ABSTRACT
BACKGROUND: BPH and LUTS have been associated to obesity, hypogonadism, and metabolic syndrome (MetS). MetS-induced prostate and bladder alterations, including inflammation and tissue remodeling, have been related to a low-testosterone and high-estrogen milieu. In addition to ERs, GPR30/GPER is able to mediate several estrogenic non-genomic actions. METHODS: Supplementing a subgroup of MetS rabbits with tamoxifen, we analyzed the in vivo effects on MetS-induced prostate and bladder alterations. The effects of selective ER/GPER ligands and GPER silencing on prostate inflammation were also studied in vitro using hBPH cells. RESULTS: ERα, ERß, and PR expression was upregulated in MetS bladder, where tamoxifen decreased ERα and PR expression, further stimulating ERß. In addition, tamoxifen-dosing decreased MetS-induced overexpression of inflammatory and tissue remodeling genes. In prostate, sex steroid receptors, pro-inflammatory and pro-fibrotic genes were upregulated in MetS. However, tamoxifen did not affect them and even increased COX-2. In hBPH cells, 17ß-estradiol increased IL-8 secretion, an effect blunted by co-treatment with GPER antagonist G15 but not by ER antagonist ICI 182,780, which further increased it. GPER agonist G1 dose-dependently (IC50 = 1.6 nM) induced IL-8 secretion. In vitro analysis demonstrated that GPER silencing reverted these stimulatory effects. CONCLUSIONS: GPER can be considered the main mediator of estrogen action in prostate, whereas in bladder the mechanism appears to rely on ERα, as indicated by in vivo experiments with tamoxifen dosing. Limiting the effects of the MetS-induced estrogen action via GPER could offer new perspectives in the management of BPH/LUTS, whereas tamoxifen dosing showed potential benefits in bladder.
Subject(s)
Metabolic Syndrome/metabolism , Prostate/metabolism , Receptors, Estrogen/physiology , Receptors, G-Protein-Coupled/physiology , Selective Estrogen Receptor Modulators/pharmacology , Tamoxifen/pharmacology , Urinary Bladder/metabolism , Animals , Cell Line , Chromosomes, Human, Pair 11/genetics , Chromosomes, Human, Pair 8/genetics , Humans , Male , Metabolic Syndrome/drug therapy , Pair Bond , Prostate/drug effects , Rabbits , Selective Estrogen Receptor Modulators/therapeutic use , Tamoxifen/therapeutic use , Urinary Bladder/drug effectsABSTRACT
The exposure of neurons to high glucose concentrations is considered a determinant of diabetic neuropathy, whereas members of the IGF system are neurotropic factors. Here, we investigated the effects of constant and intermittent high glucose concentrations on IGF1 and IGF-binding proteins (IGFBPs) in human neuroblast long-term cell cultures fetal neuroepithelial cells (FNC). These cells express the IGF1 receptor, and express and release in the culture medium IGFBP2, IGFBP4, and IGF1. The release of IGF1 was significantly increased by 17beta-estradiol (10 nM). IGF1 (100 nM) treatment determined a significant increase of IGFBP2 and a decrease of IGFBP4 release. In addition, IGF1 (1-100 nM) stimulated FNC cell proliferation in a dose-dependent manner. We hypothesized that this effect may be, at least partially, due to IGF1-induced up-regulation of the expression of the Alzheimer's disease related gene SELADIN-1 (now known as DHCR24 ), which acts as a pro-survival factor for neuronal cells. Conversely, the exposure to intermittent (20/10 mM), but not stable (20 mM), high glucose concentrations decreased the release of IGF1 and IGFBP2 in the culture medium and inhibited FNC growth by inducing apoptosis. The latter was prevented by the addition of IGF1 to the culture medium. Furthermore, high glucose concentrations reduced the expression of DHCR24. In conclusion, our results indicate for the first time that intermittent high glucose concentrations, similar to those observed in poorly controlled diabetic patients, may contribute to the development of diabetic neuropathy by interfering with the tropic effects exerted by the IGF system, and suggest the involvement of the neuroprotective factor DHCR24.
