RESUMEN
Excessive mitochondrial fission in podocytes serves as a central hub for the pathogenesis of diabetic nephropathy (DN), and the thromboxane/prostaglandin receptor (TP receptor) plays a potential role in DN. However, regulation of the TP receptor during mitochondrial dynamics disorder in podocytes remains unknown. Here, we firstly reported novel mechanistic details of TP receptor effects on mitochondrial dynamics in podocytes under diabetic conditions. Expression of the TP receptor was significantly upregulated in podocytes under diabetic conditions both in vivo and in vitro. S18886 attenuated podocyte mitochondrial fission, glomerular injury and renal dysfunction in diabetic mice. Furthermore, inhibition of the TP receptor by both genetic and pharmacological methods dramatically reduced mitochondrial fission and attenuated podocyte injury induced by high glucose through regulating dynamin-related protein 1 (Drp1) phosphorylation and its subsequent translocation to mitochondria. In contrast, TP receptor overexpression and application of TP receptor agonist U46619 in these podocytes showed the opposite effect on mitochondrial fission and podocyte injury. Furthermore, treatment with Y27632, an inhibitor of Rho-associated kinase1 (ROCK1), significantly blunted more fragmented mitochondria and reduced podocyte injuries in podocytes with TP receptor overexpression or after U46619 treatment. Finally, pharmacological inhibition of Drp1 alleviated excessive mitochondrial fragmentation and podocyte damage in TP receptor overexpressing podocytes. Our data suggests that increased expression of the TP receptor can occur in a human cultured podocyte cell line and in podocytes derived from streptozotocin (STZ)-induced diabetic mice, which contributes to mitochondrial excessive fission and podocyte injury via ROCK1-Drp1 signaling.
Asunto(s)
Diabetes Mellitus Experimental , Nefropatías Diabéticas , Enfermedades Mitocondriales , Podocitos , Ácido 15-Hidroxi-11 alfa,9 alfa-(epoximetano)prosta-5,13-dienoico/metabolismo , Ácido 15-Hidroxi-11 alfa,9 alfa-(epoximetano)prosta-5,13-dienoico/farmacología , Ácido 15-Hidroxi-11 alfa,9 alfa-(epoximetano)prosta-5,13-dienoico/uso terapéutico , Animales , Diabetes Mellitus Experimental/patología , Nefropatías Diabéticas/patología , Dinaminas/metabolismo , Glucosa/metabolismo , Glucosa/farmacología , Humanos , Ratones , Enfermedades Mitocondriales/metabolismo , Dinámicas Mitocondriales , Prostaglandinas/metabolismo , Prostaglandinas/farmacología , Prostaglandinas/uso terapéutico , Receptores de Prostaglandina/metabolismo , Receptores de Prostaglandina/uso terapéutico , Receptores de Tromboxanos/metabolismo , Receptores de Tromboxanos/uso terapéutico , Estreptozocina , Tromboxanos/metabolismo , Tromboxanos/farmacología , Tromboxanos/uso terapéutico , Quinasas Asociadas a rho/metabolismoRESUMEN
Prostaglandin E2 (PGE2) molecule and its receptors play an important role in the development of malignancies and metastases therefore PGE2 may play a crucial role in the diagnosis and a new therapeutic target in the field of radionuclide therapy of PGE2-positive tumors. PGE2 form complexes with RAMEB (randomly-methylated-beta-cyclodextrin) with high affinity therefore the aim of this present study was to synthesize a PGE2-specific DOTAGA-RAMEB, which can be labeled with diagnostic and therapeutic isotopes also and binds to PGE2-positive tumors. DOTAGA-RAMEB was labeled with 68Ga and 205/206Bi radionuclides and their radiochemical purity (RCP%), partition coefficient (logP values), and in vitro and in vivo stability were determined. For the assessment of the biological properties and the PGE2 specificity of [68Ga]Ga-DOTAGA-RAMEB and [205/206Bi]Bi-DOTAGA-RAMEB in vivo PET imaging and ex vivo biodistribution studies were performed using healthy control and PGE2-positive BxPC-3 tumor-bearing CB17 SCID mice. The RCP% of the newly synthesized [68Ga]Ga-DOTAGA-RAMEB and [205/206Bi]Bi-DOTAGA-RAMEB was higher than 98 %. In vivo studies showed that the tumor-to-background ratio of [68Ga]Ga-DOTAGA-RAMEB was 2.5 ± 0.2 as a result BxPC-3 tumors were clearly identified on PET images. Beside this the ex vivo biodistribution studies showed that the accumulation rate of [68Ga]Ga-DOTAGA-RAMEB and [205/206Bi]Bi-DOTAGA-RAMEB was similar in the PGE2-positive BxPC-3 tumors.
