RESUMEN
Six new triterpenoid saponins, named senegalosides A-F (1-6) were isolated from the seedpods and roots of Acacia senegal (Mimosaceae). Their structures were elucidated using 1D and 2D-NMR spectroscopic analysis and mass spectrometry. Compound 1 possesses an unusual sapogenin, 3ß-hydroxy-21-oxo-olean-12-en-28-oic acid (machaeric acid), and was reported here in its natural form for the first time within the genus Acacia. Senegaloside A is the first example of a machaeric-type triterpenoid glycoside in the plant kingdom. The cytotoxic effect of isolated saponins was evaluated on the H4IIE rat hepatoma cell line. As a result, compounds 1, 3-6 were not significantly cytotoxic to H4IIE cells even at 200 µM. Compound 2 was suppressed cell viability at 50-200 µM.
Asunto(s)
Acacia/química , Antineoplásicos Fitogénicos/farmacología , Saponinas/farmacología , Triterpenos/farmacología , Animales , Antineoplásicos Fitogénicos/aislamiento & purificación , Camerún , Línea Celular Tumoral , Supervivencia Celular , Ensayos de Selección de Medicamentos Antitumorales , Estructura Molecular , Fitoquímicos/aislamiento & purificación , Fitoquímicos/farmacología , Raíces de Plantas/química , Ratas , Saponinas/aislamiento & purificación , Triterpenos/aislamiento & purificaciónRESUMEN
Ricinoleic acid (RA) is the main fatty acid component of castor oil and was found to inhibit Ca2+ -signal transduction pathway-mediated cell cycle regulation in a yeast-based drug screening assay. RA is expected to have antidiabetic, antiallergy, and/or anticancer properties but its target molecule is unknown. To identify a novel pharmacological effect of RA, we investigated its target molecule in the Ca2+ -signal transduction pathway. RA inhibition of calcineurin (CN) was examined in a yeast-based CN inhibitor screening assay using the rsp5A401E mutant and in a phosphatase assay using recombinant human CN. RA showed growth-restoration activity at 5 µg/spot in the CN inhibitor screening assay with the rsp5A401E yeast strain. Furthermore, it directly inhibited CN without immunophilins at Ki = 33.7 µM in a substrate-competitive manner. The effects of RA on CN in mammalian cells were further evaluated by measuring ß-hexosaminidase (ß-HEX) release in RBL-2H3 cells. RA at 50 µM suppressed the release of ß-HEX from RBL-2H3 cells. Moreover, this compound was found to inhibit glycogen synthase kinase-3ß (GSK-3ß), as determined by a kinase assay using recombinant human GSK-3ß. RA inhibited GSK-3ß at Ki = 1.43 µM in a peptide substrate-competitive manner. The inhibition of GSK-3ß by this molecule was further assessed in mammalian cells by measuring the inhibition of glucose production in H4IIE rat hepatoma cells. RA at 25 µM suppressed glucose production in these cells. These findings indicate that RA and/or castor oil could be a useful functional fatty acid to treat allergy or type 2 diabetes.
