RESUMEN
BACKGROUND: HOX-7 is a newly developed dietary formula composed of traditional oriental herbal medicines. The formula was developed with the aim of improving weight control. We investigated the anti-obesity effect of HOX-7 on high-fat-diet (HFD)-induced obesity in C57BL/6 mice. METHODS: The mice were divided into four groups and were fed a normal diet (ND), HFD, or HFD with oral administration of HOX-7 at 100 or 200 mg/kg/day for 12 weeks. Body and fat weight, histological changes of fat tissue, and the expression of key adipogenic transcription factors were investigated. RESULTS: The body weight of mice fed the HFD with HOX-7 was significantly decreased compared to the HFD group. There were no obvious differences in weekly food intake among the 4 groups. The weight of the epididymal and total fat pads was reduced in mice fed the HFD with HOX-7. Treatment with HOX-7 also substantially attenuated the expression of key adipogenic transcription factors, including peroxisome proliferator-activated receptor γ, CCAAT/enhancer binding protein α, sterol regulatory element binding protein 1c, adipocyte P2, liver X receptor, and lipoprotein lipase in the epididymal adipose tissue. CONCLUSION: Overall, this study highlighted the anti-obesity effects of HOX-7, a finding that could contribute to the development of natural anti-obesity herbal medicines.
Asunto(s)
Adipogénesis/efectos de los fármacos , Tejido Adiposo/metabolismo , Obesidad/prevención & control , Fitoterapia , Extractos Vegetales/uso terapéutico , Factores de Transcripción/metabolismo , Aumento de Peso/efectos de los fármacos , Adipocitos/efectos de los fármacos , Adipogénesis/genética , Tejido Adiposo/citología , Animales , Fármacos Antiobesidad/farmacología , Fármacos Antiobesidad/uso terapéutico , Proteína alfa Potenciadora de Unión a CCAAT/genética , Proteína alfa Potenciadora de Unión a CCAAT/metabolismo , Dieta Alta en Grasa/efectos adversos , Ingestión de Alimentos/efectos de los fármacos , Expresión Génica/efectos de los fármacos , Magnoliopsida , Masculino , Medicina Tradicional de Asia Oriental , Ratones , Ratones Endogámicos C57BL , Ratones Obesos , Obesidad/etiología , Obesidad/genética , Obesidad/metabolismo , PPAR gamma/metabolismo , Extractos Vegetales/farmacología , Pérdida de Peso/efectos de los fármacosRESUMEN
It has been reported that [3-(1,1'-biphenyl-4-yl)-2-(1-methyl-5-dimethylamino-pentylamino)-3,4-dihydroquinazolin-4-yl]-N-benzylacetamide 2hydrochloride (KYS05090), a selective T-type Ca2+ channel blocker, reduces tumor volume and weight in the A549 xenograft model, but the molecular mechanism of cell death has not yet been elucidated. In this study, KYS05090 induced autophagy- and apoptosis-mediated cell death in human lung adenocarcinoma A549 cells. Although KYS05090 decreased intracellular Ca2+ levels, it was not directly related with KYS05090-induced cell death. In addition, KYS05090 generated intracellular reactive oxygen species (ROS) and reduced glucose uptake, and catalase and methyl pyruvate prevented KYS05090-induced cell death. These results indicate that KYS05090 can lead to autophagy and apoptosis in A549 cells through ROS generation by inhibiting glucose uptake. Our findings suggest that KYS05090 has potential chemotherapeutic value for the treatment of lung cancer.
Asunto(s)
Apoptosis/efectos de los fármacos , Bloqueadores de los Canales de Calcio/farmacología , Glucosa/metabolismo , Quinazolinas/farmacología , Autofagia/efectos de los fármacos , Calcio/metabolismo , Bloqueadores de los Canales de Calcio/química , Canales de Calcio Tipo T , Línea Celular Tumoral , Humanos , Quinazolinas/química , Especies Reactivas de Oxígeno/metabolismoRESUMEN
The anti-proliferative and apoptotic activities of new T-type calcium channel antagonist, 6e (BK10040) on human lung adenocarcinoma A549 cells were investigated. The MTT assay results indicated that BK10040 was cytotoxic against human lung adenocarcinoma (A549) and pancreatic cancer (MiaPaCa2) cells in a dose-dependent manner with IC50 of 2.25 and 0.93µM, respectively, which is ca. 2-fold more potent than lead compound KYS05090 despite of its decreased T-type calcium channel blockade. As a mode of action for cytotoxic effect of BK10040 on lung cancer (A549) cells, this cancer cell death was found to have the typical features of apoptosis, as evidenced by the accumulation of positive cells for annexin V. In addition, BK10040 triggered the activations of caspases 3 and 9, and the cleavages of poly (ADP-ribose) polymerase (PARP). Moreover, the treatment with z-VAD-fmk (a broad spectrum caspase inhibitor) significantly prevented BK10040-induced apoptosis. Based on these results, BK10040 may be used as a potential therapeutic agent for human lung cancer via the potent apoptotic activity.
