RESUMEN
The short-term effectiveness of tolvaptan (TLV) for heart failure (HF) has been established, but the long-term effects are controversial. We investigated HF patients who could not discontinue both loop diuretics and TLV at discharge from AURORA (Acute Heart Failure Registry in Osaka Rosai Hospital). We compared the following factors at discharge between the RH group, consisting of patients with rehospitalizations due to worsening HF within 1 year after discharge (RH group), and non-RH group: age, gender, blood pressure, history of HF admission, electrocardiogram and echocardiographic parameters, atherosclerotic risk factors, laboratory data, and medications. Furthermore, we compared the effects of long-term low-dose TLV (≤ 7.5 mg/day) and high-dose TLV on HF rehospitalizations. The RH group consisted of 81 patients (58.7%). A multivariate analysis revealed that a history of HF admission and the TLV dose were independently and significantly associated with 1-year HF rehospitalizations. A receiver operating characteristic curve revealed that 7.5 mg of TLV was a suitable cutoff value for 1-year HF rehospitalizations. The Kaplan-Meier curves demonstrated that the HF rehospitalization free ratio was significantly higher in the low-dose TLV group (≤ 7.5 mg/day) than in high-dose TLV group over 1 year.In conclusion, the TLV dose, in addition to a history of HF admission, was associated with 1-year HF rehospitalizations in diuretic-dependent HF patients. In these patients, long-term low-dose TLV (≤ 7.5 mg/day) may be favorable for reducing HF rehospitalizations.
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Antagonistas de los Receptores de Hormonas Antidiuréticas/administración & dosificación , Insuficiencia Cardíaca/tratamiento farmacológico , Readmisión del Paciente , Tolvaptán/administración & dosificación , Anciano , Anciano de 80 o más Años , Estudios de Cohortes , Esquema de Medicación , Femenino , Insuficiencia Cardíaca/complicaciones , Insuficiencia Cardíaca/mortalidad , Humanos , Japón , Estimación de Kaplan-Meier , Masculino , Curva ROC , Sistema de Registros , Inhibidores del Simportador de Cloruro Sódico y Cloruro Potásico/administración & dosificaciónAsunto(s)
Potenciales de Acción , Procedimientos Quirúrgicos Cardíacos/efectos adversos , Atrios Cardíacos/fisiopatología , Frecuencia Cardíaca , Válvula Mitral/cirugía , Taquicardia Supraventricular/etiología , Ablación por Catéter , Electrocardiografía , Técnicas Electrofisiológicas Cardíacas , Atrios Cardíacos/cirugía , Humanos , Válvula Mitral/diagnóstico por imagen , Válvula Mitral/fisiopatología , Recurrencia , Estudios Retrospectivos , Taquicardia Supraventricular/diagnóstico , Taquicardia Supraventricular/fisiopatología , Taquicardia Supraventricular/cirugía , Factores de Tiempo , Resultado del TratamientoRESUMEN
SCOPE: Inflammation plays a key role in obesity-related pathologies such as insulin resistance and type 2 diabetes. Hypertrophied adipocytes trigger the enhancement of macrophage infiltration and the release of various proinflammatory factors in obese adipose tissue. In this study, we examined whether auraptene, a citrus-fruit-derived compound, could suppress the production of inflammatory factors that mediate the interaction between adipocytes and macrophages. METHODS AND RESULTS: Experiments using a co-culture system of 3T3-L1 adipocytes and RAW264 macrophages showed that auraptene reduced the production of nitric oxide and tumor necrosis factor-α. In RAW264 macrophages, auraptene also suppressed the inflammation induced by either LPS or the conditioned medium derived from 3T3-L1 adipocytes. In addition, auraptene inhibited the phosphorylation of the p38 mitogen-activated protein kinase and suppressed the production of proinflammatory mediators in activated macrophages. CONCLUSION: Our findings indicate that auraptene exhibits anti-inflammatory properties by suppressing the production of inflammatory factors that mediate the interaction between adipocytes and macrophages, suggesting that auraptene is a valuable food-derived compound with a potential to attenuate chronic inflammation in adipose tissue and to improve obesity-related insulin resistance.