Asunto(s)
Inhibidores de la Calcineurina/farmacología , Señalización del Calcio/efectos de los fármacos , Aceite de Ricino/química , Ácidos Ricinoleicos/farmacología , Animales , Calcineurina/metabolismo , Evaluación Preclínica de Medicamentos , Regulación de la Expresión Génica/efectos de los fármacos , Glucosa/metabolismo , Glucógeno Sintasa Quinasa 3 beta/metabolismo , Humanos , Fosforilación , Ratas , Saccharomyces cerevisiae/genética , Saccharomyces cerevisiae/crecimiento & desarrollo , Saccharomyces cerevisiae/metabolismo , beta-N-Acetilhexosaminidasas/metabolismoRESUMEN
BACKGROUND AND AIM: The aging-dependent activation of glycogen synthase kinase-3ß (GSK-3ß) has been suggested to be important in the onset of dementia. To discover novel therapeutic Kampo medicines for dementia, we examined the effects of orengedokuto (OGT; huáng lián jiedú tang) and san'oshashinto (SST; san huáng xiè xin tang) on memory deficits and GSK-3ß activity in senescence-accelerated prone mice (SAMP8). EXPERIMENTAL PROCEDURE: The object recognition test (ORT) and conditioned fear memory test (CFT) were employed to elucidate short-term working memory and long-term fear memory. The activity of GSK-3ß and the phosphorylation of related molecules were measured using a kinase assay and Western blotting. RESULTS AND CONCLUSION: OGT and SST attenuated memory deficits in SAMP8 in ORT, but not in CFT. In ex vivo experiments, cortical GSK-3ß activity was significantly stronger in SAMP8 than in SAMR1. The enhanced cortical GSK-3ß activity in SAMP8 was accompanied by a significant increase in the level of phosphorylated collapsin response mediator protein-2 (CRMP2), an important factor that is involved in the regulation of microtubule stability. OGT and SST attenuated not only increases in cortical GSK-3ß activity, but also the levels of phosphorylated CRMP2 in SAMP8. In vitro experiments, flavonoids contained in these kampo medicines, inhibited GSK-3ß activity in concentration-dependent manners. These results suggest that OGT and SST prevent aging-induced short-term working memory deficits by inhibiting aging-dependent elevations in the cortical GSK-3ß activity and subsequent CRMP2 phosphorylation.
RESUMEN
A podocarpatriene and a labdatriene derivative, named kujiol A [13-methyl-8,11,13-podocarpatrien-19-ol (1)] and kujigamberol B [15,20-dinor-5,7,9-labdatrien-13-ol (2)], respectively, were isolated from Kuji amber through detection with the aid of their growth-restoring activity against a mutant yeast strain ( zds1Δ erg3Δ pdr1Δ pdr3Δ), which is known to be hypersensitive with respect to Ca2+-signal transduction. The structures were elucidated by spectroscopic data analysis. Compounds 1 and 2 are rare organic compounds from Late Cretaceous amber, and the mutant yeast used seems useful for elucidating a variety of new compounds from Kuji amber specimens, produced before the K-Pg boundary.
Asunto(s)
Ámbar/química , Productos Biológicos/química , Productos Biológicos/farmacología , Señalización del Calcio/efectos de los fármacos , Saccharomyces cerevisiae/efectos de los fármacos , Transducción de Señal/efectos de los fármacos , Ámbar/farmacología , Extractos Vegetales/química , Extractos Vegetales/farmacologíaRESUMEN
Many uncommon non-methylene-interrupted fatty acids (NMI FA) are present in limpet gonads, but their biological properties remain unknown. To investigate new biological effects of naturally occurring NMI FA in eukaryotic cells, the biological activities of structurally analogous (4Z,15Z)-octadecadienoic acid (1), (9Z,20Z)-tricosadienoic acid (2), and (12Z,23Z)-hexacosadienoic acid (3) were examined by using a yeast-based drug-screening system using the Ca2+-sensitive mutant strain, Saccharomyces cerevisiae (zds1Δ erg3Δ pdr1Δ pdr3Δ). Among 1-3, 1 showed restored growth activity at a dose of 80 µg/disc in the mutant yeast strain. This phenotype suggests that 1 suppresses Ca2+-signaling of the mutant yeast through inhibition of glycogen synthase kinase-3ß (GSK-3ß) or calcineurin pathways or both. From this result, the inhibitory activity of 1-3 against GSK-3ß was further determined. 1-3 showed potent inhibitory activity against GSK-3ß with IC50 values ranging from 8.7 to 21.9 µM. Inhibition of GSK-3ß reduces gene expression of the gluconeogenic key enzymes in liver, so we analyzed glucose production in rat hepatoma H4IIE cells to assess GSK-3ß inhibitory activity of 1-3. Acid 1 inhibited glucose production at 25 µM in H4IIE cells. Our results would open up new possibilities for an anti-diabetic effect of 1 and might provide important insights into understanding the biological properties of naturally occurring NMI FA.