Asunto(s)
Bloqueadores de los Canales de Calcio/química , Bloqueadores de los Canales de Calcio/farmacología , Canales de Calcio Tipo T/química , Piperazinas/química , Piperazinas/farmacología , Quinazolinas/química , Quinazolinas/farmacología , Adenocarcinoma/metabolismo , Adenocarcinoma/patología , Adenocarcinoma del Pulmón , Apoptosis/efectos de los fármacos , Bloqueadores de los Canales de Calcio/síntesis química , Canales de Calcio Tipo T/metabolismo , Puntos de Control del Ciclo Celular/efectos de los fármacos , Línea Celular Tumoral , Humanos , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patología , Piperazinas/síntesis química , Quinazolinas/síntesis químicaRESUMEN
The growth inhibition of human cancer cells via T-type Ca(2+) channel blockade has been well known. Herein, a series of new 3,4-dihydroquinazoline derivatives were synthesized via a brief SAR study on KYS05090 template and evaluated for both T-type Ca(2+) channel (Cav3.1) blockade and cytotoxicity on three human ovarian cancer cells (SK-OV-3, A2780 and A2780-T). Most of compounds except 6i generally exhibited more potent cytotoxicity on SK-OV-3 than mibefradil as a positive control regardless of the degree of T-type channel blockade. In particular, eight compounds (KYS05090, 6a and 6c-6h) showing strong channel blockade exhibited almost equal and more potent cytotoxicity on A2780 when compared to mibefradil. On A2780-T paclitaxel-resistant human ovarian carcinoma, two compounds (KYS05090 and 6d) were 20-fold more active than mibefradil. With respect to cell cycle arrest effect on A2780 and A2780-T cells, KYS05090 induced large proportion of sub-G1 phase in the cell cycle progression of A2780 and A2780-T, meaning the induction of cancer cell death instead of cell cycle arrest via blocking T-type Ca(2+) channel. Among new analogues, compounds 6g and 6h induced cell cycle arrest at G1 phase of A2780 and A2780-T cells in dose-dependent manner and exhibited strong anti-proliferation effects of ovarian cancer cells by blocking T-type Ca(2+) channel. Furthermore, 6g and 6h possessing strong cytotoxic effects could induce apoptosis of A2780 cells, which was detected by confocal micrographs using DAPI staining.
Asunto(s)
Bloqueadores de los Canales de Calcio/toxicidad , Canales de Calcio Tipo T/química , Bloqueadores de los Canales de Calcio/síntesis química , Bloqueadores de los Canales de Calcio/química , Canales de Calcio Tipo T/metabolismo , Puntos de Control del Ciclo Celular/efectos de los fármacos , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Femenino , Humanos , Neoplasias Ováricas/metabolismo , Neoplasias Ováricas/patología , Quinazolinas/síntesis química , Quinazolinas/química , Quinazolinas/toxicidad , Relación Estructura-ActividadRESUMEN
5,6,7-Trimethoxyflavone (TMF), methylations of the hydroxyl groups of oroxylin A or baicalein, was found to significantly inhibit the productions of nitric oxide (NO) and prostaglandin E2 (PGE2) in lipopolysaccharide (LPS)-treated RAW 264.7 macrophages. However, no report has been issued on the anti-inflammatory potential of TMF and the underlying molecular mechanism. In the present study, we investigated the anti-inflammatory effects of TMF in LPS-induced RAW 264.7 macrophages and LPS-induced septic shock in mice. TMF dose-dependently inhibits iNOS and COX-2 at the protein, mRNA, and promoter binding levels and that these inhibitions cause attendant decreases in the productions of NO and PGE2. TMF inhibits the productions and mRNA expressions of tumor necrosis factor-α (TNF-α), interleukin (IL)-1ß, and IL-6 induced by LPS. Furthermore, TMF suppress the transcriptional activity of nuclear factor-kappa B (NF-κB) and activator protein-1 (AP-1), and nuclear translocations of NF-κB, AP-1, and signal transducer and activator of transcription 1/3 (STAT1/3). Pretreatment with TMF increase the survival rate of mice with LPS-induced endotoxemia and reduced the serum levels of cytokines. Taken together, these findings suggest that TMF down-regulates the expressions of the pro-inflammatory iNOS, COX-2, TNF-α, IL-1ß, and IL-6 genes in macrophages by interfering with the activation of NF-κB, AP-1, and STAT1/3.
Asunto(s)
Antiinflamatorios no Esteroideos/farmacología , Flavonoides/farmacología , Mediadores de Inflamación/metabolismo , Macrófagos/efectos de los fármacos , Choque Séptico/tratamiento farmacológico , Animales , Línea Celular/efectos de los fármacos , Ciclooxigenasa 2/genética , Ciclooxigenasa 2/metabolismo , Citocinas/sangre , Relación Dosis-Respuesta a Droga , Endotoxemia/tratamiento farmacológico , Endotoxemia/mortalidad , Interleucina-6/genética , Lipopolisacáridos/farmacología , Macrófagos/inmunología , Masculino , Ratones , Ratones Endogámicos C57BL , FN-kappa B/metabolismo , Óxido Nítrico Sintasa de Tipo II/genética , Óxido Nítrico Sintasa de Tipo II/metabolismo , Choque Séptico/metabolismoRESUMEN
Obesity is a metabolic disorder characterized by chronic inflammation and dyslipidemia and is a strong predictor for the development of hypertension, diabetes mellitus, and cardiovascular disease. This study examined the antiobesity effect of an ethanol extract of Corni Fructus containing formulation (CDAP), which is a combination of four natural components: Corni Fructus, Dioscoreae Rhizoma, Aurantii Fructus Immaturus, and Platycodonis Radix. The cellular lipid content in 3T3-L1 adipocytes was assessed by Oil Red O staining. Expressions of peroxisome proliferator-activated receptor- γ (PPAR- γ ), CCAAT/enhancer-binding protein- α (C/EBP- α ), and lipin-1 were determined by real-time RT-PCR. Western blot was used to determine the protein levels of PPAR- γ , C/EBP- α , and AMP-activated protein kinase- α (AMPK- α ). The CDAP extract suppressed the differentiation of 3T3-L1 adipocytes by downregulating cellular induction of PPAR- γ , C/EBP- α , and lipin-1. The CDAP extract also significantly upregulated phosphorylation of AMPK- α . An in vivo study showed that CDAP induced weight loss in mice with high-fat-diet-induced obesity. These results indicate that CDAP has a potent anti-obesity effect due to the inhibition of adipocyte differentiation and adipogenesis.
