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1.
Med Oncol ; 41(6): 147, 2024 May 11.
Artículo en Inglés | MEDLINE | ID: mdl-38733492

RESUMEN

Wnt/ß-catenin signaling plays important role in cancers. Compound 759 is one of the compounds previously screened to identify inhibitors of the Wnt/ß-catenin pathway in A549 cells [Lee et al. in Bioorg Med Chem Lett 20:5900-5904, 2010]. However, the mechanism by which Compound 759 induces the inhibition of the Wnt/ß-catenin pathway remains unknown. In our study, we employed various assays to comprehensively evaluate the effects of Compound 759 on lung cancer cells. Our results demonstrated that Compound 759 significantly suppressed cell proliferation and Wnt3a-induced Topflash activity and arrested the cell cycle at the G1 stage. Changes in Wnt/ß-catenin signaling-related protein expression, gene activity, and protein stability including Axin, and p21, were achieved through western blot and qRT-PCR analysis. Compound 759 treatment upregulated the mRNA level of p21 and increased Axin protein levels without altering the mRNA expression in A549 cells. Co-treatment of Wnt3a and varying doses of Compound 759 dose-dependently increased the amounts of Axin1 in the cytosol and inhibited ß-catenin translocation into the nucleus. Moreover, Compound 759 reduced tumor size and weight in the A549 cell-induced tumor growth in the in vivo tumor xenograft mouse model. Our findings indicate that Compound 759 exhibits potential anti-cancer activity by inhibiting the Wnt/ß-catenin signaling pathway through the increase of Axin1 protein stability.


Asunto(s)
Proteína Axina , Proliferación Celular , Neoplasias Pulmonares , Ratones Desnudos , Vía de Señalización Wnt , Humanos , Proteína Axina/metabolismo , Vía de Señalización Wnt/efectos de los fármacos , Animales , Proliferación Celular/efectos de los fármacos , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patología , Ratones , Estabilidad Proteica/efectos de los fármacos , Ensayos Antitumor por Modelo de Xenoinjerto , Células A549 , beta Catenina/metabolismo , beta Catenina/antagonistas & inhibidores , Proteína Wnt3A/metabolismo , Línea Celular Tumoral , Antineoplásicos/farmacología , Ratones Endogámicos BALB C
2.
Anat Cell Biol ; 50(3): 219-229, 2017 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-29043101

RESUMEN

Post-menopausal osteoporosis (PMO) is a major global human health concern. Owing to the need for therapeutic drugs without side effects, natural extracts containing various polyphenolic compounds that may exert estrogenic effects have been studied in depth. Rhus verniciflua Stokes (RVS), which has been used as a traditional herbal medicine for centuries in Korea, was recently revealed to exert estrogenic effects attributable to its bioactive ingredients sulfuretin and butein, which have strong estrogen receptor-binding affinities. In this study, the protective potential of RVS in PMO was evaluated by using an experimental animal model of PMO, which was established by ovariectomy (OVX) of female Sprague Dawley rats. The oral administration of RVS at 20 mg/kg or 100 mg/kg for 8 weeks markedly protected against OVX-induced atrophy of the uterine tube and reversed the elevation in the ratio of serum receptor activator of nuclear factor-κB ligand to osteoprotegerin, which is a marker of disease severity. In addition, RVS inhibited OVX-induced tibia bone loss, activated osteogenic activity, and suppressed osteoclastic activity in the tibial epiphyseal plate, a region of bone remodeling. Collectively, these factors indicated that the oral intake of RVS might be beneficial for the prevention of PMO.

