RESUMEN
Tomatidine is isolated from the leaves and green fruits of some plants in the Solanaceae family, and has been reported to have anti-inflammatory and antitumor effects. Previous studies have found that tomatidine decreases hepatic lipid accumulation via regulation of vitamin D receptor and activation of AMP-activated protein kinase (AMPK) phosphorylation. However, whether tomatidine reduces weight gain and improves nonalcoholic fatty liver disease (NAFLD) remains unclear. In this study, we investigated how tomatidine ameliorates NAFLD in obese mice and evaluated the regulatory mechanism of lipogenesis in hepatocytes. Male C57BL/6 mice were fed a high-fat diet (HFD) to induce obesity and NAFLD, and treated with tomatidine via intraperitoneal injection. In vitro, FL83B hepatocytes were incubated with oleic acid and treated with tomatidine to evaluate lipid metabolism. Our results demonstrate that tomatidine significantly decreases body weight and fat weight compared to HFD-fed mice. In addition, tomatidine decreased hepatic lipid accumulation and improved hepatocyte steatosis in HFD-induced obese mice. We also found that tomatidine significantly regulated serum total cholesterol, fasting blood glucose, low-density lipoprotein, and triglyceride levels, but the serum high-density lipoprotein and adiponectin concentrations were higher than in the HFD-fed obese mice. In vivo and in vitro, tomatidine significantly suppressed the expression of fatty acid synthase and transcription factors involved in lipogenesis, and increased the expression of adipose triglyceride lipase. Tomatidine promoted the sirtuin 1 (sirt1)/AMPK signaling pathway to increase lipolysis and ß-oxidation in fatty liver cells. These findings suggest that tomatidine potentially ameliorates obesity and acts against hepatic steatosis by regulating lipogenesis and the sirt1/AMPK pathway.
Asunto(s)
Antiinflamatorios/uso terapéutico , Enfermedad del Hígado Graso no Alcohólico/tratamiento farmacológico , Enfermedad del Hígado Graso no Alcohólico/etiología , Obesidad/complicaciones , Tomatina/análogos & derivados , Animales , Masculino , Ratones , Ratones Endogámicos C57BL , Enfermedad del Hígado Graso no Alcohólico/patología , Tomatina/uso terapéuticoRESUMEN
Tomatidine is isolated from the fruits of tomato plants and found to have anti-inflammatory effects in macrophages. In the present study, we investigated whether tomatidine suppresses airway hyperresponsiveness (AHR) and eosinophil infiltration in asthmatic mice. BALB/c mice were sensitized with ovalbumin and treated with tomatidine by intraperitoneal injection. Airway resistance was measured by intubation analysis as an indication of airway responsiveness, and histological studies were performed to evaluate eosinophil infiltration in lung tissue. Tomatidine reduced AHR and decreased eosinophil infiltration in the lungs of asthmatic mice. Tomatidine suppressed Th2 cytokine production in bronchoalveolar lavage fluid. Tomatidine also blocked the expression of inflammatory and Th2 cytokine genes in lung tissue. In vitro, tomatidine inhibited proinflammatory cytokines and CCL11 production in inflammatory BEAS-2B bronchial epithelial cells. These results indicate that tomatidine contributes to the amelioration of AHR and eosinophil infiltration by blocking the inflammatory response and Th2 cell activity in asthmatic mice.