RESUMEN
The pharmacological profile of BR-A-657, 2-n-butyl-5-dimethylamino-thiocarbonyl-methyl-6-methyl-3-{[2-(1H-tetrazole-5-yl)biphenyl-4-yl]methyl}-pyrimidin-4(3H)-one, a new nonpeptide AT1-selective angiotensin receptor antagonist, has been investigated in a variety of in vitro and in vivo experimental models. In the present study, BR-A-657 displaced [(125)I][Sar(1)-Ile(8)]angiotensin II (Ang II) from its specific binding sites to AT1 subtype receptors in membrane fractions of HEK-293 cells with an IC50 of 0.16 nM. In a functional assay using isolated rabbit thoracic aorta, BR-A-657 inhibited the contractile response to Ang II (pD'2: 9.15) with a significant reduction in the maximum. In conscious rats, BR-A-657 (0.01, 0.1, 1 mg/kg; intravenously (i.v.)) dose-dependently antagonized Ang II-induced pressor responses. In addition, BR-A-657 dose-dependently decreased mean arterial pressure in furosemide-treated rats and renal hypertensive rats. Moreover, BR-A-657 given orally at 1 and 3 mg/kg reduced blood pressure in conscious renal hypertensive rats. Taken together, these findings indicate that BR-A-657 is a potent and specific antagonist of Ang II at the AT1 receptor subtype, and reveal the molecular basis responsible for the marked lowering of blood pressure in conscious rats.
Asunto(s)
Bloqueadores del Receptor Tipo 1 de Angiotensina II/farmacología , Compuestos de Bifenilo/farmacología , Pirimidinas/farmacología , Receptor de Angiotensina Tipo 1/metabolismo , Tetrazoles/farmacología , Bloqueadores del Receptor Tipo 1 de Angiotensina II/uso terapéutico , Animales , Aorta Torácica/efectos de los fármacos , Aorta Torácica/metabolismo , Sitios de Unión , Compuestos de Bifenilo/uso terapéutico , Relación Dosis-Respuesta a Droga , Células HEK293 , Humanos , Hipertensión Renal/tratamiento farmacológico , Hipertensión Renal/metabolismo , Técnicas In Vitro , Masculino , Estructura Molecular , Unión Proteica , Pirimidinas/uso terapéutico , Conejos , Ratas , Ratas Sprague-Dawley , Tetrazoles/uso terapéutico , Vasoconstricción/efectos de los fármacosRESUMEN
Cheonggukjang is a Korean whole soybean paste fermented by Bacillus subtilis and regarded as a healthy food. The objective of this study was to investigate the immunostimulatory activity of polysaccharides from Cheonggukjang (PSCJ) in RAW 264.7 macrophages and an animal model. PSCJ induced mRNA expressions of inducible nitric oxide synthase and tumor necrosis factor-α (TNF-α) by activating nuclear factor-κB, and subsequently increased the productions of nitric oxide (NO) and TNF-α in murine recombinant interferon-γ-primed RAW 264.7 macrophages. Furthermore, after daily oral administration of PSCJ, immobility time decreased significantly in the PSCJ-administered group (200 or 400 mg/kg) on day 10. Taken together, these results suggest that the PSCJ has a possible role improving immune function through regulatory effects on immunological parameters, such as NO and TNF-α productions and changes in indicators related to fatigue.