3.
Pharmacogn Mag ; 13(49): 153-158, 2017.
Artículo en Inglés | MEDLINE | ID: mdl-28216900

RESUMEN

BACKGROUND: The androgen comprises a group of hormones that play roles in male reproductive activity as well as personal characteristics. OBJECTIVE: We investigated the androgenic activity of various herbal medicines in human prostate cancer 22Rv1 cells. MATERIALS AND METHODS: Herbal extracts of Trichosanthes kirilowii (TK), Asarum sieboldii (AS), Sanguisorba officinalis (SO), and Xanthium strumarium (XS) were selected to have androgenic effects based on a preliminary in vitro screening system. RESULTS: TK, AS, SO, and XS enhanced the proliferation of 22Rv1 cells without having cytotoxic effects. All tested herbal extracts increased androgen receptor (AR)-induced transcriptional activity in the absence or presence of dihydrotestosterone (DHT). In an AR-binding assay, TK, but not AS, SO, or XS, produced a significant inhibition of AR binding activity, indicating it has androgenic activity. Additionally, TK treatment positively regulated mRNA expression of the AR-related molecular targets prostate-specific antigen (PSA) and kallikrein 2 (KLK2) compared with untreated control. CONCLUSION: Taken together, TK-enhanced AR-mediated transcriptional activity might be an attractive candidate drug for treating androgen-related diseases. SUMMARY: Trichosantheskirilowii (TK), Asarumsieboldii (AS), Sanguisorbaofficinalis (SO), and Xanthium strumarium (XS) enhanced the proliferation of 22Rv1 cells without having cytotoxic effects.TK, AS, SO, and XS increased androgen receptor (AR)-induced transcriptional activity.TK, but not AS, SO, or XS, produced a significant inhibition against AR-binding activity.TK treatment positively regulated mRNA expression of the AR-related molecular targets prostate-specific antigen and kallikrein 2. Abbreviations used: BPH: benign prostatic hyperplasia; AR: androgen receptor; DHT: dihydrotestosterone; PSA: prostate-specific antigen; TK: Trichosanthes kirilowii; AS: Asarum sieboldii; SO: Sanguisorba officinalis; XS: Xanthium strumarium; ATCC: American Type Culture Collection; FBS: fetal bovine serum; PBS: phosphate-buffered saline; SD: standard deviation; ARE: androgenresponsive element; KLK: kallikrein.

4.
Toxicol Sci ; 154(1): 27-42, 2016 11.
Artículo en Inglés | MEDLINE | ID: mdl-27511942

RESUMEN

Ethylmercury (EtHg) is derived from the degradation of thimerosal, the most widely used organomercury compound. In this study, EtHg-induced toxicity and autophagy in the mouse kidney was observed and then the mechanism of toxicity was explored in vitro in HK-2 cells. Low doses of EtHg induced autophagy without causing any histopathological changes in mouse kidneys. However, mice treated with high doses of EtHg exhibited severe focal tubular cell necrosis of the proximal tubules with autophagy. EtHg dose-dependently increased the production of reactive oxygen species, reduced the mitochondrial membrane potential, activated the unfolded protein response, and increased cytosolic Ca2+ levels in HK-2 cells. Cell death induced by EtHg exposure was caused by autophagy and necrosis. N-acetyl cysteine and 4-phenylbutyric acid attenuated EtHg-induced stress and ameliorated the autophagic response in HK-2 cells. Furthermore, EtHg blocked autophagosome fusion with lysosomes, which was demonstrated via treatment with wortmannin and chloroquine. Low doses of EtHg and rapamycin, which resulted in minimal cytotoxicity, increased the levels of the autophagic SNARE complex STX17 (syntaxin 17)-VAMP8-SNAP29 without altering mRNA levels, but high dose of EtHg was cytotoxic. Inhibition of autophagic flux by chloroquin increased autophagosome formation and necrotic cell death in HK-2 cells. Collectively, our results show that EtHg induces autophagy via oxidative and ER stress and blockade of autophagic flux. Autophagy might play a dual role in EtHg-induced renal toxicity, being both protective following treatment with low doses of EtHg and detrimental following treatment with high doses.


Asunto(s)
Autofagosomas/efectos de los fármacos , Autofagia , Estrés del Retículo Endoplásmico/efectos de los fármacos , Compuestos de Etilmercurio/toxicidad , Lisosomas/efectos de los fármacos , Estrés Oxidativo/efectos de los fármacos , Animales , Calcio/metabolismo , Línea Celular , Relación Dosis-Respuesta a Droga , Humanos , Riñón/efectos de los fármacos , Túbulos Renales Proximales/efectos de los fármacos , Potencial de la Membrana Mitocondrial , Ratones , Ratones Endogámicos C57BL , Ratas , Especies Reactivas de Oxígeno/metabolismo , Respuesta de Proteína Desplegada
5.
Immunopharmacol Immunotoxicol ; 38(5): 311-8, 2016 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-27310149