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Antiinflamatorios/farmacología , Cumarinas/farmacología , Macrófagos/efectos de los fármacos , Extractos Vegetales/farmacología , Proteínas Quinasas p38 Activadas por Mitógenos/genética , Células 3T3-L1 , Adipocitos/efectos de los fármacos , Adipocitos/metabolismo , Tejido Adiposo/efectos de los fármacos , Tejido Adiposo/metabolismo , Animales , Línea Celular Tumoral , Quimiocina CCL2/metabolismo , Citrus/química , Técnicas de Cocultivo , Medios de Cultivo Condicionados , Frutas/química , Inflamación/tratamiento farmacológico , Inflamación/patología , Resistencia a la Insulina , Lipopolisacáridos/efectos adversos , Macrófagos/metabolismo , Ratones , Óxido Nítrico/antagonistas & inhibidores , Óxido Nítrico/metabolismo , Obesidad/metabolismo , Fosforilación , Factor de Necrosis Tumoral alfa/antagonistas & inhibidores , Factor de Necrosis Tumoral alfa/biosíntesis , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismoRESUMEN
Fruits and vegetables contain numerous antioxidants, such as carotenoids. Recent epidemiologic studies have demonstrated that a high dietary consumption of fruit and vegetables rich in carotenoids or with high serum carotenoid concentrations results in lower risks of certain cancers, diabetes, and cardiovascular disease. These results indicate that absorbed carotenoids are stored in various organs. Previously, we found that ß-cryptoxanthin, found especially in Satsuma mandarin (Citrus unshiu MARC.), is easily absorbed and can also survive for a relatively long time in the human body; however, little is known about the absorption, storage, and tissue distribution of ß-cryptoxanthin. In this study, we measured serum and the content of ß-cryptoxanthin in several rat tissues after chronic ingestion of Satsuma mandarin extract rich in ß-cryptoxanthin. Rats were fed a standard commercial diet containing Satsuma mandarin extract (containing ß-cryptoxanthin at 11.7 mg/kg diet) for eight weeks. After 3 h of fasting, serum, liver, spleen, kidney, lung, heart, testis, brain, and epididymal fat were collected. The concentrations of ß-cryptoxanthin in serum and tissues were evaluated by high-performance liquid chromatography. There was a wide range in the tissue levels of ß-cryptoxanthin; liver had the greatest value, with 1265.3 ng/g tissue, followed by spleen, kidney, lung, heart, brain, and testis. Epididymal fat had the lowest value, with 6.99 ng/g tissue. ß-Cryptoxanthin was also detected in serum in a concentration of 5.76 ng/mL. These results indicate that ß-cryptoxanthin is easily absorbed and accumulated in several organs.
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Carotenoides/farmacocinética , Citrus , Extractos Vegetales/farmacocinética , Absorción , Animales , Carotenoides/administración & dosificación , Carotenoides/sangre , Extractos Vegetales/administración & dosificación , Extractos Vegetales/sangre , Ratas , Ratas Wistar , Distribución TisularRESUMEN
The activation of mitogen-activated protein/extracellular signal-regulated kinase (MEK) is well known to be associated with tumor invasion and metastasis. We previously reported that a polymethoxyflavonoid, nobiletin (5,6,7,8,3',4'-hexamethoxyflavone), derived from Citrus depressa (Hayata), inhibits the phosphorylation of MEK and thereby suppresses matrix metalloproteinase (MMP) expression in a tumor-metastasis stimulator, 12-O-tetradecanoyl phorbol 13-acetate (TPA)-stimulated human fibrosarcoma HT-1080 cells [Mol. Cancer Ther. 3 (2004) 839-847]. In the present study, we investigated whether or not nobiletin might directly influence MEK activity to exhibit the antitumor metastatic activity in vitro. MEK kinase assay using myelin basic protein (MBP) revealed that TPA-augmented MEK activity in HT-1080 cells and that the augmented MEK activity was diminished by nobiletin treatment. In addition, the decrease in MEK activity caused by nobiletin was found to inhibit the phosphorylation of extracellular regulated kinases (ERK), a downstream signaling factor for MEK. Furthermore, when an immunoprecipitated active MEK was incubated with nobiletin under cell-free conditions, nobiletin was found to inhibit the MEK-mediated MBP phosphorylation. In contrast, other citrus polymethoxyflavonoids such as 3-hydroxy-5,6,7,8,3',4'-hexamethoxyflavone (natsudaidain) and 3,5,6,7,8,3',4'-heptamethoxyflavone, did not directly inhibit MEK activity. Moreover, natsudaidain and 3,5,6,7,8,3',4'-heptamethoxyflavone exhibited no or less inhibitory effect than nobiletin on the proMMP-9/progelatinase B production in HT-1080 cells. Therefore, these results provide novel evidence that nobiletin directly inhibits MEK activity and decreases the sequential phosphorylation of ERK, exhibiting the antitumor metastatic activity by suppressing MMP expression in HT-1080 cells.