Asunto(s)
Fatiga/prevención & control , Alimentos Funcionales/análisis , Factores Inmunológicos/uso terapéutico , Macrófagos/inmunología , Polisacáridos/uso terapéutico , Alimentos de Soja/análisis , Bazo/inmunología , Animales , Bacillus subtilis/inmunología , Bacillus subtilis/metabolismo , Línea Celular Transformada , Células Cultivadas , Dieta/etnología , Carbohidratos de la Dieta/administración & dosificación , Carbohidratos de la Dieta/metabolismo , Carbohidratos de la Dieta/uso terapéutico , Fatiga/inmunología , Fatiga/metabolismo , Fermentación , Alimentos Funcionales/microbiología , Regulación de la Expresión Génica , Factores Inmunológicos/administración & dosificación , Factores Inmunológicos/metabolismo , Activación de Macrófagos , Macrófagos/enzimología , Macrófagos/metabolismo , Masculino , Ratones , Ratones Endogámicos ICR , Óxido Nítrico Sintasa de Tipo II/biosíntesis , Óxido Nítrico Sintasa de Tipo II/genética , Óxido Nítrico Sintasa de Tipo II/metabolismo , Polisacáridos/administración & dosificación , Polisacáridos/metabolismo , República de Corea , Alimentos de Soja/microbiología , Bazo/citología , Bazo/metabolismo , Factor de Necrosis Tumoral alfa/biosíntesis , Factor de Necrosis Tumoral alfa/genética , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
ETHNOPHARMACOLOGICAL RELEVANCE: Artemisia princeps Pampanini (Asteraceae) is used as a traditional medicine to immune function-related diseases, such as dysmenorrhea, inflammation, cancer, and ulcers. AIM OF THE STUDY: The purpose of this study is to evaluate the immunostimulatory effects of the hot water extract from the leaves of Artemisia princeps Pampanini (WAPP) in recombinant interferon-γ (rIFN-γ)-primed RAW 264.7 macrophages and in cyclophosphamide (20mg/kg, i.p.)-induced immunosuppressed Sprague-Dawley rats. MATERIALS AND METHODS: RAW 264.7 macrophages were treated with WAPP and production and expressions of nitric oxide (NO) and tumor necrosis factor-α (TNF-α) via nuclear factor-κB (NF-κB) were detected by immunoassay, western blot, qRT-PCR and reporter gene assay. In addition, in vivo immunomodulatory activity was studied by cyclophosphamide-induced myelosuppression in rats. RESULTS: In rIFN-γ-primed RAW 264.7 macrophages, pretreatment with WAPP increased the productions of nitric oxide (NO) and tumor necrosis factor-α (TNF-α),and increased the expressions of inducible nitric oxide synthase (iNOS) at the protein level and of iNOS and TNF-α at the mRNA level. Molecular data revealed that WAPP upregulated the transcriptional activity and translocation of nuclear factor-κB (NF-κB) by activating inhibitory kappa B-α (IκB-α) degradation and phosphorylation. Furthermore, WAPP upregulated the phosphorylations of p38 MAP kinase, c-Jun NH2-terminal kinase (JNK), and extracellular signal-regulated kinase 1/2 (ERK1/2). In cycloheximide-induced immunosuppressed rats, pretreatment with WAPP (100, 200, or 400mg/kg, p.o.) increased the serum levels of albumin and globulin, and reduced immobility times. CONCLUSION: Our results suggest that upregulations of the expressions of iNOS and TNF-α via the activations of NF-κB and MAPK are responsible for the immunostimulatory effects of WAPP.
Asunto(s)
Adyuvantes Inmunológicos/farmacología , Artemisia/química , Etnofarmacología , Medicina Tradicional Coreana , Extractos Vegetales/farmacología , Adyuvantes Inmunológicos/aislamiento & purificación , Animales , Técnicas de Cultivo de Célula , Línea Celular , Calor , Macrófagos/efectos de los fármacos , Macrófagos/inmunología , Ratones , Óxido Nítrico/biosíntesis , Óxido Nítrico/inmunología , Extractos Vegetales/aislamiento & purificación , Hojas de la Planta/química , Ratas , Ratas Sprague-Dawley , República de Corea , Natación , Factor de Necrosis Tumoral alfa/biosíntesis , Factor de Necrosis Tumoral alfa/inmunología , Agua/químicaRESUMEN
BACKGROUND & OBJECTIVES: Obesity is now considered as a major risk factor for the development of fatty liver diseases, cardiovascular diseases, and atherosclerosis. SoSoSo is a newly developed dietary supplement made of seven medicinal herbs. This study was aimed at examining the anti-obesity effect of SoSoSo or its active ingredient chrysophanol on the production of inflammatory cytokines and adipokine in macrophyage cell line RAW264 and 3T3-L1 adipocytes. METHODS: No release was measured as a form of nitrite by Griess method. The production of inflammatory cytokines and adipokine were measured with the ELISA method. The m-RNA expression of each cytokine and adipokine were measured using RT-PCR. The nuclear proteins for NF-κB were analyzed with western blotting. RESULTS: SoSoSo or chrysophanol significantly inhibited the nitric oxide production in lipopolysaccharide-stimulated RAW264 cells as well as in RAW264 cells-conditioned medium (CM)-treated 3T3-L1 cells. The production of interleukin (IL)-6 and tumour necrosis factor (TNF)-α were inhibited by SoSoSo or chrysophanol. In addition, SoSoSo or chrysophanol inhibited the activation of nuclear factor-κB in RAW264 cells. SoSoSo or chrysophanol inhibited the productions of IL-6, TNF-α, and monocyte chemoattractant protein-1 as well as the reduction of adiponectin production in CM-treated 3T3-L1 cells. INTERPRETATION & CONCLUSIONS: These results suggest a potential of SoSoSo or chrysophanol as a source of anti-inflammatory agent for obesity. Further in vivo studies would be required to confirm these findings.