RESUMEN

Cimicifugae rhizoma has been widely used as a traditional herbal medicine to treat inflammation and menopausal symptoms. In this study, we found that some of the triterpenoidal saponins purified from the ethanol extract of Cimicifugae rhizoma dramatically induced histamine release. The structure-related induction of mast cell degranulation by them and the mechanism of action were determined. ß-Hexosaminidase release in HMC-1 cells was increased in a concentration-dependent manner, with maximal 6.5- and 8.5-fold increases, by 200 µg/mL 24-epi-7,8-didehydrocimigenol-3-O-xyloside (comp 1) and cimigenol 3-O-beta-d-xyloside (comp 4) compared with those treated with phorbol 12-myristate 13-acetate and A23187 (PMACI), respectively. However, ß-hexosaminidase release was not changed by 7,8-dihydrocimigenol (comp 3), or 23-OAc-shengmanol-3-O-xyloside (comp 7). These triterpenoidal saponins changed neither the intracellular Ca(2+ )level nor the activation of PKC, both of which play essential roles in histamine release. However, cromolyn and ketotifen, membrane stabilizers, effectively inhibited the ß-hexosaminidase release induced by comp 1 or comp 4 by 39 and 45%, respectively. Collectively, xylose on the cimigenol-related backbone among triterpene glycosides isolated from Cimicifugae rhizoma may play an important role in activating mast cells and induction of degranulation partly via membrane destabilization of mast cells.


Asunto(s)
Señalización del Calcio/efectos de los fármacos , Degranulación de la Célula/efectos de los fármacos , Cimicifuga/química , Mastocitos/inmunología , Saponinas/farmacología , Triterpenos/farmacología , Animales , Señalización del Calcio/inmunología , Degranulación de la Célula/inmunología , Línea Celular Tumoral , Humanos , Ratas , Saponinas/química
6.
Reprod Toxicol ; 60: 156-66, 2016 04.
Artículo en Inglés | MEDLINE | ID: mdl-26867867

RESUMEN

The endocrine-disrupting effects of androgenic signaling play crucial roles in several androgen-related diseases. In attempting to develop an in vitro cell line to be used in androgen receptor (AR)-mediated reporter gene assays, we developed a stable 22Rv1/MMTV cell line, which is a human prostate cancer cell line that endogenously expresses functional AR, to evaluate AR-mediated transcriptional activation (TA). Using 22Rv1/MMTV cells, we established and optimized a test protocol for the AR-TA assay and validated the proposed assay using 20 compounds recommended by the Interagency Coordinating Committee on the Validation of Alternative Methods (ICCVAM). All the performance parameters for agonist and antagonist assays were 91-100% comparable between the 22Rv1/MMTV assay and the ICCVAM report. In conclusion, the AR-TA assay using 22Rv1/MMTV cells might be a quick and relatively inexpensive method for screening large numbers of chemicals for their potential to activate or inhibit AR-mediated gene transcription.


Asunto(s)
Antagonistas de Andrógenos/farmacología , Andrógenos/farmacología , Receptores Androgénicos/genética , Activación Transcripcional/efectos de los fármacos , Bioensayo , Línea Celular Tumoral , Genes Reporteros , Humanos , Luciferasas/metabolismo
7.
J Chromatogr Sci ; 54(3): 390-6, 2016 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-26499118

RESUMEN

The purpose of this study was to develop a simultaneous method to quantify 10 bioactive compounds in Rhus verniciflua extracts using high-performance liquid chromatography-tandem mass spectrometry. The chromatographic separation was performed using a C18 column under gradient elution with 0.1% formic acid and acetonitrile as the mobile phase solvents. The analytes were detected in the negative-ion mode using multiple-reaction monitoring detection with an electrospray ionization interface. The calibration curves for all the analytes showed good linearity (r(2) >0.997) over the concentration range of 1-1,000 ng/mL. The recovery values were within 89.53-110.14%, and the intra- and interday coefficients of variation were <4.86% for all the tested compounds. The developed method was successfully applied to a quality assessment of the R. verniciflua extract samples.


