea Arenas, Carolina Valencia Neira, Valery Samara Meza, Steffy Picón Carrillo y Gabriela Portilla Castellanos.Especial 70 años. Instituto Caldas 6 Reloj Solar 2021 43 IX Concurso de Lectura en Voz Alta 46 La Cuna de Excélsior 48 Equipo de Maestros 51 Perfiles Caldistas 54 Expresiones Caldistas 58 Día Caldista 98 Galería de Imágenes 103Special: Instituto Caldas, 70 years of history In the following pages, the students pay homage to our beloved Institution, especially through the Word. My eternal gratitude to each of them, young readers, writers, cartoonists but, above all, Caldistas of HEART: Laura Camila Herrera, Victoria Chacón Gil, María Paula Méndez, Steven Gómez Guerrero, Constanza Narváez Solano, Yatana Zea Arenas, Carolina Valencia Neira, Valery Samara Meza, Steffy Picón Carrillo and Gabriela Portilla Castellanos