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1.
J Ethnopharmacol ; 193: 450-455, 2016 Dec 04.
Artículo en Inglés | MEDLINE | ID: mdl-27647013

RESUMEN

ETHNOPHARMACOLOGICAL RELEVANCE: Endometriosis is a gynecological disorder characterized by the presence of endometrial tissue outside the uterine cavity. The fruits of Viburnum opulus L. have been used to treat gynecological disorders including primary and secondary dysmenorrhea and ovarian cysts. MATERIALS AND METHODS: Air-dried and powdered fruits of V. opulus were extracted sequentially with n-hexane, ethyl acetate (EtOAc), and methanol (MeOH), respectively for four days. Endometriosis was induced by suturing 15mm piece of endometrium into abdominal wall of Sprague Dawley rats. In second laparotomy, the dimensions of endometrial implants were measured and intra-abdominal adhesions were scored. The abdomen was closed. Extracts were daily administered to the rats. At the end of the experiment, rats were sacrified and endometriotic foci areas and intra-abdominal adhesions were re-evaluated. The tissues were also histopathologically investigated. Furthermore, tumor necrosis factor-α (TNF-α), vascular endothelial growth factor (VEGF) and interleukin-6 (IL-6) levels of peritoneal fluid were measured. HPLC analyses were conducted on the most potent EtOAc and MeOH extracts to determine the amount of the major compound, chlorogenic acid. RESULTS: The endometriotic volumes were found to be reduced significantly in the EtOAc extract-administered group to 30.1mm3 and in the MeOH extract-administered group to 34.7mm3 as compared to the control group. No adhesion was observed in the reference and EtOAc groups. Histopathological data also supported the results. Both EtOAc and MeOH extract-administered groups displayed significant remission in the levels of TNF-α, VEGF and IL-6. When the active extracts were subjected to HPLC analysis, chlorogenic acid was found to be the major compound and the amount of this compound was calculated as 0.5112±0.0012mg and 1.7072±0.0277mg/100mg extract, repectively. CONCLUSIONS: The results of the present study indicate that the effectiveness of the fruit extract of V. opulus could be partially attributed chlorogenic acid. Other phenolic compounds could potentiate the activity due to their amount.


Asunto(s)
Endometriosis/tratamiento farmacológico , Endometrio/efectos de los fármacos , Extractos Vegetales/farmacología , Viburnum/química , Animales , Líquido Ascítico/metabolismo , Biopsia , Ácido Clorogénico/aislamiento & purificación , Ácido Clorogénico/farmacología , Cromatografía Líquida de Alta Presión , Modelos Animales de Enfermedad , Endometriosis/metabolismo , Endometriosis/patología , Endometrio/metabolismo , Endometrio/patología , Endometrio/trasplante , Femenino , Frutas/química , Interleucina-6/metabolismo , Fitoterapia , Extractos Vegetales/aislamiento & purificación , Plantas Medicinales , Ratas Sprague-Dawley , Solventes/química , Factor de Necrosis Tumoral alfa/metabolismo , Factor A de Crecimiento Endotelial Vascular/metabolismo
2.
Reprod Sci ; 21(11): 1362-9, 2014 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-24604232

RESUMEN

Resveratrol is a natural phytoestrogen with antiproliferative properties present in red wine, grapes, and berries. Published reports on the effects of resveratrol in human endometrial function are limited. The objective of this study was to investigate the expression of estrogen receptor α (ESR1), Ki-67 (a proliferative marker), aryl hydrocarbon receptor (AhR), and members of the cytochrome P450 superfamily of enzymes (CYP1A1 and CYP1B1) in an in vitro and vivo assay. Alkaline phosphatase assay of estrogenicity was used to compare estrogen activity of different concentrations of resveratrol to estradiol (E2) and diethylstilbestrol (DES), using Ishikawa cell culture. Immunohistochemical expression of ESR1 and Ki67, and reverse transcriptase polymerase chain reaction of AhR, CYP1A1, and CYP1B1 were analyzed from xenograft implants of human endometrial tissue in ovariectomized immunodeficient RAG-2-γ(c) mice, after 30 days of treatment with subcutaneous pellets of E2, E2 plus progesterone (P4), or E2 plus resveratrol (6, 30, or 60 mg) for 30 days. Compared to E2, resveratrol acted as an agonist and antagonist of estrogen in low and high concentrations, respectively, when combined with E2. Xenografts of human endometrial tissues in RAG-2 mice exhibited reduced expression of ESR1 and proliferative activity (Ki67) with 60 mg of resveratrol. This study suggests that resveratrol, at high doses, has the potential benefit to reduce proliferation of human endometrium through ESR1.