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Antineoplásicos/administración & dosificación , Fibrosarcoma/metabolismo , Fibrosarcoma/secundario , Flavonas/administración & dosificación , Proteínas Quinasas Activadas por Mitógenos/antagonistas & inhibidores , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Citrus/metabolismo , Relación Dosis-Respuesta a Droga , Activación Enzimática/efectos de los fármacos , Fibrosarcoma/patología , Humanos , Extractos Vegetales/administración & dosificaciónRESUMEN
Citrus fruit compounds have many health-enhancing effects. In this study, using a luciferase ligand assay system, we showed that citrus auraptene activates peroxisome proliferator-activated receptor (PPAR)-alpha and PPARgamma. Auraptene induced up-regulation of adiponectin expression and increased the ratio of the amount of high-molecular-weight multimers of adiponectin to the total adiponectin. In contrast, auraptene suppressed monocyte chemoattractant protein (MCP)-1 expression in 3T3-L1 adipocytes. Experiments using PPARgamma antagonist demonstrated that these effects on regulation of adiponectin and MCP-1 expression were caused by PPARgamma activations. The results indicate that auraptene activates PPARgamma in adipocytes to control adipocytekines such as adiponectin and MCP-1 and suggest that the consumption of citrus fruits, which contain auraptene can lead to a partial prevention of lipid and glucose metabolism abnormalities.
Asunto(s)
Adipocitos/metabolismo , Quimiocina CCL2/metabolismo , Citrus/metabolismo , Cumarinas/administración & dosificación , Receptores Activados del Proliferador del Peroxisoma/agonistas , Extractos Vegetales/administración & dosificación , Células 3T3-L1 , Adipocitos/efectos de los fármacos , Animales , Relación Dosis-Respuesta a Droga , RatonesRESUMEN
Acne vulgaris is characterized by excess sebum production, and apart from all-trans retinoic acid (atRA) or 13-cis retinoic acid (13-cisRA), there are few effective agents for acne therapy that directly suppresses sebaceous lipogenesis. In this study, we demonstrated that topical application of a citrus polymethoxy flavonoid, nobiletin, to hamster auricles decreased skin surface triacylglycerols (TG) level and the size of sebaceous glands along with inhibition of diacylglycerol acyltransferase (DGAT)-dependent TG synthesis and sebocyte proliferation. The inhibitory actions were similar to that observed with atRA and 13-cisRA in hamster sebocytes. The antilipogenic and antiproliferative actions of nobiletin were also reproduced in UVB (5.4 kJ/m2)-irradiated hamsters, which showed aberrant enhancement of sebum accumulation and sebaceous enlargement. Furthermore, nobiletin, but not 13-cisRA, augmented sebum excretion along with increases in intracellular cAMP level, protein kinase A (PKA) activation, and apoptosis-independent phosphatidylserine (PS) externalization in cell membrane. These phenomena were reproduced by forskolin and inhibited by a PKA inhibitor, H-89. These results provide early evidence that nobiletin is an effective candidate for acne therapy through mechanisms that include the inhibition of DGAT-dependent TG synthesis and sebocyte proliferation, and the progression of apoptosis-independent and PS-externalization-dependent sebum excretion by PKA activation.