Asunto(s)
Asma/tratamiento farmacológico , Hiperreactividad Bronquial/tratamiento farmacológico , Citocinas/inmunología , Células Th2/efectos de los fármacos , Tomatina/análogos & derivados , Animales , Asma/inmunología , Hiperreactividad Bronquial/inmunología , Citocinas/análisis , Modelos Animales de Enfermedad , Eosinófilos/efectos de los fármacos , Eosinófilos/fisiología , Femenino , Pulmón/efectos de los fármacos , Pulmón/metabolismo , Ratones , Ratones Endogámicos BALB C , Células Th2/inmunología , Tomatina/farmacología , Tomatina/uso terapéuticoRESUMEN
PURPOSE OF REVIEW: Here, we discuss a recently developed experimental strategy for discovering small molecules with potential to prevent and treat skeletal muscle atrophy. RECENT FINDINGS: Muscle atrophy involves and requires widespread changes in skeletal muscle gene expression, which generate complex but measurable patterns of positive and negative changes in skeletal muscle mRNA levels (a.k.a. mRNA expression signatures of muscle atrophy). Many bioactive small molecules generate their own characteristic mRNA expression signatures, and by identifying small molecules whose signatures approximate mirror images of muscle atrophy signatures, one may identify small molecules with potential to prevent and/or reverse muscle atrophy. Unlike a conventional drug discovery approach, this strategy does not rely on a predefined molecular target but rather exploits the complexity of muscle atrophy to identify small molecules that counter the entire spectrum of pathological changes in atrophic muscle. We discuss how this strategy has been used to identify two natural compounds, ursolic acid and tomatidine, that reduce muscle atrophy and improve skeletal muscle function. SUMMARY: Discovery strategies based on mRNA expression signatures can elucidate new approaches for preserving and restoring muscle mass and function.
Asunto(s)
Proteínas Musculares/metabolismo , Músculo Esquelético/patología , Atrofia Muscular/tratamiento farmacológico , ARN Mensajero/metabolismo , Tomatina/análogos & derivados , Triterpenos/uso terapéutico , Descubrimiento de Drogas/métodos , Expresión Génica , Humanos , Proteínas Musculares/genética , Músculo Esquelético/metabolismo , Transducción de Señal , Tomatina/uso terapéutico , Ácido UrsólicoRESUMEN
αTomatine is a glycoalkaloid that occurs naturally in tomatoes (Lycopersicon esculentum). In the present study, the effects of αtomatine on human myeloid leukemia HL60 cells were investigated. Treatment of HL60 cells with αtomatine resulted in growth inhibition and apoptosis in a concentrationdependent manner. Tomatidine, the aglycone of tomatine had little effect on the growth and apoptosis of HL60 cells. Growth inhibition and apoptosis induced by αtomatine in HL60 cells was partially abrogated by addition of cholesterol indicating that interactions between αtomatine and cell membraneassociated cholesterol may be important in mediating the effect of αtomatine. Activation of nuclear factorκB by the phorbol ester, 12Otetradecanoylphorbol13acetate failed to prevent apoptosis in HL60 cells treated with αtomatine. In animal experiments, it was found that treatment of mice with αtomatine inhibited the growth of HL60 xenografts in vivo. Results from the present study indicated that αtomatine may have useful antileukemia activities.
Asunto(s)
Apoptosis/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Tomatina/análogos & derivados , Animales , Peso Corporal/efectos de los fármacos , Colesterol/farmacología , Femenino , Células HL-60 , Humanos , Leucemia Mieloide/tratamiento farmacológico , Leucemia Mieloide/metabolismo , Leucemia Mieloide/patología , Ratones , Ratones SCID , FN-kappa B/metabolismo , Acetato de Tetradecanoilforbol/farmacología , Tomatina/química , Tomatina/farmacología , Tomatina/uso terapéutico , Trasplante HeterólogoRESUMEN
Alpha (α)-tomatine, a major saponin found in tomato has been shown to inhibit the growth of androgen-independent prostate cancer PC-3 cells. The effects of α-tomatine in combination with the chemotherapeutic agent paclitaxel against PC-3 cells were investigated in the present study. Combined treatment with a sub-toxic dose of α-tomatine and paclitaxel significantly decreased cell viability with concomitant increase in the percentage of apoptotic PC-3 cells. The combined treatment, however, had no cytotoxic effect on the non-neoplastic prostate RWPE-1 cells. Apoptosis of PC-3 cells was accompanied by the inhibition of PI3K/Akt pro-survival signaling, an increase in the expression of the pro-apoptotic protein BAD but a decrease in the expressions of anti-apoptotic proteins, Bcl-2 and Bcl-xL. Results from a mouse xenograft model showed the combined treatment completely suppressed subcutaneous tumor growth without significant side effects. Consistent with its in vitro anti-cancer effects, tumor materials from mice showed increased apoptosis of tumor cells with reduced protein expression of activated PI3K/Akt. These results suggest that the synergistic anti-cancer effects of paclitaxel and α-tomatine may be beneficial for refractory prostate cancer treatment.