Asunto(s)
Adipoquinas/biosíntesis , Antraquinonas/administración & dosificación , Citocinas/biosíntesis , Obesidad/dietoterapia , Células 3T3-L1 , Adipocitos/efectos de los fármacos , Adipocitos/metabolismo , Animales , Antraquinonas/química , Suplementos Dietéticos , Regulación de la Expresión Génica , Humanos , Macrófagos/efectos de los fármacos , Ratones , FN-kappa B/biosíntesis , Obesidad/genética , Obesidad/patología , Plantas MedicinalesRESUMEN
In a previous study, we found that the 3,4-dihydroquinazoline derivative, 4-(Benzylcarbamoylmethyl)-2-(biphenyl-4-ylamino)-3-(5-tert-butyloxycarbamoyl-1-pentyl)-3,4-dihydroquinazoline (KYS05047), was a selective T-type Ca(2+) channel blocker with anti-proliferative effects against various cancer cells. However, the mechanism responsible for its effects has not been studied. In this study, we investigated the effect of KYS05047 on cell cycle arrest and the mechanisms involved in human lung adenocarcinoma A549 cells. Among the G(1) phase cell cycle-related proteins examined, the levels of cyclin-dependent protein kinase (Cdk2) and Cdk4 were reduced by KYS05047 (7 µM), whereas the steady-state levels of cyclin D1 and E were unaffected. In addition, KYS05047 increased the protein level of p27(KIP1) and suppressed the kinase activities of Cdk2 and Cdk4. In addition, pretreatment with KCl, which increases intracellular Ca(2+) levels, prevented KYS05047-induced intracellular Ca(2+) decreases and cell cycle arrest. Furthermore, the administration of KYS05047 (2 or 10 mg/kg, po) for 21 days was also found to significantly inhibit tumor growth in an A549 xenograft nude mice model. In conclusion, our results suggested that KYS05047 induced G(1) phase cell cycle arrest in A549 cells associated with a decrease in intracellular Ca(2+) concentrations and inhibited the in vivo tumor growth of A549 xenograft mice.
Asunto(s)
Bloqueadores de los Canales de Calcio/farmacología , Canales de Calcio Tipo T/química , Calcio/metabolismo , Puntos de Control de la Fase G1 del Ciclo Celular/efectos de los fármacos , Quinazolinas/farmacología , Adenocarcinoma/tratamiento farmacológico , Adenocarcinoma del Pulmón , Animales , Bloqueadores de los Canales de Calcio/química , Bloqueadores de los Canales de Calcio/uso terapéutico , Canales de Calcio Tipo T/metabolismo , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Quinasa 2 Dependiente de la Ciclina/metabolismo , Quinasa 4 Dependiente de la Ciclina/metabolismo , Humanos , Neoplasias Pulmonares/tratamiento farmacológico , Ratones , Ratones Endogámicos BALB C , Quinazolinas/química , Quinazolinas/uso terapéutico , Trasplante HeterólogoRESUMEN
Nodakenin, a coumarin isolated from the roots of Angelicae gigas, has been reported to possess neuroprotective, antiaggregatory, antibacterial, and memory-enhancing effects. In the present study, we investigated the anti-inflammatory effects of nodakenin by examining its in vitro inhibitory effects on inducible nitric-oxide synthase (iNOS), cyclooxygenase-2 (COX-2), and proinflammatory cytokines in lipopolysaccharide (LPS)-induced RAW 264.7 macrophages and mouse peritoneal macrophages and its in vivo effects on LPS-induced septic shock in mice. Our results indicate that nodakenin concentration-dependently inhibits iNOS and COX-2 at the protein, mRNA, and promoter binding levels, and these inhibitions cause attendant decreases in the production of nitric oxide (NO) and prostaglandin E2 (PGE2). Furthermore, we found that nodakenin inhibits the production and mRNA expression of tumor necrosis factor-α (TNF-α), interleukin (IL)-6, and IL-1ß induced by LPS. Molecular data revealed that nodakenin suppressed the transcriptional activity and translocation of nuclear factor-κB (NF-κB) by inhibiting inhibitory κB-α degradation and IκB kinase-α/ß phosphorylation. In addition, nodakenin was found to significantly inhibit the LPS-induced binding of transforming growth factor-ß-activated kinase 1 to tumor necrosis factor receptor-associated factor 6 (TRAF6) by reducing TRAF6 ubiquitination. Pretreatment with nodakenin reduced the serum levels of NO, PGE2, and proinflammatory cytokines and increased the survival rate of mice with LPS-induced endotoxemia. Taken together, our data suggest that nodakenin down-regulates the expression of the proinflammatory iNOS, COX-2, TNF-α, IL-6, and IL-1ß genes in macrophages by interfering with the activation of TRAF6, thus preventing NF-κB activation.