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Flavonas/uso terapéutico , Flavonoides/uso terapéutico , Sebo/citología , Sebo/metabolismo , Animales , Antioxidantes/uso terapéutico , Membrana Celular/metabolismo , Proliferación Celular , Cricetinae , Proteínas Quinasas Dependientes de AMP Cíclico/metabolismo , Diacilglicerol O-Acetiltransferasa/metabolismo , Isoquinolinas/farmacología , Modelos Biológicos , Fosfatidilserinas/química , Sulfonamidas/farmacología , Tretinoina/farmacología , Triglicéridos/metabolismoRESUMEN
To investigate the relationship between a carotenoid profile and gene expression for carotenoid cleavage dioxygenases, three citrus varieties that exhibit different 9-cis-violaxanthin levels in their juice sacs, Satsuma mandarin (Citrus unshiu Marc.; a variety accumulating a low level of 9-cis-violaxanthin), Valencia orange (Citrus sinensis Osbeck; variety accumulating a high level of 9-cis-violaxanthin), and Lisbon lemon (Citrus limon Burm.f.; a variety accumulating an undetectable level of 9-cis-violaxanthin) were used. Three cDNAs (CitCCD1, CitNCED2, and CitNCED3) were cloned. The recombinant CitCCD1 protein cleaved beta-cryptoxanthin, zeaxanthin, and all-trans-violaxanthin at the 9-10 and 9'-10' positions and 9-cis-violaxanthin at the 9'-10' position. The recombinant CitNCED2 and CitNCED3 proteins cleaved 9-cis-violaxanthin at the 11-12 position to form xanthoxin, a precursor of abscisic acid (ABA). The gene expression of CitCCD1 increased in the flavedos and juice sacs of the three varieties during maturation. In Satsuma mandarin, the gene expression of CitNCED2 and CitNCED3 increased noticeably, accompanying a massive accumulation of ABA in the flavedo and juice sacs. In Valencia orange, the gene expression of CitNCED3 increased with a slight elevation of the ABA level in the flavedo, whereas neither the gene expression of CitNCED2 nor the ABA level increased noticeably in the juice sacs. In Lisbon lemon, the gene expression of CitNCED2 increased remarkably, accompanying increases in the ABA level in the flavedo and juice sacs. These results suggest that, in the juice sacs, the efficient cleavage reaction for ABA synthesis reduces the 9-cis-violaxanthin level in Satsuma mandarin and Lisbon lemon, whereas the low cleavage reaction maintains the predominant 9-cis-violaxanthin accumulation in Valencia orange.
Asunto(s)
Carotenoides/metabolismo , Citrus/metabolismo , Dioxigenasas/metabolismo , Frutas/metabolismo , Oxigenasas/metabolismo , Ácido Abscísico/metabolismo , Citrus/genética , Citrus/crecimiento & desarrollo , ADN Complementario/química , Frutas/crecimiento & desarrollo , Regulación del Desarrollo de la Expresión Génica , Regulación de la Expresión Génica de las Plantas , Genes de Plantas , Proteínas de Plantas , Proteínas Recombinantes/química , Xantófilas/metabolismoRESUMEN
Recent epidemiological studies have demonstrated that high dietary consumption of fruit and vegetables results in lower risks of diabetes. In this study, we investigated the effects of chronic administration of fruit extract (Citrus unshiu Marc.) on glucose tolerance in GK rats, a model of type 2 diabetes. After 10 weeks administration of the fruit extract, intraperitoneal glucose tolerance tests revealed significant decrements of blood glucose levels after glucose loading. Our findings further support an advantageous association of fruit consumption with diabetes.