Asunto(s)
Ácidos Grasos Insaturados/farmacología , Glucosa/metabolismo , Glucógeno Sintasa Quinasa 3 beta/metabolismo , Saccharomyces cerevisiae/crecimiento & desarrollo , Animales , Calcineurina/metabolismo , Calcio/metabolismo , Línea Celular , Supervivencia Celular/efectos de los fármacos , Evaluación Preclínica de Medicamentos , Ácidos Grasos Insaturados/química , Células HL-60 , Humanos , Ratas , Saccharomyces cerevisiae/genéticaRESUMEN
A new norlabdane compound, named kujigamberol has previously been isolated from Kuji amber (but not from Baltic amber) by activity guided fractionation. However, there has been no study of biological compounds in Dominican amber. Biological activities were examined using the hypersensitive mutant yeast (zds1Δ erg3Δ pdr1Δ pdr3Δ) with respect to Ca(2+)-signal transduction, enzymes and rat basophilic leukemia (RBL)-2H3 cells. The structures were elucidated on the basis of spectral analysis including high resolution (HR)-EI-MS, 1D NMR and 2D NMR. Three diterpenoid compounds, 5(10)-halimen-15-oic acid (1), 3-cleroden-15-oic acid (2) and 8-labden-15-oic acid (3), which are different from the bioactive compounds in Kuji and Baltic ambers, were isolated from Dominican amber. They inhibited both calcineurin (CN) (IC50=40.0, 21.2 and 34.2µM) and glycogen synthase kinase-3ß (GSK-3ß) (IC50=48.9, 43.8 and 41.1µM) which are involved in the growth restored activity against the mutant yeast. The most abundant compound 2 showed inhibitory activity against both degranulation and Ca(2+)-influx in RBL-2H3 cells. The compounds having the growth restoring activity against the mutant yeast have potential as anti-allergic compounds.
Asunto(s)
Ámbar/química , Señalización del Calcio/efectos de los fármacos , Degranulación de la Célula/efectos de los fármacos , Mastocitos/efectos de los fármacos , Saccharomyces cerevisiae/efectos de los fármacos , Animales , Línea Celular , República Dominicana , RatasRESUMEN
A new biological activity of falcarindiol isolated from Japanese parsley (Oenanthe javanica) using the mutant yeast YNS17 strain (zds1Δ erg3Δ pdr1Δ pdr3Δ) was discovered as an inhibitor of glycogen synthase kinase-3ß (GSK-3ß). Falcarindiol inhibited GSK-3ß in an ATP noncompetitive manner with a Ki value of 86.9 µM using a human enzyme and luminescent kinase assay platform. Falcarindiol also both suppressed gene expression of glucose-6-phosphatase (G6Pase) in rat hepatoma H4IIE cells and protected mouse neuroblastoma HT22 cells from glutamate-induced oxidative cell death at 10 µM. During an oral glucose tolerance test (OGTT), the blood glucose level was significantly decreased in the rats treated with oral administration of O. javanica extract containing falcarindiol (15 mg/kg). These findings indicate that Japanese parsley could be a useful food ingredient against type-2 diabetes and Alzheimer's disease.