Asunto(s)
Antiinflamatorios/farmacología , Cumarinas/farmacología , Glucósidos/farmacología , Inflamación/metabolismo , Lipopolisacáridos/farmacología , Macrófagos/efectos de los fármacos , FN-kappa B/antagonistas & inhibidores , Choque Séptico/prevención & control , Factor 6 Asociado a Receptor de TNF/antagonistas & inhibidores , Animales , Células Cultivadas , Ciclooxigenasa 2/genética , Ciclooxigenasa 2/metabolismo , Dinoprostona/antagonistas & inhibidores , Dinoprostona/genética , Dinoprostona/metabolismo , Regulación hacia Abajo/efectos de los fármacos , Regulación hacia Abajo/genética , Interacciones Farmacológicas , Quinasa I-kappa B/antagonistas & inhibidores , Quinasa I-kappa B/genética , Quinasa I-kappa B/metabolismo , Proteínas I-kappa B/antagonistas & inhibidores , Proteínas I-kappa B/genética , Proteínas I-kappa B/metabolismo , Inflamación/tratamiento farmacológico , Inflamación/genética , Interleucina-1beta/antagonistas & inhibidores , Interleucina-1beta/genética , Interleucina-1beta/metabolismo , Interleucina-6/antagonistas & inhibidores , Interleucina-6/genética , Interleucina-6/metabolismo , Quinasas Quinasa Quinasa PAM/genética , Quinasas Quinasa Quinasa PAM/metabolismo , Macrófagos/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Quinasas de Proteína Quinasa Activadas por Mitógenos/antagonistas & inhibidores , Quinasas de Proteína Quinasa Activadas por Mitógenos/genética , Quinasas de Proteína Quinasa Activadas por Mitógenos/metabolismo , Inhibidor NF-kappaB alfa , FN-kappa B/genética , FN-kappa B/metabolismo , Óxido Nítrico/antagonistas & inhibidores , Óxido Nítrico/genética , Óxido Nítrico/metabolismo , Óxido Nítrico Sintasa de Tipo II/antagonistas & inhibidores , Óxido Nítrico Sintasa de Tipo II/genética , Óxido Nítrico Sintasa de Tipo II/metabolismo , Fosforilación/efectos de los fármacos , Fosforilación/genética , Regiones Promotoras Genéticas/efectos de los fármacos , Choque Séptico/tratamiento farmacológico , Choque Séptico/metabolismo , Transducción de Señal/efectos de los fármacos , Transducción de Señal/genética , Factor 6 Asociado a Receptor de TNF/genéticaRESUMEN
The regulations of the NO and PGE(2) productions are research topics of interest in the field of anti-inflammatory drug development. In the present study, 5,6,7-trimethoxy- and 5,6,7-trihydroxyflavones 3a-3g were synthesized from cinnamic acid derivatives. In particular, 4'-bromo-5,6,7-trimethoxyflavone (3b) most potently inhibited the productions of NO and PGE(2) in LPS-treated RAW 264.7 cells (IC(50)=14.22 ± 1.25 and 10.98 ± 6.25 µM, respectively), and these inhibitory effects were more potent than those of oroxylin A or baicalein. Consistent with these findings, 3b concentration-dependently reduced the LPS-induced expressions of iNOS and COX-2 at the protein and mRNA levels. In addition, the release of TNF-α, IL-6, and IL-1ß and the mRNA expressions of these cytokines were reduced by 3b in a concentration-dependent manner. Furthermore, 3b attenuated the LPS-induced transcriptional activities of NF-κB and this was accompanied by parallel reductions in the degradation and phosphorylation of IκB-α, and consequently by a decrease in the nuclear translocation of the p65 subunit of NF-κB. Taken together, these results suggest that suppressions of the expressions of iNOS, COX-2, TNF-α, IL-6, and IL-1ß via NF-κB inactivation are responsible for the anti-inflammatory effects of 3b.
Asunto(s)
Ciclooxigenasa 2/metabolismo , Flavonas/síntesis química , Flavonoides/farmacología , Macrófagos/metabolismo , Óxido Nítrico Sintasa de Tipo II/antagonistas & inhibidores , Animales , Antiinflamatorios/farmacología , Supervivencia Celular , Relación Dosis-Respuesta a Droga , Diseño de Fármacos , Flavonas/farmacología , Inflamación , Concentración 50 Inhibidora , Interleucina-1beta/metabolismo , Interleucina-6/metabolismo , Lipopolisacáridos/metabolismo , Ratones , Modelos Biológicos , Modelos Químicos , FN-kappa B/metabolismo , Óxido Nítrico/química , Óxido Nítrico Sintasa de Tipo II/metabolismo , ARN Mensajero/metabolismo , Transducción de Señal , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
An extension of our previously reported 3,4-dihydroquinazoline derivative is investigated. Oral anti-tumoral activity of 3,4-dihydroquinazoline derivative (KYS05090) as potent and selective T-type calcium channel blocker was in vivo evaluated against A549 xenograft in BALB/c(nu/nu) nude mice. The rate of tumor volume increment in mouse model with KYS05090-treated group was remarkably slower than that of control group. With respect to tumor weight, it exhibited 60% and 67% tumor growth inhibition through oral administration of 1 and 5mg/kg of bodyweight, respectively, compared to control and was more potent than paclitaxel (53%). In addition, KYS05090 (10 and 50mg/kg, po) was found to have a marked analgesic effect in acetic acid-induced writhing test, whereas it did not show any effect on hot plate test.
Asunto(s)
Antineoplásicos/farmacología , Neoplasias/tratamiento farmacológico , Quinazolinas/farmacología , Administración Oral , Animales , Antineoplásicos/administración & dosificación , Antineoplásicos/química , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Humanos , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos ICR , Ratones Desnudos , Estructura Molecular , Neoplasias/patología , Quinazolinas/administración & dosificación , Quinazolinas/química , Relación Estructura-Actividad , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Soybean is a useful component of traditional Korean medicine with well-documented health-promoting effects. We investigated the effects of alcohol-fermented soybean (AFS) on immune function. When AFS treatment was used in combination with recombinant interferon-γ (rIFN-γ), there was a marked cooperative induction of nitric oxide (NO) and tumor necrosis factor (TNF)-α production in mouse peritoneal macrophages. AFS increased the expression of inducible NO synthase mRNA and protein in rIFN-γ-primed macrophages. Treating macrophages with pyrrolidine dithiocarbamate, an inhibitor of nuclear factor-κB (NF-κB), decreased the synergistic effects of AFS. In addition, AFS in combination with rIFN-γ increased the phosphorylation of p38 and c-Jun N-terminal kinase (JNK) but not extracellular signal-regulated kinase. However, AFS had no effect on phosphorylation of mitogen-activated protein kinases by itself. The p38 inhibitor SB203580 or the JNK inhibitor SP600125 inhibited the AFS-induced NO and TNF-α production. When AFS was used in combination with rIFN-γ, there was a co-operative activation of NF-κB and receptor-interacting protein 2 (Rip2)/IκB kinase (IKK)-ß. Our results indicate that AFS increases the production of NO and TNF-α through the activation of Rip2/IKK-ß in rIFN-γ-primed macrophages.