Asunto(s)
Diabetes Mellitus Tipo 2/dietoterapia , Modelos Animales de Enfermedad , Frutas/química , Extractos Vegetales/administración & dosificación , Extractos Vegetales/farmacología , Animales , Glucemia/metabolismo , Peso Corporal/efectos de los fármacos , Citrus/química , Diabetes Mellitus Tipo 2/sangre , Prueba de Tolerancia a la Glucosa , Masculino , RatasRESUMEN
Flavonoids from medicinal plants have been therapeutically administered for cancer therapy. We recently reported that nobiletin (5,6,7,8,3',4'-hexamethoxy flavone) exhibits novel antitumor invasive activities by suppressing the production of pro-matrix metalloproteinases (proMMPs) and augmenting the expression of tissue inhibitor of metalloproteinases-1 (TIMP-1) in vivo and in vitro. In the present study, intracellular target molecules associated with the actions of nobiletin against tumor invasion were identified. Nobiletin inhibited the phosphorylation of mitogen-activated protein/extracellular signal-regulated kinase (MEK) 1/2, but not the activity of Ras or the phosphorylation of Raf. Moreover, a MEK1/2 inhibitor, U0126, mimicked nobiletin's ability to decrease the production of proMMPs-1 and 9 in human fibrosarcoma HT-1080 cells stimulated by 12-O-tetradecanoyl phorbol-13-acetate (TPA). In addition, neither the activity of phosphatidylinositol 3-kinase (PI3K) nor the phosphorylation of Akt was influenced by nobiletin. However, nobiletin was found to augment the phosphorylation of c-Jun NH2-terminal kinase (JNK), a downstream signal factor of the PI3K-Akt pathway, in TPA-treated HT-1080 cells. A similar augmentation of JNK phosphorylation was observed on treatment with a PI3K inhibitor, LY-294002. Furthermore, nobiletin enhancement of TIMP-1 production in TPA-stimulated HT-1080 cells was found to be diminished by adding a JNK inhibitor, SP600125. Moreover, protein kinase C (PKC) inhibitor experiments showed that PKCbetaII/epsilon were associated with the nobiletin-mediated augmentation of JNK phosphorylation. Therefore, these results introduce novel evidence that the antitumor effects of nobiletin are finely regulated by the following intracellular mechanisms: (1) the inhibition of MEK1/2 activity is involved in the suppression of MMP expression and (2) the activation of the novel PKCbetaII/epsilon-JNK pathway is associated with the augmentation of TIMP-1 expression.
Asunto(s)
Antineoplásicos/farmacología , Flavonas/farmacología , Proteínas Quinasas JNK Activadas por Mitógenos/metabolismo , Quinasas de Proteína Quinasa Activadas por Mitógenos/metabolismo , Proteína Quinasa C/metabolismo , Acetato de Tetradecanoilforbol/análogos & derivados , Antracenos/farmacología , Butadienos/farmacología , Línea Celular Tumoral , Colagenasas/metabolismo , Activación Enzimática/efectos de los fármacos , Precursores Enzimáticos/metabolismo , Humanos , Proteínas Quinasas JNK Activadas por Mitógenos/análisis , Proteínas Quinasas JNK Activadas por Mitógenos/efectos de los fármacos , MAP Quinasa Quinasa 1/metabolismo , MAP Quinasa Quinasa 2/metabolismo , Metaloproteinasa 9 de la Matriz , Invasividad Neoplásica , Nitrilos/farmacología , Fosfatidilinositol 3-Quinasas/metabolismo , Fosforilación/efectos de los fármacos , Proteína Quinasa C beta , Proteínas Serina-Treonina Quinasas/metabolismo , Proteínas Proto-Oncogénicas/metabolismo , Proteínas Proto-Oncogénicas c-akt , Acetato de Tetradecanoilforbol/farmacología , Inhibidor Tisular de Metaloproteinasa-1/metabolismo , Quinasas raf/metabolismo , Proteínas ras/metabolismoRESUMEN
We isolated from soybean miso 8-hydroxyglycitein and 6-hydroxydaidzein as DPPH-radical scavengers, and elucidated their chemical structures by mass spectrometric, and (1)H- and (13)C-NMR spectrosopic analyses. These compounds showed DPPH-radical scavenging activity as high as that of alpha-tocopherol, 8-hydroxygenistein and 8-hydroxydaidzein. This is the first report of the isolation of 8-hydroxyglycitein from a natural source.