Asunto(s)
Enfermedad de Alzheimer/enzimología , Diabetes Mellitus Tipo 2/enzimología , Diinos/química , Inhibidores Enzimáticos/química , Alcoholes Grasos/química , Glucógeno Sintasa Quinasa 3/antagonistas & inhibidores , Oenanthe/química , Extractos Vegetales/química , Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/fisiopatología , Animales , Apoptosis/efectos de los fármacos , Línea Celular , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Diabetes Mellitus Tipo 2/metabolismo , Diinos/administración & dosificación , Diinos/aislamiento & purificación , Inhibidores Enzimáticos/administración & dosificación , Inhibidores Enzimáticos/aislamiento & purificación , Alcoholes Grasos/administración & dosificación , Alcoholes Grasos/aislamiento & purificación , Glucosa/metabolismo , Glucosa-6-Fosfatasa/antagonistas & inhibidores , Glucosa-6-Fosfatasa/genética , Glucosa-6-Fosfatasa/metabolismo , Glucógeno Sintasa Quinasa 3/genética , Glucógeno Sintasa Quinasa 3/metabolismo , Humanos , Cinética , Masculino , Ratones , Extractos Vegetales/administración & dosificación , Extractos Vegetales/aislamiento & purificación , RatasRESUMEN
In the course of our screening program for a new inhibitor of the Ca(2+) signalling pathway using mutant yeast [Saccharomyces cerevisiae (zds1Δ erg3Δ pdr1Δ pdr3Δ)], a mouse PP2Cα activator, pisiferdiol, isolated from Chamaecyparis pisifera, was found to alleviate the Ca(2+) signal-mediated growth inhibition. Pisiferdiol showed growth inhibition activity against the mpk1Δ strain compared with the cnb1Δ strain and induced Li(+) sensitivity to the wild-type strain, indicating that it suppresses the calcineurin pathway in the yeast. However, the Li(+) sensitivity to ptc1Δ strain by pisiferdiol was diminished. Pisiferdiol showed growth restored activity in the zds1Δ strain without immunophilins Fkb1p or Cph1p, and in the pmc1Δ strain. It inhibited calcineurin-induced expression in the reporter gene assay and decreased the protein expression (Western blots) of calcineurin (Cnb1p) in addition to a decrease of Swe1p and phosphorylation of Cdc28p in the mutant yeast. These results showed that pisiferdiol could suppress indirectly the action of calcineurin and restored the growth inhibition of the mutant yeast through Ptc1p activation.
Asunto(s)
Inhibidores de la Calcineurina , Señalización del Calcio/efectos de los fármacos , Diterpenos/farmacología , Proteína Fosfatasa 2/metabolismo , Proteínas de Saccharomyces cerevisiae/metabolismo , Saccharomyces cerevisiae/efectos de los fármacos , Calcineurina/metabolismo , Chamaecyparis/química , Activadores de Enzimas/farmacología , Eliminación de Gen , Regulación Fúngica de la Expresión Génica , Inmunofilinas/metabolismo , Litio/farmacología , Fosfoproteínas Fosfatasas/metabolismo , Fosforilación , Extractos Vegetales/farmacología , Proteína Fosfatasa 2C , Saccharomyces cerevisiae/genética , Saccharomyces cerevisiae/crecimiento & desarrollo , Saccharomyces cerevisiae/fisiología , Proteínas de Saccharomyces cerevisiae/antagonistas & inhibidores , Estrés PsicológicoRESUMEN
A new compound, 15,20-dinor-5,7,9-labdatriene-18-ol (1), named kujigamberol, was isolated from amber, fossilized tree resin from the Kuji area in Japan, has been dated as being 85 million years old (late Cretaceous). Kujigamberol was identified using the hypersensitive mutant yeast (zds1∆ erg3∆ pdr1∆ pdr3∆) with respect to Ca(2+)-signal transduction. The structure was elucidated on the basis of spectroscopic analysis including 1D NMR, 2D NMR and HR-EI-MS. It was different from known diterpenoids with a similar activity isolated from Baltic amber (agathic acid 15-monomethyl ester (2), dehydroabietic acid (3) and pimaric acid (4)). Kujigamberol showed glycogen synthase kinase-3ß (GSK-3ß) inhibition activity involving the growth restored activity against the mutant yeast and was cytotoxic to HL60 cells (IC(50)=19.6 µM).
Asunto(s)
Ámbar/química , Antineoplásicos Fitogénicos/aislamiento & purificación , Diterpenos/aislamiento & purificación , Inhibidores Enzimáticos/aislamiento & purificación , Fósiles , Fitoterapia , Extractos Vegetales/química , Antineoplásicos Fitogénicos/farmacología , Antineoplásicos Fitogénicos/uso terapéutico , Calcio/metabolismo , Diterpenos/farmacología , Diterpenos/uso terapéutico , Inhibidores Enzimáticos/farmacología , Inhibidores Enzimáticos/uso terapéutico , Glucógeno Sintasa Quinasa 3/antagonistas & inhibidores , Glucógeno Sintasa Quinasa 3 beta , Células HL-60 , Humanos , Japón , Estructura Molecular , Extractos Vegetales/farmacología , Extractos Vegetales/uso terapéutico , Transducción de Señal , LevadurasRESUMEN
Renal cell carcinoma (RCC) accounts for approximately 2% of all cancer cases worldwide. Metastatic disease is often present at the time of diagnosis of RCC and its poor response to chemotherapy and radiotherapy causes poor prognosis. Immunotherapy is relatively effective for RCC, but the response rate is approximately 15-20%. Therefore, new therapeutic approaches are necessary for these patients with metastatic RCC. Recently, the mechanisms responsible for the growth of RCC have been clarified, and molecular targeted therapy has been developed. In this paper, we review the new molecular targeted therapeutic agents effective for RCC.