Asunto(s)
Fermentación , Glycine max/metabolismo , Quinasa I-kappa B/genética , Macrófagos Peritoneales/efectos de los fármacos , Proteína Serina-Treonina Quinasas de Interacción con Receptores/genética , Animales , Western Blotting , Ciclooxigenasa 2/genética , Ciclooxigenasa 2/metabolismo , Quinasas MAP Reguladas por Señal Extracelular/genética , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Quinasa I-kappa B/metabolismo , Interferón gamma/metabolismo , Proteínas Quinasas JNK Activadas por Mitógenos/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , FN-kappa B/genética , FN-kappa B/metabolismo , Óxido Nítrico/biosíntesis , Óxido Nítrico Sintasa de Tipo II/genética , Óxido Nítrico Sintasa de Tipo II/metabolismo , Fosforilación , Pirrolidinas/metabolismo , Proteína Serina-Treonina Quinasa 2 de Interacción con Receptor , Proteína Serina-Treonina Quinasas de Interacción con Receptores/metabolismo , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Tiocarbamatos/metabolismo , Factor de Necrosis Tumoral alfa/biosíntesis , Factor de Necrosis Tumoral alfa/genéticaRESUMEN
Previously, the authors demonstrated that the triterpenoid glycoside niga-ichigoside F1 (NIF1) and its aglycone 23-hydroxytormentic acid (23-HTA) isolated from the unripe fruits of Rubus coreanus (Rosaceae) ameliorate cisplatin-induced toxicity in renal epithelial LLC-PK1 cells. In the present study, the nephroprotective effects of NIF1 and 23-HTA were investigated in Sprague-Dawley rats with acute renal injury induced by a single intraperitoneal (i.p.) injection of cisplatin (7 mg/kg). Pretreatment with 23-HTA (10 mg/kg/d, per os (p.o.)) significantly reduced cisplatin-induced elevations in blood urea nitrogen (BUN) and serum creatinine level, whereas NIF1 (10 mg/kg, p.o.) slightly reduced these levels. In addition, pretreatment with 23-HTA prevented cisplatin-induced hydroxyl radical generation, malondialdehyde (MDA) production, glutathione (GSH) depletion, and cisplatin-induced changes in the activities of oxidant and antioxidant enzymes in rat renal tissues. In addition, histopathological examinations showed that 23-HTA pretreatment reduced cisplatin-induced acute tubular necrosis and histological changes. In contrast, NIF1 was found to have a slight or no influence on cisplatin-induced oxidative enzymes and acute tubular necrosis. Taken together, these results suggest that protective effect of 23-HTA pretreatment on cisplatin-induced renal damage is associated with the attenuation of oxidative stress and the preservation of antioxidant enzymes.
Asunto(s)
Antineoplásicos/toxicidad , Cisplatino/toxicidad , Enfermedades Renales/tratamiento farmacológico , Triterpenos/farmacología , Animales , Antioxidantes/metabolismo , Nitrógeno de la Urea Sanguínea , Creatinina/sangre , Glutatión/metabolismo , Radical Hidroxilo/metabolismo , Enfermedades Renales/inducido químicamente , Enfermedades Renales/metabolismo , Células LLC-PK1 , Masculino , Malondialdehído/metabolismo , Ratas , Ratas Sprague-Dawley , PorcinosRESUMEN
The unripe fruits of Rubus coreanus (Rosaceae) are used in traditional Chinese medicine to relieve kidney dysfunction. In the present study, we evaluated the protective effects of the triterpenoid glycoside niga-ichigoside F1 (NIF1) and of its aglycone 23-hydroxytormentic acid (23-HTA) isolated from the unripe fruits of Rubus coreanus (Rosaceae) against cisplatin-induced cytotoxicity in renal epithelial LLC-PK1 cells. Pretreating LLC-PK1 cells with 23-HTA or NIF1 was found to prevent cisplatin-induced cytotoxicity and apoptosis. In addition, 23-HTA or NIF1 pretreatment significantly improved the changes associated with cisplatin toxicity by increasing levels of glutathione (GSH) and decreasing levels of malondialdehyde (MDA) and reactive oxygen species (ROS). The activity of antioxidant enzymes including catalase (CAT) and superoxide dismutase (SOD) was significantly lower in cisplatin-treated LL-PK1 cells, and 23-HTA or NIF1 treatment notably increased the these enzyme activity and protein and mRNA levels of CAT and manganese SOD (MnSOD). Moreover, cisplatin caused a significant decrease in nuclear levels of nuclear factor erythroid 2-related factor 2 (Nrf2) and pretreatment with 23-HTA or NIF1 significantly suppressed the cisplatin-induced translocation of Nrf2 in LLC-PK1 cells. Taken together, these results suggest that 23-HTA ameliorates cisplatin-induced toxicity via modulation of antioxidant enzymes through activation of Nrf2 in LLC-PK1 cells.