Asunto(s)
Glycine max/química , Isoflavonas/aislamiento & purificación , Compuestos de Bifenilo , Proliferación Celular/efectos de los fármacos , Depuradores de Radicales Libres/química , Depuradores de Radicales Libres/aislamiento & purificación , Depuradores de Radicales Libres/farmacología , Células HL-60 , Humanos , Hidrazinas , Isoflavonas/química , Isoflavonas/farmacología , Estructura Molecular , Resonancia Magnética Nuclear Biomolecular , Fitoestrógenos/química , Fitoestrógenos/aislamiento & purificación , Fitoestrógenos/farmacología , PicratosRESUMEN
The relationship between carotenoid accumulation and the expression of carotenoid biosynthetic genes during fruit maturation was investigated in three citrus varieties, Satsuma mandarin (Citrus unshiu Marc.), Valencia orange (Citrus sinensis Osbeck), and Lisbon lemon (Citrus limon Burm.f.). We cloned the cDNAs for phytoene synthase (CitPSY), phytoene desaturase (CitPDS), zeta-carotene (car) desaturase (CitZDS), carotenoid isomerase (CitCRTISO), lycopene beta-cyclase (CitLCYb), beta-ring hydroxylase (CitHYb), zeaxanthin (zea) epoxidase (CitZEP), and lycopene epsilon-cyclase (CitLCYe) from Satsuma mandarin, which shared high identities in nucleotide sequences with Valencia orange, Lisbon lemon, and other plant species. With the transition of peel color from green to orange, the change from beta,epsilon-carotenoid (alpha-car and lutein) accumulation to beta,beta-carotenoid (beta-car, beta-cryptoxanthin, zea, and violaxanthin) accumulation was observed in the flavedos of Satsuma mandarin and Valencia orange, accompanying the disappearance of CitLCYe transcripts and the increase in CitLCYb transcripts. Even in green fruit, high levels of beta,epsilon-carotenoids and CitLCYe transcripts were not observed in the juice sacs. As fruit maturation progressed in Satsuma mandarin and Valencia orange, a simultaneous increase in the expression of genes (CitPSY, CitPDS, CitZDS, CitLCYb, CitHYb, and CitZEP) led to massive beta,beta-xanthophyll (beta-cryptoxanthin, zea, and violaxanthin) accumulation in both the flavedo and juice sacs. The gene expression of CitCRTISO was kept low or decreased in the flavedo during massive beta,beta-xanthophyll accumulation. In the flavedo of Lisbon lemon and Satsuma mandarin, massive accumulation of phytoene was observed with a decrease in the transcript level for CitPDS. Thus, the carotenoid accumulation during citrus fruit maturation was highly regulated by the coordination of the expression among carotenoid biosynthetic genes. In this paper, the mechanism leading to diversity in beta,beta-xanthophyll compositions between Satsuma mandarin and Valencia orange was also discussed on the basis of the substrate specificity of beta-ring hydroxylase and the balance of expression between upstream synthesis genes (CitPSY, CitPDS, CitZDS, and CitLCYb) and downstream synthesis genes (CitHYb and CitZEP).