Asunto(s)
Cromatografía Liquida/normas , Flavonoides/aislamiento & purificación , Ácido Gálico/aislamiento & purificación , Extractos Vegetales/química , Rhus/química , Espectrometría de Masas en Tándem/normas , Acetonitrilos , Calibración , Cromatografía Liquida/métodos , Formiatos , Humanos , Variaciones Dependientes del Observador , Sensibilidad y Especificidad , Solventes , Espectrometría de Masa por Ionización de Electrospray , Espectrometría de Masas en Tándem/métodos
8.
J Agric Food Chem ; 63(22): 5410-6, 2015 Jun 10.
Artículo en Inglés | MEDLINE | ID: mdl-25998231

RESUMEN

Rhus verniciflua (Toxicodendron vernicifluum) is a medicinal tree popularly used in Asian countries such as China, Japan, and Korea as a food additive or herbal medicine because of its beneficial effects. R. verniciflua extract (RVE) contains diverse phenolic compounds, such as flavonoids, as its major biological active constituents. In this study, the pharmacokinetic profiles of eight phenolic compounds were investigated following oral administration of RVE to rats. The eight phenolic compounds were 2,4-dihydroxybenzoic acid, 3,4-dihydroxybenzoic acid, fisetin, fustin, butin, sulfuretin, taxifolin, and garbanzol. The plasma concentrations of the eight compounds were determined by using a liquid chromatography-triple-quadrupole mass spectrometer before and after treatment with ß-glucuronidase. When 1.5 g/kg RVE was administered, the eight compounds were all detected in plasma, mainly as conjugated forms. These pharmacokinetic data would be useful for understanding the pharmacological effects of RVE.


Asunto(s)
Fenoles/farmacocinética , Extractos Vegetales/farmacocinética , Rhus/química , Administración Oral , Animales , Masculino , Estructura Molecular , Fenoles/administración & dosificación , Fenoles/sangre , Corteza de la Planta/química , Extractos Vegetales/administración & dosificación , Extractos Vegetales/sangre , Ratas , Ratas Sprague-Dawley , República de Corea
9.
Toxicol Appl Pharmacol ; 285(3): 159-69, 2015 Jun 15.
Artículo en Inglés | MEDLINE | ID: mdl-25902338

RESUMEN

Cytochrome P450 (CYP) 1A1 is a heme-containing enzyme involved in detoxification of hydrophobic pollutants. Its Ala62Pro variant has been identified previously. Ala62 is located in α-helix A of CYP1A1. Residues such as Pro and Gly are α-helix breakers. In this study, the Ala62Pro variant was characterized using heterologous expression. E. coli expressing the Ala62Pro variant, and the purified variant protein, had lower CYP (i.e. holoenzyme) contents than their wild-type (WT) equivalents. The CYP variant from E. coli and mammalian cells exhibited lower 7-ethoxyresorufin O-dealkylation (EROD) and benzo[a]pyrene hydroxylation activities than the WT. Enhanced supplementation of a heme precursor during E. coli culture did not increase CYP content in E. coli expressing the variant, but did for the WT. As for Ala62Pro, E. coli expressing an Ala62Gly variant had a lower CYP content than the WT counterpart, but substitution of Ala62 with α-helix-compatible residues such as Ser and Val partially recovered the level of CYP produced. Microsomes from mammalian cells expressing Ala62Pro and Ala62Gly variants exhibited lower EROD activities than those expressing the WT or Ala62Val variant. A region harboring α-helix A has interactions with another region containing heme-interacting residues. Site-directed mutagenesis analyses suggest the importance of interactions between the two regions on holoenzyme expression. Together, these findings suggest that the Ala62Pro substitution leads to changes in protein characteristics and function of CYP1A1 via structural disturbance of the region where the residue is located.


Asunto(s)
Citocromo P-450 CYP1A1/genética , Proteínas Recombinantes/genética , Secuencia de Aminoácidos , Animales , Benzo(a)pireno/metabolismo , Células CHO , Clonación Molecular , Cricetulus , Citocromo P-450 CYP1A1/metabolismo , Escherichia coli/genética , Hemo/química , Humanos , Hidroxilación , Microsomas/metabolismo , Modelos Moleculares , Datos de Secuencia Molecular , Mutagénesis Sitio-Dirigida , Sistemas de Lectura Abierta , Oxazinas/metabolismo , Polimorfismo Genético , Conformación Proteica , Proteínas Recombinantes/metabolismo , Alineación de Secuencia
10.
Arch Pharm Res ; 38(11): 2049-58, 2015 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-25784057