Asunto(s)
Endometrio/efectos de los fármacos , Fitoestrógenos/farmacología , Estilbenos/farmacología , Vino , Fosfatasa Alcalina/metabolismo , Animales , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/efectos de los fármacos , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/genética , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/metabolismo , Proliferación Celular/efectos de los fármacos , Citocromo P-450 CYP1A1/genética , Citocromo P-450 CYP1A1/metabolismo , Citocromo P-450 CYP1B1/genética , Citocromo P-450 CYP1B1/metabolismo , Proteínas de Unión al ADN/deficiencia , Proteínas de Unión al ADN/genética , Dietilestilbestrol/farmacología , Relación Dosis-Respuesta a Droga , Endometrio/trasplante , Estradiol/farmacología , Receptor alfa de Estrógeno/efectos de los fármacos , Receptor alfa de Estrógeno/metabolismo , Femenino , Xenoinjertos , Humanos , Antígeno Ki-67/metabolismo , Ratones Endogámicos C57BL , Ratones Noqueados , Ovariectomía , Receptores de Hidrocarburo de Aril/efectos de los fármacos , Receptores de Hidrocarburo de Aril/genética , Receptores de Hidrocarburo de Aril/metabolismo , Resveratrol , Factores de Tiempo
3.
Reprod Sci ; 18(1): 28-45, 2011 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-20884991

RESUMEN

One primary goal of medical treatment of endometriosis is to alleviate pain and there is a pressing need for new therapeutics for endometriosis with better efficacy and side-effect profiles. Levo-tetrahydropalmatine (l-THP) has been used as a sedative or analgesic for chronic pains in China since 1970s. In this study, we sought to evaluate the efficacy of l-THP, with or without valproic acid (VPA), in a rat model of endometriosis. We surgically induced endometriosis in 55 adult female rats. Two weeks after, all rats were further divided into 5 groups randomly: untreated, low- and high-dose of l-THP, VPA, and l-THP + VPA. Response latency in hotplate test was measured before the surgery, before and after 3-week treatment of respective drugs. All rats were then sacrificed for analysis. The average lesion size and the immunoreactivity to N-methyl-D-asparate receptor 1 (NMDAR1), acid-sensing ion channel 3 (ASIC3), calcitonin gene-related peptide (CGRP), c-Fos, tyrosine kinase receptor A (TrkA), and histone deacetylase 2 (HDAC2) in dorsal root ganglia (DRG), to phorphorylated p65, HDAC2, TrkA, and CGRP in ectopic endometrium and to phorphorylated p65 and CGRP in eutopic endometrium were evaluated. We found that rats receiving l-THP, with or without VPA, had significantly reduced lesion size and exhibited significantly improved response to noxious thermal stimulus. The treatment also significantly lowered immunoreactivity to all mediators involved in central sensitization and to HDAC2 in DRG, to TrkA and CGRP in ectopic endometrium, and to CGRP in eutopic endometrium. In summary, l-THP reduces lesion growth and generalized hyperalgesia. Thus, l-THP may be a promising therapeutics for endometriosis.


Asunto(s)
Analgésicos no Narcóticos/uso terapéutico , Alcaloides de Berberina/uso terapéutico , Endometriosis/tratamiento farmacológico , Hiperalgesia/tratamiento farmacológico , Canales Iónicos Sensibles al Ácido , Analgésicos no Narcóticos/administración & dosificación , Animales , Alcaloides de Berberina/administración & dosificación , Péptido Relacionado con Gen de Calcitonina/análisis , Modelos Animales de Enfermedad , Endometriosis/metabolismo , Endometriosis/patología , Endometrio/química , Endometrio/trasplante , Femenino , Histona Desacetilasa 2/análisis , Calor , Intestino Delgado , Proteínas del Tejido Nervioso/análisis , Dimensión del Dolor , Peritoneo , Proteínas Proto-Oncogénicas c-fos/análisis , Ratas , Ratas Sprague-Dawley , Proteínas Tirosina Quinasas Receptoras/análisis , Receptores de N-Metil-D-Aspartato/análisis , Canales de Sodio/análisis , Factor de Transcripción ReIA/análisis , Ácido Valproico/administración & dosificación
4.
J Pathol ; 222(2): 148-57, 2010 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-20821752