Asunto(s)
Carotenoides/biosíntesis , Citrus/genética , Enzimas/genética , Frutas/genética , Proteínas de Plantas/genética , Transferasas Alquil y Aril/genética , Transferasas Alquil y Aril/metabolismo , Secuencia de Bases , Carotenoides/química , Citrus/enzimología , Citrus/crecimiento & desarrollo , Citrus sinensis/enzimología , Citrus sinensis/genética , Citrus sinensis/crecimiento & desarrollo , Clonación Molecular , ADN Complementario/química , ADN Complementario/genética , Enzimas/metabolismo , Frutas/enzimología , Frutas/crecimiento & desarrollo , Regulación Enzimológica de la Expresión Génica , Regulación de la Expresión Génica de las Plantas , Geranilgeranil-Difosfato Geranilgeraniltransferasa , Liasas Intramoleculares/genética , Liasas Intramoleculares/metabolismo , Datos de Secuencia Molecular , Oxidorreductasas/genética , Oxidorreductasas/metabolismo , Pigmentos Biológicos/biosíntesis , Pigmentos Biológicos/química , Proteínas de Plantas/metabolismo , Análisis de Secuencia de ADN , Especificidad por Sustrato , Xantófilas/biosíntesis , Xantófilas/químicaRESUMEN
The inhibitory effects of dietary feeding of citrus nobiletin on azoxymethane (AOM)-induced rat colon carcinogenesis using a long-term bioassay were investigated. Five-week old male F344 rats were initiated with two weekly subcutaneous injections of AOM (20 mg/kg bw) to induce colonic tumors. They were also given the diets containing 0.01% or 0.05% nobiletin for 34 weeks, starting one week after the last dosing of AOM. At the end of the study, the incidence of colonic adenocarcinoma were 67% in the AOM alone group, 55% in the AOM-->0.01% nobiletin group, 35% (p<0.05) in the AOM-->0.05% nobiletin group. Also, nobiletin feeding reduced the cell-proliferation activity, increased the apoptotic index, and decreased the prostaglandin E2 content in colonic adenocarcinoma and/or colonic mucosa. These findings might suggest that citrus nobiletin has chemopreventive ability against AOM-induced rat colon carcinogenesis.
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Anticarcinógenos/farmacología , Citrus , Neoplasias del Colon/prevención & control , Flavonas/farmacología , Animales , Apoptosis/efectos de los fármacos , Azoximetano , Neoplasias del Colon/inducido químicamente , Dinoprostona/metabolismo , Mucosa Intestinal/efectos de los fármacos , Mucosa Intestinal/metabolismo , Mucosa Intestinal/patología , Masculino , Fitoterapia , Poliaminas/metabolismo , Antígeno Nuclear de Célula en Proliferación/análisis , Ratas , Ratas Endogámicas F344RESUMEN
Medicinal plants contain pharmacological substances including flavonoids, and their extracts have been therapeutically administered for cancer therapy in vitro and in vivo. We investigated the efficacy of a polymethoxy flavonoid, nobiletin, from Citrus depressa on tumor invasion in vitro. Nobiletin inhibited the tumor-invasive activity of human fibrosarcoma HT-1080 cells in the Matrigel model, whereas a similar inhibition was observed upon exogenously adding tissue inhibitors of metalloproteinases (TIMPs)-1 and -2. The gene expression and production of pro-matrix metalloproteinase 9 (proMMP-9)/progelatinase B and proMMP-1/interstitial procollagenase were specifically suppressed by nobiletin in 12-O-tetradecanoylphorbol 13-acetate-stimulated HT-1080 cells. In contrast, the gene expression and production of TIMP-1, but not TIMP-2, were enhanced by nobiletin. We also demonstrated that nobiletin suppressed the 12-O-tetradecanoylphorbol 13-acetate-induced binding activity of activator protein-1. Furthermore, a phosphatidylinositol 3-kinase inhibitor, LY-294002, was found to mimic the different actions of nobiletin on the production of proMMP-9 and TIMP-1. These results suggest that nobiletin inhibits tumor cell invasive activity not only by suppressing the expression of MMPs but also augmenting TIMP-1 production in tumor cells, and that the nobiletin-mediated inhibition of activator protein-1 binding activity is at least partly involved in the suppression of MMP expression. Furthermore, we suggest a possible mechanism by which nobiletin may interfere in the phosphatidylinositol 3-kinase pathway, which divergently regulates the production of MMP and TIMP-1.