Subject(s)
Cell Survival/drug effects , Glucose/pharmacology , Nerve Tissue Proteins/physiology , Neuroepithelial Cells/drug effects , Neuroepithelial Cells/metabolism , Oxidoreductases Acting on CH-CH Group Donors/physiology , Receptor, IGF Type 1/metabolism , Cell Proliferation/drug effects , Cells, Cultured , Enzyme-Linked Immunosorbent Assay , Humans , Immunoblotting , In Situ Nick-End Labeling , Insulin-Like Growth Factor Binding Protein 2/genetics , Insulin-Like Growth Factor Binding Protein 2/metabolism , Insulin-Like Growth Factor Binding Protein 2/pharmacology , Insulin-Like Growth Factor Binding Protein 4/genetics , Insulin-Like Growth Factor Binding Protein 4/metabolism , Insulin-Like Growth Factor Binding Protein 4/pharmacology , Insulin-Like Growth Factor I/genetics , Insulin-Like Growth Factor I/metabolism , Insulin-Like Growth Factor I/pharmacology , Nerve Tissue Proteins/genetics , Neuroepithelial Cells/cytology , Oxidoreductases Acting on CH-CH Group Donors/genetics , Receptor, IGF Type 1/genetics , Reverse Transcriptase Polymerase Chain Reaction , Signal Transduction/drug effectsABSTRACT
Para dilucidar los mecanismos tóxicos responsables de la nefrotoxicidad inducida por el Allopurinol y las respuestas protectoras endógenas, se investigaron las variaciones de la Creatinina plasmática, la peroxidación lipídica renal, los factores de producción de radicales libres del O2: xantina oxidasa y sus sustratos: xantina e hipoxantina y los factores de eliminación de tales radicales: superóxido dismutasa y catalasa. Las ratas recibieron subcutáneamente inyecciones de Allopurinol en dosis de 100 mg/kg de peso, por día y durante tres días. Comparando ratas normales, se observaron los siguientes cambios: a) un aumento en las proporciones de creatinina plasmática y en los niveles tisulares de la catalasa y de la supeóxido dismutasa; c) los valores máximos y mínimos se observaron al tercer día de administración de la droga y posteriormente todos los parámetros se normalizan a sus niveles originales; d) estos resultados sugieren que la nefrotoxicidad del Allopurinol se atribuiría al aumento de la peroxidación lipídica, que por un lado, aumenta la producción de radicales libres del O2, y por otro lado, estarían dismunuidos los mecanismos de su eliminación
Subject(s)
Animals , Rats , Allopurinol/adverse effects , Free Radicals/antagonists & inhibitors , Medicamentous Disease , Kidney , Allopurinol/pharmacology , Allopurinol/toxicity , Catalase/drug effects , Malondialdehyde/metabolism , Rats, Inbred Strains , Superoxide Dismutase , Xanthine Oxidase/drug effectsABSTRACT
Para dilucidar los mecanismos tóxicos responsables de la nefrotoxicidad inducida por el Allopurinol y las respuestas protectoras endógenas, se investigaron las variaciones de la Creatinina plasmática, la peroxidación lipídica renal, los factores de producción de radicales libres del O2: xantina oxidasa y sus sustratos: xantina e hipoxantina y los factores de eliminación de tales radicales: superóxido dismutasa y catalasa. Las ratas recibieron subcutáneamente inyecciones de Allopurinol en dosis de 100 mg/kg de peso, por día y durante tres días. Comparando ratas normales, se observaron los siguientes cambios: a) un aumento en las proporciones de creatinina plasmática y en los niveles tisulares de la catalasa y de la supeóxido dismutasa; c) los valores máximos y mínimos se observaron al tercer día de administración de la droga y posteriormente todos los parámetros se normalizan a sus niveles originales; d) estos resultados sugieren que la nefrotoxicidad del Allopurinol se atribuiría al aumento de la peroxidación lipídica, que por un lado, aumenta la producción de radicales libres del O2, y por otro lado, estarían dismunuidos los mecanismos de su eliminación (AU)
Subject(s)
Animals , Rats , Allopurinol/adverse effects , Kidney/drug effects , Free Radicals/antagonists & inhibitors , Medicamentous Disease , Allopurinol/pharmacology , Allopurinol/toxicity , Rats, Inbred Strains , Catalase/drug effects , Malondialdehyde/metabolism , Xanthine Oxidase/drug effects , Superoxide Dismutase/drug effectsABSTRACT