Asunto(s)
Antineoplásicos Fitogénicos/uso terapéutico , Apoptosis/efectos de los fármacos , Paclitaxel/uso terapéutico , Fitoterapia , Neoplasias de la Próstata/tratamiento farmacológico , Solanum lycopersicum/química , Tomatina/análogos & derivados , Andrógenos/metabolismo , Animales , Antineoplásicos Fitogénicos/farmacología , Línea Celular Tumoral , Sinergismo Farmacológico , Quimioterapia Combinada , Humanos , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Paclitaxel/farmacología , Fosfatidilinositol 3-Quinasas/metabolismo , Extractos Vegetales/farmacología , Extractos Vegetales/uso terapéutico , Próstata/efectos de los fármacos , Neoplasias de la Próstata/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Transducción de Señal , Tomatina/farmacología , Tomatina/uso terapéutico , Proteína X Asociada a bcl-2/metabolismo , Proteína Letal Asociada a bcl/metabolismoRESUMEN
BACKGROUND: α-Tomatine, synthesized by Lycopersicon and some Solanum species, is a steroidal glycoalkaloid which functions to protect against pathogens and insects. Although glycoalkaloids are generally considered toxic, α-tomatine appears to be well tolerated in humans. α-Tomatine has numerous potential health benefits including the ability to inhibit cancer cell growth in in vitro studies. α-Tomatine is influenced by numerous agronomic factors including fertilization and nitrogen availability. Herein, the levels of α-tomatine were compared in dried tomato samples (Lycopersicon esculentum L. cv. Halley 3155) produced in organic and conventional cropping systems that had been archived over the period from 1994 to 2004 from the Long Term Research on Agricultural Systems project (LTRAS) at UC Davis. RESULTS: The α-tomatine levels of tomatoes in both cropping systems ranged from 4.29 to 111.85 µg g(-1) dry weight. Mean levels of α-tomatine were significantly higher in the organically grown tomatoes than conventional ones (P < 0.001). In the organic management system, α-tomatine content was also significantly (P < 0.001) different between cropping years, suggesting that other influencing factors such as environmental conditions also affect α-tomatine content in tomato. CONCLUSIONS: The organically produced tomatoes had higher average α-tomatine content than their conventional counterpart over the 10-year study. Significant annual variability in the α-tomatine content in tomatoes was also observed and suggests that environmental factors, external to nitrogen fertilization, influence α-tomatine content in tomatoes.
Asunto(s)
Agricultura/métodos , Dieta , Agricultura Orgánica/métodos , Solanum lycopersicum/metabolismo , Tomatina/análogos & derivados , Frutas/metabolismo , Humanos , Neoplasias/prevención & control , Tomatina/metabolismo , Tomatina/uso terapéutico , Verduras/metabolismoRESUMEN
α-Tomatine, isolated from Lycopersicon esculentum Linn., is a naturally occurring steroidal glycoalkaloid in immature green tomatoes. Some reports demonstrated that α-tomatine had various anticarcinogenic properties. The purpose of this study is to investigate the anti-metastatic effect of α-tomatine in NCI-H460 human non-small cell lung cancer cells. First, the results showed that α-tomatine significantly suppressed the abilities of the adhesion, invasion, and migration of NCI-H460 cells under non-cytotoxic concentrations. Molecular data also showed α-tomatine could inhibit the activation of focal adhesion kinase (FAK) and phosphatidylinositol 3-kinase (PI3K)/Akt signal involve in the downregulation the enzyme activities, protein and messenger RNA levels of matrix metalloproteinase-7 (MMP-7). Next, α-tomatine also strongly inhibited the degradation of inhibitor of kappaBα (IκBα) and the nuclear levels of nuclear factor kappa B (NF-κB). Also, a dose-dependent inhibition on the binding ability of NF-κB by α-tomatine treatment was further observed. Furthermore, α-tomatine significantly decreased the levels of phospho-Akt and MMP-7 in Akt1-cDNA-transfected cells concomitantly with a marked reduction on cell invasion and migration. Presented results indicated α-tomatine might be further application for treating cancer metastasis.