RESUMEN
The acute promyelocytic leukemia (APL) is a rare disease, affecting 0.1/100,000 individuals globally. Despite significant advances in APL therapy, some patients still experience relapsed disease. Currently, arsenic trioxide (As2O3) was found to be effective in relapsed APL treatment and considered as standard treatment for these cases. However, it has been shown that exposure to As2O3 may exert adverse effects on the male reproductive system since this substance might also induce apoptosis of other important cell types including stem cells. Studies demonstrated that treatment with this metallic substance decreased plasma levels of testosterone and interfered with sperm parameters such as concentration, motility, and viability. In addition, As2O3 was found to produce significant damage to spermatocytes, which may be associated with testicular toxicity and consequent inhibition of spermatogenesis. The aim of this study was to determine sub-chronic treatment effects of As2O3 on sperm and testicular morphology, androgen receptor (AR) immunoreactivity in testes and epididymis, in addition to evaluation of fertility parameters in adult male mice. Thirty adult Swiss mice were divided into three experimental groups: control; received distilled water (vehicle) while treated received 0.3 or 3 mg/kg/day As2O3 subcutaneously, for 5 days per week, followed by 2 days of interruption, for 5 weeks. Results showed that As2O3 (1) decreased spermatozoa number, (2) produced seminiferous epithelium degeneration and exfoliation of germ cells tubule lumen (3) altered nucleus/cytoplasm proportion of Leydig cells and (4) reduced AR immunoreactivity in both Leydig and epithelial epididymal cells. Further, fetal viability tests demonstrated an increase in post-implantation loss in females that were mated with As2O3-treated males. Data indicate that As2O3 exposure altered the spermatogenic process and subsequently fetal viability.
Asunto(s)
Viabilidad Fetal/efectos de los fármacos , Óxidos/toxicidad , Testículo/efectos de los fármacos , Animales , Trióxido de Arsénico , Arsenicales/administración & dosificación , Modelos Animales de Enfermedad , Epidídimo/efectos de los fármacos , Epidídimo/metabolismo , Fertilidad/efectos de los fármacos , Leucemia Promielocítica Aguda/tratamiento farmacológico , Células Intersticiales del Testículo/efectos de los fármacos , Células Intersticiales del Testículo/metabolismo , Masculino , Ratones , Óxidos/administración & dosificación , Receptores Androgénicos/metabolismo , Reproducción/efectos de los fármacos , Epitelio Seminífero/efectos de los fármacos , Epitelio Seminífero/metabolismo , Espermatogénesis/efectos de los fármacos , Espermatozoides/efectos de los fármacos , Espermatozoides/metabolismo , Testículo/metabolismo , Pruebas de Toxicidad Subcrónica , Aumento de Peso/efectos de los fármacosRESUMEN
Recent innovations in the genomic understanding of medulloblastomas have provided new ways to explore this highly invasive malignant brain cancer arising from the cerebellum. Among the four different medulloblastoma subgroups described to date, the sonic hedgehog (SHH) genetic pathway is the pathway activated in the tumorigenesis of medulloblastoma. SHH-related medulloblastomas are usually of nodular/desmoplastic histology and frequently occur in children under the age of three, an age group highly susceptible to the acute and long-term effects of treatment. Several new drugs aimed at SHH modulation are currently under development. This review focuses on the role of arsenic trioxide, a drug well established in clinical practice and probably an under-explored agent in medulloblastoma management, in the SHH pathway.
Asunto(s)
Antineoplásicos/administración & dosificación , Arsenicales/administración & dosificación , Neoplasias Cerebelosas/tratamiento farmacológico , Proteínas Hedgehog/metabolismo , Meduloblastoma/tratamiento farmacológico , Óxidos/administración & dosificación , Adolescente , Antineoplásicos/farmacología , Trióxido de Arsénico , Arsenicales/farmacología , Neoplasias Cerebelosas/metabolismo , Niño , Preescolar , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Lactante , Meduloblastoma/metabolismo , Óxidos/farmacología , Transducción de Señal/efectos de los fármacosRESUMEN
Arsenic trioxide (As2O3) has shown effectiveness in treatment of leukemia but is also associated with reproductive toxicity. Since remediation with N-acetylcysteine (NAC) may mitigate the adverse effects caused by exposure, we assessed the effects of As2O3 and its potential reversibility after exposure cessation or coadministration of NAC. Animals received 0.3 or 3.0 mg/Kg/day of As2O3 subcutaneously and 40 mM of NAC in tap water. As2O3 treatment impaired spermatogenesis and sperm motility and decreased seminal vesicle weight and testosterone serum levels; after suspension of treatment, these parameters remained altered. When NAC was administered, animals showed improvement in sperm parameters and seminal vesicle weight. In vitro epididymal contractility was increased in As2O3-treated animals. We concluded that As2O3 is toxic to the male mouse genital system by compromising sperm quality and quantity; these effects persisted even after suspension of the treatment. However, the coadministration of NAC ameliorates the harmful effects of the drug on the male genital system.