RESUMEN

Endometriosis affects 6-10% of women in their reproductive years, causing chronic pelvic pain and infertility. Its pathogenesis remains poorly understood and current treatments, based on hormonal therapy or surgery, are often insufficient. The purpose of our study was to investigate the role of the ERK pathway in the development of endometriosis and to test the effects of protein kinase inhibitors on the proliferation of endometriotic cells in vitro and in vivo. We studied ex vivo human endometrial and endometriotic cells in culture. Stromal and epithelial cells were extracted from endometrial and endometriotic biopsies from patients with endometriosis and from patients without endometriosis. The ERK pathway was explored by western blot on cell lysates and by ELISA on total crushed specimens of endometrium. Cells in culture were treated with A771726, PD98059, and U0126. Human endometriotic lesions were implanted in nude mice. Mice were treated with A771726, leflunomide, PD98059, U0126 or PBS during 2 weeks before sacrifice and extraction of the endometriotic implants for histological examination. We found that the ERK pathway was significantly activated in endometriotic cells and in endometrial cells from patients with endometriosis compared to endometrial cells of control patients, both by ELISA and by western blot. This phenomenon was associated with an increased proliferation of endometriotic cells compared to endometrial cells. Treating endometriotic cells with A771726, PD98059 or U0126 abrogated the phosphorylation of ERK and significantly decreased the cellular proliferation in vitro. In vivo, A771726, leflunomide, PD98059, and U0126 controlled the growth of endometriotic implants in the mouse model of endometriosis. Our study shows that protein kinase inhibitors could be new candidates to treat endometriosis. However, further studies are needed to evaluate their effects and tolerability in humans.


Asunto(s)
Endometriosis/tratamiento farmacológico , Endometrio/efectos de los fármacos , Inhibidores de Proteínas Quinasas/uso terapéutico , Adulto , Animales , Proliferación Celular/efectos de los fármacos , Células Cultivadas , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Evaluación Preclínica de Medicamentos , Endometriosis/enzimología , Endometriosis/patología , Endometrio/enzimología , Endometrio/patología , Endometrio/trasplante , Ensayo de Inmunoadsorción Enzimática/métodos , Células Epiteliales/patología , Quinasas MAP Reguladas por Señal Extracelular/fisiología , Femenino , Humanos , Sistema de Señalización de MAP Quinasas/fisiología , Ratones , Ratones Desnudos , Inhibidores de Proteínas Quinasas/farmacología , Células del Estroma/patología
5.
Eur J Obstet Gynecol Reprod Biol ; 153(1): 72-6, 2010 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-20667645

RESUMEN

OBJECTIVE: To determine the effects of pinealectomy on endometrial explants in rats and evaluate the activity of superoxide dismutase (SOD) and catalase (CAT) and the levels of malondialdehyde (MDA) in the rat endometriosis model. STUDY DESIGN: Rats with experimentally induced endometriosis were randomly divided into three groups after second-look laparotomies. Group 1 (pinealectomy, n = 8) and Group 2 (pinealectomy+melatonin, n = 8) underwent pinealectomies after the second-look laparotomies. Group 3 was presented as control group (vehicle solution+without pinealectomy (n = 6)). Melatonin was administered intraperitoneally for 4 weeks in Group 2, whereas an equal volume of vehicle solution was given to Groups 1 and 3. Evaluation of the volume of the endometrial explants, histopathological examination and preservation of explant epitheliums according to the scoring system were undertaken. RESULTS: There was a statistically significant increase in spherical explant volumes of Group 1 compared to Groups 2 and 3. In Group 1, the level of MDA was significantly higher and SOD and CAT activity was significantly lower compared to Groups 2 and 3. A statistically significant increase in the epithelial lining scores of explants was noted in Group 1 compared to Groups 2 and 3. CONCLUSION: The effects of pinealectomy on the progression of endometriosis explants were reversed by melatonin.