Asunto(s)
Antineoplásicos/administración & dosificación , Carcinoma de Células Renales/tratamiento farmacológico , Neoplasias Renales/tratamiento farmacológico , Proteínas Reguladoras de la Apoptosis , Bencenosulfonatos/administración & dosificación , Sistemas de Liberación de Medicamentos , Humanos , Indoles/administración & dosificación , Interferón beta/administración & dosificación , Péptidos y Proteínas de Señalización Intracelular/administración & dosificación , Liposomas , Proteínas Mitocondriales/administración & dosificación , Niacinamida/análogos & derivados , Compuestos de Fenilurea , Piridinas/administración & dosificación , Pirroles/administración & dosificación , Sirolimus/administración & dosificación , Sirolimus/análogos & derivados , Sorafenib , SunitinibAsunto(s)
Neoplasias Encefálicas/terapia , Óxido Ferrosoférrico/administración & dosificación , Glioma/terapia , Hipertermia Inducida/métodos , Animales , Neoplasias Encefálicas/inmunología , Linfocitos T CD8-positivos/inmunología , Modelos Animales de Enfermedad , Humanos , Hipertermia Inducida/instrumentación , Liposomas , Activación de Linfocitos , NanoestructurasRESUMEN
Interleukin (IL)-8 produced from glioblastoma is suggested to contribute to its own proliferation and progression. Since various external stimuli have been shown to increase intracellular Ca(2+) in glioma cells, we investigated Ca(2+) mobilization-dependent IL-8 expression and effect of cyclosporin A (CsA), an inhibitor of calcineurin (Cn), on the expression and invasive potential of human glioblastoma U251MG cells. Combined treatment with Ca(2+)-ionophore and phorbol-myristate-acetate (A23187/PMA) increased IL-8 mRNA and protein levels. This increase was suppressed by CsA and by another Cn inhibitor FK506. Luciferase reporter gene assay and electrophoretic mobility shift assay revealed that activation of p65-containing nuclear factor-kappaB was essential for A23187/PMA-dependent activation of IL-8 promoter. CsA suppressed the promoter activity by attenuating IkappaB-alpha degradation. U251MG cells expressed IL-8 receptors CXCR-1 and -2, and Matrigel invasion assay revealed that CsA attenuated A23187/PMA-dependent stimulation of invasive potential, probably by inhibiting IL-8 production. In addition, IL-8-dependent proliferation was also suppressed by CsA. Taken together, these results demonstrate the novel inhibitory effects of CsA on glioblastoma cell functions, suggesting CsA as a potential therapeutic adjuvant for glioma treatment.