Asunto(s)
Antineoplásicos/toxicidad , Antioxidantes/farmacología , Cisplatino/toxicidad , Glicósidos/farmacología , Riñón/efectos de los fármacos , Estrés Oxidativo/efectos de los fármacos , Triterpenos/farmacología , Animales , Apoptosis/efectos de los fármacos , Línea Celular , Núcleo Celular/efectos de los fármacos , Núcleo Celular/metabolismo , Supervivencia Celular/efectos de los fármacos , Células Epiteliales/efectos de los fármacos , Células Epiteliales/metabolismo , Frutas/química , Frutas/crecimiento & desarrollo , Regulación Enzimológica de la Expresión Génica/efectos de los fármacos , Glutatión/metabolismo , Riñón/metabolismo , Factor 2 Relacionado con NF-E2/metabolismo , Oxidorreductasas/genética , Oxidorreductasas/metabolismo , Transporte de Proteínas/efectos de los fármacos , ARN Mensajero/metabolismo , Rosaceae/química , Sus scrofaRESUMEN
ß-Eudesmol is sesquiterpenoid alcohol which contains the rhizome of Atractylodes lancea. Although it has multiple pharmacological effects, the anti-inflammatory effect of ß-eudesmol and its molecular mechanisms are poorly elucidated. In this study, we investigated the regulatory mechanism of ß-eudesmol on mast cell-mediated inflammatory response. The results indicated that ß-eudesmol inhibited the production and expression of interleukin (IL)-6 on phorbol 12-myristate 13-acetate and calcium ionophore A23187-stimulated human mast cell (HMC). In activated HMC-1 cells, ß-eudesmol suppressed activation of p38 mitogen-activated protein kinase (MAPKs) and nuclear factor-κB. In addition, ß-eudesmol suppressed the activation of caspase-1 and expression of receptor-interacting protein-2. These results provide new insights into the pharmacological actions of ß-eudesmol as a potential molecule for use in therapy in mast cell-mediated inflammatory diseases.
Asunto(s)
Antiinflamatorios no Esteroideos/farmacología , Inhibidores de Caspasas , Inmunidad Celular/efectos de los fármacos , Mastocitos/efectos de los fármacos , Sesquiterpenos de Eudesmano/farmacología , Western Blotting , Calcimicina/farmacología , Línea Celular , Relación Dosis-Respuesta a Droga , Activación Enzimática , Ensayo de Inmunoadsorción Enzimática , Humanos , Interleucina-6/biosíntesis , Interleucina-6/inmunología , Mastocitos/enzimología , Mastocitos/inmunología , FN-kappa B/antagonistas & inhibidores , FN-kappa B/inmunología , Fosforilación , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Acetato de Tetradecanoilforbol/farmacología , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismoRESUMEN
Proinflammatory cytokines secreted from adipose tissue contribute to the morbidity associated with obesity. IL-1α is one of the proinflammatory cytokines; however, it has not been clarified whether IL-1α may also cause obesity. In this study, we investigated whether polymorphisms in IL-1α contribute to human obesity. A total of 260 obese subjects were genotyped for IL-1α C-889T (rs1800587) and IL-1α G+4845T (rs17561). Analyses of genotype distributions revealed that both IL-1α polymorphisms C-889T (rs1800587) and G+4845T (rs17561) were associated with an increase in body mass index in obese healthy women. In addition, the effect of rs1800587 on the transcriptional activity of IL-1α was explored in pre-adipocyte 3T3-L1 cells. Significant difference was found between the rs1800587 polymorphism in the regulatory region of the IL-1α gene and transcriptional activity. We extended these observations in vivo to a high-fat diet-induced obese mouse model and in vitro to pre-adipocyte 3T3-L1 cells. IL-1α levels were dramatically augmented in obese mice, and triglyceride was increased 12 hours after IL-1α injection. Taken together, IL-1α treatment regulated the differentiation of preadipocytes. IL-1α C-889T (rs1800587) is a functional polymorphism of IL-1α associated with obesity. IL-1α may have a critical function in the development of obesity.
Asunto(s)
Interleucina-1alfa/genética , Interleucina-1alfa/fisiología , Obesidad/genética , Polimorfismo Genético , Células 3T3-L1 , Animales , Secuencia de Bases , Índice de Masa Corporal , Cartilla de ADN , Ensayo de Inmunoadsorción Enzimática , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Reacción en Cadena en Tiempo Real de la Polimerasa , Transcripción Genética/fisiologíaRESUMEN
The objective of this study was to investigate the effects of hot water extracts of Chlorella vulgaris (CVE) on a deteriorated immune function through utilization of a protein-energy malnutrition (PEM) diet. Unicellular algae, C. vulgaris, were used as biological response modifier. PEM is associated with decreased host immune defense. Male C57BL/6J mice, initially four weeks old, were fed for 8 days with standard diet or a PEM diet. Mice in the PEM diet group were orally administered 0.1 g/kg and 0.15 g/kg of CVE for the following week. Nutritional parameters such as the total protein, albumin, glucose, and interferon γ (IFN-γ) were increased in blood serum of the CVE-treated group compared with the non-treated group. The mononuclear cell numbers from spleen, superficial, and mesenteric lymph node were reduced in mice fed with PEM diet, but numbers from the spleen and superficial lymph node were increased by the CVE (0.1 and 0.15 g/kg) treatment. We also investigated the effect of CVE on the production of cytokines in human T-cell line, MOLT-4 cells, and primary cultured splenocytes. The CVE treatment significantly increased the production of both interleukin (IL)-2 and IL-4 compared with the media control, but did not affect the production of IFN-γ. These results suggest that CVE may be useful in improving the immune function.