Asunto(s)
Endometriosis/etiología , Endometrio/trasplante , Melatonina/administración & dosificación , Glándula Pineal/cirugía , Animales , Suplementos Dietéticos , Modelos Animales de Enfermedad , Endometriosis/tratamiento farmacológico , Endometriosis/metabolismo , Femenino , Malondialdehído/análisis , Estrés Oxidativo , Ratas , Ratas Wistar
6.
Hum Reprod ; 24(8): 1900-8, 2009 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-19401321

RESUMEN

BACKGROUND: Doxycycline (Dox) has a number of non-antibiotic properties. One of them is the inhibition of matrix metalloproteinase (MMP) activity. The aim of this study was to assess the effects of Dox in a rat endometriosis model. METHODS: Endometriosis was surgically induced in 40 rats by transplanting of endometrial tissue. After 3 weeks, repeat laparotomies were performed to check the implants and the animals were randomized into four groups: Group I, low-dose Dox (5 mg/kg/day); Group II, high-dose Dox (40 mg/kg/day); Group III, leuprolide acetate 1 mg/kg single dose, s.c.; and Group VI (controls), no medication. The treatment, initiated on the day of surgery and continuing for 3 weeks, was administered to the study groups. Three weeks later, the rats were euthanized and the implants were evaluated morphologically and histologically for immunoreactivity of MMP-2 and -9, and interleukin-6 (IL-6) concentration in the peritoneal fluid was assayed. RESULTS: Treatment with leuprolide acetate, or high-dose or low-dose Dox caused significant decreases in the implant areas compared with the controls (P = 0.03, P = 0.006, and P = 0.001, respectively). IL-6 levels in peritoneal fluid decreased in Group I (P = 0.02) and Group III (P < 0.05). MMP H scores were significantly lower in the group that received low-dose Dox in both epithelial and stromal MMP-2 and -9 immunostaining when compared with the control group [P = 0.048, P = 0.002, P = 0.007 and P = 0.002, respectively, MMP-2 (epithelia), MMP-2 (stroma), MMP-9 (epithelia) and MMP-9 (stroma)]. CONCLUSIONS: Low-dose Dox caused regression of endometriosis in this experimental rat model.


Asunto(s)
Doxiciclina/uso terapéutico , Endometriosis/tratamiento farmacológico , Animales , Endometriosis/patología , Endometrio/trasplante , Femenino , Inmunohistoquímica , Interleucina-6/metabolismo , Leuprolida/uso terapéutico , Metaloproteinasa 2 de la Matriz/metabolismo , Metaloproteinasa 9 de la Matriz/metabolismo , Ratas , Ratas Wistar
7.
Hum Reprod ; 22(5): 1474-80, 2007 May.
Artículo en Inglés | MEDLINE | ID: mdl-17234677

RESUMEN

BACKGROUND: This prospective randomized-controlled animal study was designed to determine the effects of atorvastatin on experimentally induced endometriosis in a rat model. METHODS: Thirty-seven Wistar-Albino rats in which endometriotic implants were induced were randomly divided into four groups. Group I (Low-dose atorvastatin group, eight rats) were given 0.5 mg kg(-1) day(-1) oral atorvastatin. Group II (High-dose atorvastatin group, 10 rats) were given 2.5 mg kg(-1) day(-1) oral atorvastatin. Group III were given a single dose of 1 mg kg(-1) s.c. leuprolide acetate (GnRH agonist group, nine rats). Group IV were given no medication and served as controls (10 rats). All rats received the treatment for 21 days and were then euthanized to assess the implants' size, vascular endothelial growth factor (VEGF) level in peritoneal fluid and histological score. RESULTS: At the end of the treatment, the mean areas of implants were smaller and VEGF levels in peritoneal fluid were lower in Groups II and III than those in Group I and the control group (all P < 0.05). The mean areas of implants decreased from 41.2 +/- 13.9 to 22.7 +/- 13.9 mm(2) after medication in Group II and decreased from 41.2 +/- 18.1 to 13.1 +/- 13.8 mm(2) in Group III (both P < 0.05), whereas in Group I, the mean area increased from 43.0 +/- 12.7 to 50.5 +/- 13.9 mm(2) (P < 0.05). CONCLUSIONS: High-dose atorvastatin caused a significant regression of endometriotic implants.


Asunto(s)
Endometriosis/tratamiento farmacológico , Ácidos Heptanoicos/administración & dosificación , Pirroles/administración & dosificación , Animales , Atorvastatina , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Endometriosis/patología , Endometrio/trasplante , Femenino , Leuprolida/uso terapéutico , Ratas , Ratas Wistar , Factor A de Crecimiento Endotelial Vascular/análisis
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