Asunto(s)
Calcio/metabolismo , Ciclosporina/farmacología , Glioblastoma/patología , Interleucina-8/genética , Calcimicina/farmacología , División Celular/efectos de los fármacos , Línea Celular Tumoral , Glioblastoma/metabolismo , Humanos , Quinasa I-kappa B , FN-kappa B/metabolismo , Invasividad Neoplásica , Regiones Promotoras Genéticas , Proteínas Serina-Treonina Quinasas/metabolismo , ARN Mensajero/análisis , Receptores de Interleucina-8A/genética , Receptores de Interleucina-8B/genética , Acetato de Tetradecanoilforbol/farmacologíaRESUMEN
OBJECT: The goal of this study was to evaluate the neuroprotective effects conferred by long-term electrical stimulation of the subthalamic nucleus (STN) against degeneration of dopaminergic neurons by assessing motor functional and immunohistological findings in hemiparkinsonian rats. METHODS: In 13 of 25 rats, a concentric microelectrode was stereotactically implanted into the right STN under the guidance of extracellular microelectrode recording. After this had been done the animals were given an injection of 6-hydroxydopamine (6-OHDA) into the right striatum. Seven of the rats received continuous stimulation (frequency 130 Hz, intensity 80-100 microA) for 2 weeks (Group A); the other six did not receive any stimulation during this period (Group B). Twelve rats did not receive electrode implantation and underwent 6-OHDA injection only; these animals served as a control group (Group C). After 2 weeks, motor function in the rats was evaluated by conducting an amphetamine-induced rotation test. Finally, tyrosine hydroxylase-immunoreactive neurons in the pars compacta of the substantia nigra (SNc) were counted to evaluate the extent of degeneration of dopaminergic neurons. Ipsilateral rotation was significantly decreased in Group A, regardless of the effects of stimulation delivered during the test (p < 0.05). Rats in Group B demonstrated typical circling as did those in Group C, except that on stimulation Group B rats immediately stopped circling or changed direction. Tyrosine hydroxylase-immunoreactive neurons in the SNc were significantly preserved in the animals in Group A, whereas neurons in animals in Groups B and C were moderately depleted (p < 0.01). CONCLUSIONS: Acutely, STN stimulation improved rotation symmetry in rats with moderate SNc degeneration. When STN stimulation had been applied for the preceding 2 weeks, motor function was better and SNc neural degeneration was significantly milder. Subthalamic nucleus stimulation thus appears to protect dopaminergic neurons in this hemiparkinsonian model, in addition to improving motor function in these animals.
Asunto(s)
Terapia por Estimulación Eléctrica , Enfermedad de Parkinson/fisiopatología , Enfermedad de Parkinson/terapia , Receptores Dopaminérgicos/fisiología , Núcleo Subtalámico/fisiología , Adrenérgicos/administración & dosificación , Adrenérgicos/farmacología , Animales , Modelos Animales de Enfermedad , Humanos , Destreza Motora , Neuronas/patología , Oxidopamina/administración & dosificación , Oxidopamina/farmacología , Enfermedad de Parkinson/veterinaria , Ratas , Ratas Sprague-DawleyRESUMEN
In this study we demonstrated that heat shock protein (HSP) 70 expression by hyperthermia induced antitumor immunity in the T-9 rat glioma. Our hyperthermic system using magnetic nanoparticles induced necrotic cell death that correlated with HSP70 expression. We purified the HSP70-peptide complexes from the tumor after hyperthermia to investigate whether HSP70 was involved in the antitumor immunity, and we found that in the F344 rats immunized with T-9-derived HSP70 the tumor growth of T-9 was significantly suppressed. Tumor rejection assay after hyperthermic treatment of implanted T-9 cells with incorporated magnetite cationic liposomes (MCL) was performed to investigate whether antitumor immunity was induced by release of HSP70 from the necrotic cells in the F344 rat. Tumor growth was strongly suppressed in the rats subjected to hyperthermia of implanted T-9 cells, and 50% of rats were protected from challenge with T-9 cells. Immunogenicity was enhanced when the HSP70-overexpressing T-9 cells were killed via necrosis in rats by hyperthermia, after which all rats were completely protected from challenge with T-9 cells. Our hyperthermic system produces vaccination with HSP70-peptide via necrotic tumor cell death in vivo, resulting in antitumor immunity. This phenomenon, which may be termed in situ vaccination, has important implications for the development of novel antitumor therapies.