The effect of allopurinol, a xanthine oxidase inhibitor, on canine experimental ischemic pancreatitis was studied. The animals were divided into nine groups: 1. Group 1. Control with pancreatic ischemia; 2. Group 2. Received allopurinol once, previous to ischemia; 3. Group 3. Received allopurinol once, immediately after ischemia; 4. Group 4. Received allopurinol immediately after ischemia and then daily; and 5. Groups 5, 6, and 7 were controls for the operation, allopurinol, and its vehicle, respectively; 6. Group 8 (pancreatic ischemia) and Group 9 (that received allopurinol after ischemia and daily) were also studied histologically. Serum amylase was determined in all animals. In Groups 1 and 5, following the ischemic period, hyperamylasemia developed and a peak was reached 24 h after ischemia. In Group 2, a significant decrease of amylase levels was found, compared to matched controls immediately after ischemia and then rose, reaching on the fifth day a peak that was less than the controls at 24 h. In Group 3, the serum amylase level increased immediately to values similar to controls; later, there was a drop to levels lower than those found in controls, followed by a peak on the fifth day. In Group 4, there was no significant elevation in the amylase values. Groups 6 and 7 showed no changes of amylasemia. In this experimental model, allopurinol blocked or ameliorated significantly cellular injury, as shown by a decrease of amylase levels in blood, and of histopathological changes, depending on dose and time of administration. These results offer the possibility of a prophylactic therapy for chronic relapsing and idiopathic pancreatitis.
Subject(s)
Allopurinol/therapeutic use , Ischemia/drug therapy , Pancreatitis/drug therapy , Amylases/blood , Animals , Dogs , Female , Free Radicals , Ischemia/enzymology , Ischemia/pathology , Male , Pancreas/blood supply , Pancreatitis/enzymology , Pancreatitis/pathologySubject(s)
Enalapril/adverse effects , Hyperlipidemias/chemically induced , Adult , Aged , Female , Humans , Male , Middle AgedABSTRACT
El autotrasplante de tejido insular pancreatico, obtenido por metodo mecanico-enzimatico y realizado mediante la embolizacion portal, ha provocado la hipertension portal aguda en la totalidad de los 43 animales transplantados. La utilizacion de heparina y aprotinina logro reducir parcialmente las cifras tensionales, pero solo una anastomosis portocava laterolateral no amplia, evito este fenomeno. La hipertension portal aguda, causada esencialmente por coagulacion intravascular es capaz de conducir a la muerte, alejando este procedimiento de la aparente inocuidad senalada inicialmente
Subject(s)
Male , Female , Animals , Dogs , Hypertension, Portal , Islets of Langerhans , Transplantation, AutologousABSTRACT
El autotrasplante de tejido insular pancreatico, obtenido por metodo mecanico-enzimatico y realizado mediante la embolizacion portal, ha provocado la hipertension portal aguda en la totalidad de los 43 animales transplantados. La utilizacion de heparina y aprotinina logro reducir parcialmente las cifras tensionales, pero solo una anastomosis portocava laterolateral no amplia, evito este fenomeno. La hipertension portal aguda, causada esencialmente por coagulacion intravascular es capaz de conducir a la muerte, alejando este procedimiento de la aparente inocuidad senalada inicialmente
Subject(s)
Male , Female , Animals , Dogs , Hypertension, Portal , Islets of Langerhans , Transplantation, AutologousABSTRACT
The effects of pimozide, a dopamine receptor-blocking agent, were studied in the pars distalis of the rat. The animals received 100 micrograms/100 g pimozide daily for 5, 10, 15, and 20 days. Pimozide induces striking ultrastructural changes after 5 days of treatment. The number of luteotroph (LTH) cells is signficantly increased; they display characteristics of stimulation. The extrusion of granules into the intercellular space via exocytosis is frequently observed. The intercellular spaces are highly dilated, forming a lacunar system filled with an amorphous material, erythrocytes and involuted LTH cells. Transitional stages in the process of involution are observed in LTH cells. Luteotroph cells also form a syncytium. Twenty days after treatment the above-described changes decrease in magnitude. The present findings suggest that pimozide stimulates the mechanism of synthesis and release in the luteotroph cells, an effect that is less evident with longer treatment.