Asunto(s)
Acetilcisteína/administración & dosificación , Arsenicales/administración & dosificación , Epidídimo/efectos de los fármacos , Óxidos/administración & dosificación , Testículo/efectos de los fármacos , Testosterona/metabolismo , Animales , Arsénico/sangre , Trióxido de Arsénico , Arsenicales/efectos adversos , Peso Corporal , Epidídimo/fisiología , Masculino , Ratones , Tamaño de los Órganos , Óxidos/efectos adversos , Distribución Aleatoria , Especies Reactivas de Oxígeno/metabolismo , Motilidad Espermática/efectos de los fármacos , Espermatogénesis/efectos de los fármacos , Espermatozoides/fisiología , Testículo/fisiología , Testosterona/sangreRESUMEN
En América Latina la presencia del arsénico en el ambiente y en las fuentes de agua para consumo humano, se debe a factores naturales de origen geológico como a actividades antropogénicas. El arsénico en las aguas naturales se encuentra principalmente como trivalente (arsenito) o pentavalente (arsenato). El objetivo de este trabajo fue determinar las alteraciones que provoca el trióxido de arsénico a nivel de la morfología del bazo de ratas (Rattus norvegicus - Sprague-Dawley). Se utilizaron 24 ratas de ambos sexos de 55 días de vida. Las ratas fueron pesadas y divididas en 3 grupos (4 hembras y 4 machos). Los grupos tratados fueron inyectados con 5 mg y 10 mg de As2O3 respectivamente, en dosis única diaria vía intraperitoneal por 15 días. Al grupo control se le aplicó agua destilada sin arsénico. Después del tratamiento los animales fueron sacrificados por eutanasia convencional y se obtuvo el bazo, los cuales fueron lavados, pesados y seccionados en cuatro partes, que fueron fijadas en formol tamponado al 10 por ciento. Mediante técnica histológica se obtuvieron 4 muestras seriadas de cada bazo, de 5 micrones de espesor con una separación de 100 micrones entre si. Posteriormente fueron teñidas con H-E. Se analizaron 30 campos (120 campos por órgano). Los datos obtenidos permiten concluir que ratas tratadas con trióxido de arsénico, presentan alteración a nivel de los compartimentos del bazo, con un aumento del compartimento de la pulpa roja, una depleción en el tamaño y número de folículos linfoides y de la zona marginal. A su vez, se observó pérdida de la celularidad de la vaina linfoide periarteriolar (PALS).
In Latin America, the presence of arsenic in the environment and water sources for human consumption is due to natural geological factors and anthropogenic activities. Arsenic in natural waters is mainly found as trivalent (arsenite) or pentavalent (arsenate). The aim of this study was to determine the alterations causing arsenic trioxide-level morphology of the spleen of rats (Rattus norvegicus - Sprague-Dawley). Were used 24 rats of both sexes of 55 days of life. The rats were weighed and divided into 3 groups (4 females and 4 males). The treated groups were injected with 5 mg and 10 mg of As2O3 respectively, intraperitoneally daily dosing for 15 days. The control group was administered arsenic-free distilled water. After treatment the animals were euthanized conventionally, and spleen was removed, which was washed, weighed and sectioned into four parts, which were fixed in 10 percent buffered formalin. Histological technique using four serial samples were obtained from each spleen of 5 microns thick with a spacing of 100 microns between them. Subsequently these were stained with H-E. We analyzed 30 fields (120 fields per organ). The data obtained indicates that rats treated with arsenic trioxide have an altered level of the compartments of the spleen, with an increased red pulp chamber, depletion in the size and number of lymphoid follicles and marginal zone. Furthermore, loss of cellularity of periarteriolar lymphoid sheath (PALS) was observed.
Asunto(s)
Masculino , Animales , Femenino , Ratas , Arsenicales/administración & dosificación , Bazo , Óxidos/administración & dosificación , Ratas Sprague-DawleyRESUMEN
El nombre sífilis proviene del griego siph: cerdo y philus: amor. Recuerda al personaje de una obra, llamado Syphilo, que fue castigado por los dioses a sufrir una terrible enfermedad. Se analizan los datos sobre la sífilis en la antigüedad (que difieren según su fuente). Su mención en la Edad Media, su controversial origen, la ayuda de los paleopatólogos para encontrarlo. Luego de la Revolución Francesa y el inicio de la Edad Contemporánea, el porcentaje de enfermos fue creciendo y se acentuó la segregación de los mismos por la sociedad. Desde el año 1500 hasta principios del siglo XX el tratamiento de la sífilis dependía del mercurio. Tenía una gran variedad de formas de aplicación. La vía tópica: el ungüento gris, en calomelano o tabletas, en inyecciones, en fricciones y fumigaciones en donde el mercurio se introducía en el cuerpo por lo pulmones. Se adjudicó a la madera del guayaco pretendidas características curativas, que no poseía. Los ioduros se utilizaron para el terciarismo. Ehrlich en 1907, patentó el compuesto 606 o Salvarsan y en 1910, el Neo-Salvarsan o Arsfenamina (compuesto 914). Por estos descubrimientos recibió el Premio Nobel. En 1887, Julios Wagner Jauregg sugirió que la fiebre terapéuticamente inducida era útil en el tratamiento de enfermos psicóticos. En 1912 publicó sus satisfactorios resultados al tratar la paresias con una combinación de mercurio-iodo y tuberculina de Koch. En 1917 ingresó a su servicio un enfermo de malaria, con cuya sangre escarificaron la piel palúdica de tres paréticos, en lugar de darle inmediatamente quinina. Por ello fue galardona con el Premio Nobel. Se utilizó luego el bismuto, a partir de 1922, pero posteriormente fue sustituido por las sulfamidas, de aplicación dificultosa. El avance terapéutico más importante ocurrió en 1943, año en que se comenzó a utilizar la penicilina por Mahoney y colaboradores. Luego se confirmó la eficacia de la tetraciclina para los alérgicos a la penicilina. Últimamente se confirmó la eficacia de la azitromicina en dosis de 500mg cada día, durante los 10 días o el régimen de 500mg en días alternos.