Asunto(s)
Glioma/terapia , Proteínas HSP70 de Choque Térmico/biosíntesis , Hipertermia Inducida/métodos , Hierro/administración & dosificación , Óxidos/administración & dosificación , Animales , Cationes , Femenino , Óxido Ferrosoférrico , Glioma/patología , Liposomas , Necrosis , Ratas , Ratas Endogámicas F344RESUMEN
Electrochemical properties of various para-substituted phenylthio-, phenylseleno-, and phenyltelluroglucopyranosides bearing acetyl, benzoyl, and benzyl protecting groups have been investigated to estimate the reactivity of chalcogenoglycosides toward electrochemical glycosylations. The oxidation potential of the chalcogenoglycosides shows good correlation with the ionization potential of chalcogen atoms, and decreases in the order thio-, seleno-, and telluroglycosides. It is also affected by the para-substituents, and the substitution effect correlates very well with the HOMO energy of para-substituted benzenechalcogenol and with the Hammett sigma p + value. Electrochemical glycosylation of telluroglycosides has been examined, and it was found that the use of an undivided cell is more effective than the use of a divided cell. Selective activation of the chalcogenoglycosides in bulk electrolysis based on their oxidation potentials has been examined, and the relative reactivity of the telluroglycosides can be estimated from their oxidation potentials. However, the relative reactivity of selenoglycosides in the preparative glycosylation was rather insensitive to the oxidation potential values.
Asunto(s)
Calcógenos/química , Técnicas Químicas Combinatorias , Glicósidos/química , Electroquímica , Glicosilación , Estructura Molecular , Oxidación-Reducción , Selenio/química , EstereoisomerismoRESUMEN
Various kinds of hyperthermic treatment for malignant glioma had been inhibited due to both their incomplete feverish action and strict cooling effect of the brain. The author shows an effective results of hyperthermia for the treatment of malignant glioma in an in vivo study using stick type carboxymethylcellulose (CMC)-magnetite, a newly manufactured magnetite-product. A stick type CMC-magnetite, containing magnetite particles, was inserted into the T-9 glioma in the rat brain stereotactically, and the rats were exposed to an alternative magnetic field (AMF). The application time of AMF, which measured 88.9 kHz and 380 Oe, was 30 min a day. The rats were divided into three groups: three AMF applications (group I), one AMF application (group II) and no application but only injection of CMC-magnetite (control). As a result, the mean survival in days of these three groups measured 44.2+/-10.9 (group I), 17.0+/-1.5 (group II) and 14.4+/-1.5 (control). This investigation showed both significant effectiveness in attacking malignant glioma and significant prolonging of the survival time in rats. It is also a characteristic feature of the magnetite particles to spread through the tumor diffusely after three applications of AMF. This feature seemed to be one of the main factors that caused greater hyperthermic effect on glioma in this study. This method of hyperthermic treatment could be a useful strategy in the treatment of malignant glioma.
Asunto(s)
Neoplasias Encefálicas/terapia , Glioma/terapia , Hipertermia Inducida/métodos , Hierro , Óxidos , Animales , Neoplasias Encefálicas/patología , Óxido Ferrosoférrico , Glioma/patología , Ratas , Ratas Endogámicas F344 , Análisis de Supervivencia , Factores de TiempoRESUMEN
Peroxisome proliferator-activated receptor gamma (PPARgamma) belongs to a superfamily of thyroid / steroid hormone receptors and regulates transcription of their target genes in a ligand-dependent manner. Recently, PPARgamma was reported to be expressed in several cell lines derived from breast, colon, stomach and lung cancers. Activation of PPARgamma by its ligand inhibits the growth of these tumor cells, suggesting that PPARgamma ligand is a potential anti-cancer agent in PPARgamma-expressing tumors. However, its expression in brain tumors has not been studied. We thus studied the expression in glioma samples with different pathological stages from 20 patients. It was demonstrated that 95% of the glioma tissue expressed PPARgamma mRNA. The results prompted us to study whether PPARgamma ligand affects the growth of cell lines derived from brain tumors. The receptor expression was studied in 9 cell lines either derived from malignant glioma or neuroblastoma. The expression was detected in a glioma cell line SK-MG-1 and in a neuroblastoma cell line NB-1. Addition of one of the PPARgamma ligands, troglitazone, induced growth inhibition in both cell lines. Further analyses revealed that this growth inhibition is caused by a PPARgamma-mediated induction of apoptosis. These results suggest that PPARgamma ligands could be a potential therapeutic agent for the treatment of the brain tumors expressing this receptor.