Asunto(s)
Neoplasias , beta-Ciclodextrinas , Animales , Bismuto , Línea Celular Tumoral , Dinoprostona/metabolismo , Radioisótopos de Galio/química , Ratones , Ratones SCID , Neoplasias/tratamiento farmacológico , Tomografía de Emisión de Positrones , Radioisótopos , Receptores de Prostaglandina/metabolismo , Receptores de Prostaglandina/uso terapéutico , Distribución Tisular , beta-Ciclodextrinas/químicaRESUMEN
Objetivo. Revisar y actualizar las pautas del aborto farmacológico. Material y método. Revisión de la literatura. Resultados. La pauta terapéutica más utilizada en gestaciones de menos de 9 semanas (63 días) es la que combina 200 mg de mifepristona seguidos, a las 24-48 horas, de 800 mcg de misoprostol administrados por vía bucal o vaginal. Con esta pauta las tasas de eficacia oscilan entre el 96,12 y el 97,43% y la tasa de efectos secundarios mayores se sitúa entorno al 0,2%. Conclusiones. El aborto farmacológico es eficaz y seguro hasta las 9 semanas de gestación y, por ello, debería de ser ofrecido, como una opción válida, a todas las mujeres que consultan para interrumpir una gestación de menos de 9 semanas (AU)
Objectives. To review and update the different treatment options of pharmacological abortion. Material and methods. Literature search and review. Results. The most widely used treatment in pregnancies of less than 9 weeks (63 days) is a combination of 200 mg of mifepristone followed by 800 micrograms of misoprostol at 24-48 hours administered either vaginally or orally. Efficacy rates vary from 96.12% to 97.43% and the incidence of severe effects is low (0.2%). Conclusions. Medical abortion is safe and effective and should be offered to all women requesting a termination up to 63 days of gestation (AU)
Asunto(s)
Femenino , Humanos , Embarazo , Aborto , Primer Trimestre del Embarazo , Complicaciones del Embarazo/tratamiento farmacológico , Misoprostol/efectos adversos , Misoprostol/uso terapéutico , Mifepristona/efectos adversos , Mifepristona/uso terapéutico , Receptores de Prostaglandina/uso terapéutico , Prostaglandinas/uso terapéutico , Noretindrona/uso terapéutico , Resultado del Tratamiento , Evaluación de Eficacia-Efectividad de Intervenciones , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/complicaciones , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/diagnósticoAsunto(s)
Humanos , Femenino , Adulto , Lupus Eritematoso Sistémico/complicaciones , Lupus Eritematoso Sistémico/diagnóstico , Vasoespasmo Coronario/complicaciones , Vasoespasmo Coronario/diagnóstico , Prostaglandinas/uso terapéutico , Angioscopía Microscópica , Enfermedades Cutáneas Vasculares/complicaciones , Enfermedades Cutáneas Vasculares/diagnóstico , Enfermedades Cutáneas Eccematosas/complicaciones , Arteriolas , Arteriolas/patología , Trombosis/complicaciones , Trombosis/diagnóstico , Trombosis/patología , Aspirina/uso terapéutico , Receptores de Prostaglandina/uso terapéuticoRESUMEN
BACKGROUND: Although development of visceral pain is an important defensive mechanism, hypersensitivity results in a significant clinical problem and is likely to be one of the major factors involved in the pathogenesis of abdominal and chest pain in functional bowel disorders (FBDs). Understanding of the molecular mechanisms involved in peripheral sensitization of visceral nociceptors has advanced as a result of the experimental studies, especially in animal models, which have led to knowledge and identification of key mediators and receptors. AIM: To provide a comprehensive review focused on the peripheral mechanisms believed to be responsible for sensitization and potential molecular targets for a disorder which is common, distressing and has sub-optimal treatment options. METHODS: Literature review using Ovid and Pubmed from 1966. RESULTS: There is substantial interest in the development of new drugs for treatment of FBDs in the background of advances in understanding the molecular and physiological mechanisms of visceral hypersensitivity. The potential drug targets include TPRV1, ASICs, voltage-gated sodium channels, ATP, PAR-2, cannabinoid, prostaglandin, tachykinin and 5HT(3) receptors. CONCLUSION: It is anticipated that with advancing molecular understanding of the basis of visceral hypersensitivity, the next decade will see accelerated development of new molecules for treatment of functional bowel diseases.
Asunto(s)
Péptido Relacionado con Gen de Calcitonina/antagonistas & inhibidores , Hipersensibilidad/fisiopatología , Síndrome del Colon Irritable/fisiopatología , Dolor/fisiopatología , Aferentes Viscerales/fisiopatología , Péptido Relacionado con Gen de Calcitonina/uso terapéutico , Humanos , Hipersensibilidad/tratamiento farmacológico , Síndrome del Colon Irritable/tratamiento farmacológico , Nociceptores , Dolor/tratamiento farmacológico , Receptores de Prostaglandina/uso terapéutico , Receptores Proteinasa-Activados/uso terapéutico , Canales de Sodio/uso terapéutico , Canales Catiónicos TRPV/uso terapéuticoRESUMEN
To find new prostanoid FP-receptor agonists possessing potent ocular-hypotensive effects with minimal side effects, we evaluated the agonistic activities of newly synthesized prostaglandin F(2alpha) derivatives for the prostanoid FP-receptor both in vitro and in vivo. The iris constrictions induced by the derivatives and their effects on melanin content were examined using cat isolated iris sphincters and cultured B16 melanoma cells, respectively. The effects of derivative ester forms on miosis and intraocular pressure (IOP) were evaluated in cats and cynomolgus monkeys, respectively. Of these derivatives, 6 out of 12 compounds were more potent iris constrictors, with EC(50) values of 0.6 to 9.4 nM, than a carboxylic acid of latanoprost (EC(50)=13.6 nM). A carboxylic acid of latanoprost (100 microM) significantly increased the melanin content of cultured B16 melanoma cells, but some 15,15-difluoro derivatives, such as AFP-157 and AFP-172, did not. Topically applied AFP-168, AFP-169 and AFP-175 (isopropyl ester, methyl ester and ethyl ester forms, respectively, of AFP-172) induced miosis in cats more potently than latanoprost. AFP-168 (0.0005%) reduced IOP to the same extent as 0.005% latanoprost (for at least 8 h). These findings indicate that 15,15-difluoroprostaglandin F(2alpha) derivatives, especially AFP-168, have more potent prostanoid FP-receptor agonistic activities than latanoprost. Hence, AFP-168 may be worthy of further evaluation as an ocular-hypotensive agent.