The name Syphilis comes from greek language: Siph: Pig and Philus: Love, meaning, in honor of the Sheppard of a story where the Character, Named Syphilo, is punished by the gods to suffer a terrible disease. Data about Syphilis was analized in ancient times (which differ according to the source). Its mention in the middle age, its controversial origin, the help provided from paleopathologists to find it. When the French revolution and the beginning of the contemporary age began, the percentage of sick people grew. The segregation of these is proved by the society. From the year 1500 to the beginnings of the XX century, the treatment of Syphilis depended on mercury. There were a great variety of application methods: topical: the grey ointment, in «calomelanos or tabs¼, in injections, in frictions and fumigations where the mercury was introduced in the body by the lungs. Guayacos wood was named with curative features which it did not posses. The iodides were used for tertiary syphilis. In 1907, Ehrlich formulates the 606 compound or Salvarsan and in 1910 the Neo-Salvarsan or Arsfenamina or compound 914.Due to these discoveries he received the nobel prize. In 1887, Julius Wagner of Jauregg suggested that: the inducted therapeutic fiber was useful in the treatment of the psychosis. In 1912 he published his satisfactory results in treating the paresis with a combination of mercury and iodides and tuberculin of Koch. In 1917 he treated a patient who had malaria and instead of giving him immediately quinine, he made a scarification with his paludic blood the skin of 3 paretic patients. Because of this he was awarded with the nobel prize. Since 1922 bismuth was used, but then it was substituted by the sulphamidas of difficult application. The most important therapeutical advance happened in 1943, year in which penicillin was put in use by Mahoney and col. Later it was confirmed the efficiency of the tetracycline for the penicillin-allergic patients. Lately it has been confirmed the efficiency of the azithromizine in 500 mg dosis each day during 10 days or the regimen of 500 mg in alternate days.
Asunto(s)
Humanos , Masculino , Femenino , Sífilis/tratamiento farmacológico , Sífilis/historia , Arsenicales/administración & dosificación , Arsenicales/uso terapéutico , Arsfenamina/uso terapéutico , Bismuto/uso terapéutico , Compuestos de Yodo/uso terapéutico , Mercurio/administración & dosificación , Mercurio/uso terapéutico , Penicilinas/uso terapéuticoRESUMEN
A key regulatory step in the steroidogenic hormones signaling pathway is the synthesis of steroidogenic acute regulatory protein (StAR). This protein facilitates the delivery of cholesterol to the inner mitochondrial membrane, the rate-limiting step in steroidogenesis. ACTH and LH pathway also includes tyrosine dephosphorylation processes. Indeed, our previous studies have demonstrated that both hormones increase protein tyrosine phosphatase (PTP) activity by a PKA-dependent mechanism and that the action of PTPs is required for the stimulation of steroid biosynthesis in adrenal and Leydig cells. In order to test the putative relationship between PTP activity and StAR protein induction in adrenocortical cells, in the present study we evaluated steroid production and StAR protein level in Y1 adrenocortical cells under PTP inhibition. Phenylarsine oxide (PAO), a powerful cell permeable PTP inhibitor, reduced ACTH-stimulated steroidogenesis in a concentration-dependent fashion. A concentration of 2.5 microM of this compound inhibited steroid synthesis in a 56% (ACTH = 318 +/- 30, ACTH + PAO = 145 +/- 18 ng progesterone/mL, P < 0.001) and also abrogated StAR protein induction. Phenylarsine oxide reduced the protein level after 60 min and this effect still remained at 120 min. A second PTP inhibitor, benzyl phosphonic acid, acting by a different mechanism, reproduced PAO effects on both steroidogenesis and StAR protein. Taken together, these results indicate that PTP activity participates in StAR protein induction and led us to attribute to the PKA-mediated PTP activation in steroidogenic systems a functional role, as mediator of StAR protein induction.