RESUMEN

Rhus verniciflua stokes (RVS) is a popular medicinal plant in oriental medicines which is commonly used to resolve extravasated blood. To elucidate the molecular mechanism of the role of RVS extracts on the regulation of lipid and cholesterol biosynthesis, we investigated whether RVS extract protect the hyperlipidemia in western diet-induced C57BL6/J mice. Mice fed a western diet and additionally RVS extracts was administered orally at a dose of 0.1 or 1 g/kg/day for 2 weeks respectively. Group with higher dose of RVS extract showed a significantly decreased body weight compared with western diet fed mice groups. And total cholesterol, LDL-cholesterol levels and fatty liver formation were also improved especially in group of mice fed western diet supplemented high dose RVS extracts. Next, synthesis of hepatic bile acids were significantly increased in RVS extract fed groups. Furthermore, RVS extracts significantly increase promoter activity of Cyp7a1 via up-regulate the transcriptional expression level of LXRα. Our data suggest that RVS extracts could be a potent therapeutic ingredient for prevent a hyperlipidemia via increase of bile acids biosynthesis.


Asunto(s)
Ácidos y Sales Biliares/biosíntesis , Hiperlipidemias/prevención & control , Extractos Vegetales/farmacología , Rhus/química , Animales , Colesterol/biosíntesis , Colesterol 7-alfa-Hidroxilasa/metabolismo , Dieta Occidental/efectos adversos , Relación Dosis-Respuesta a Droga , Lípidos/biosíntesis , Receptores X del Hígado , Masculino , Ratones , Ratones Endogámicos C57BL , Receptores Nucleares Huérfanos/genética , Extractos Vegetales/administración & dosificación
11.
J Med Food ; 18(1): 21-30, 2015 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-25372471

RESUMEN

Rhus verniciflua stokes (RVS) is known to promote blood circulation by preventing blood stasis, although the active ingredients and the underlying mechanism are unclear. Platelets are the primary cells that regulate circulation and contribute to the development of diverse cardiovascular diseases by aggregation and thrombosis. The study assessed the antiplatelet activity of RVS and sought to identify the active constituents. Pretreatment of washed platelets with RVS heartwood extract blunted the aggregatory response of platelets to collagen. In the subfractions, fisetin, butein, and sulfuretin were identified as effective inhibitors of platelet aggregation by collagen, thrombin, and adenosine-5'-diphosphate. Antiplatelet activities of all three compounds were concentration dependent, and fisetin had longer in vitro duration of action compared with butein or sulfuretin. Extracellular signal-regulated kinase (ERK) mitogen-activated protein kinase activation by collagen was prevented by fisetin, whereas butein and sulfuretin failed to inhibit ERK and p38 activation was not affected by any of the compounds. Rats orally administered 100 mg/(kg·day(-1)) fisetin for 7 days were resistant to arterial thrombosis, although total extract of RVS heartwood exhibited little effect at a dose of 1000 mg/(kg·day(-1)). RVS heartwood may have cardiovascular protective activity by inhibiting platelet aggregation. The active constituents are fisetin, butein, and sulfuretin, and fisetin is orally effective against thrombosis.


Asunto(s)
Benzofuranos/farmacología , Plaquetas/efectos de los fármacos , Chalconas/farmacología , Flavonoides/farmacología , Inhibidores de Agregación Plaquetaria/farmacología , Agregación Plaquetaria/efectos de los fármacos , Rhus/química , Animales , Benzofuranos/uso terapéutico , Enfermedades Cardiovasculares/metabolismo , Enfermedades Cardiovasculares/prevención & control , Chalconas/uso terapéutico , Relación Dosis-Respuesta a Droga , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Flavonoides/uso terapéutico , Flavonoles , Masculino , Fitoterapia , Extractos Vegetales/farmacología , Extractos Vegetales/uso terapéutico , Inhibidores de Agregación Plaquetaria/uso terapéutico , Ratas Sprague-Dawley , Trombosis/metabolismo , Trombosis/prevención & control , Madera/química , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismo
12.
Anal Bioanal Chem ; 406(14): 3443-9, 2014 May.
Artículo en Inglés | MEDLINE | ID: mdl-24705958

RESUMEN

Aromatase (CYP 19A1) is a key steroidogenic enzyme that catalyzes the conversion of androgen to estrogen. In this study, a liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for aromatase inhibitor screening was developed and validated. The substrate androstenedione was incubated with human CYP 19A1 supersomes in the presence of NADPH for 30 min, and estrone formation was determined by LC-MS/MS analysis. Cortisone was used as internal standard. The incubation mixture was extracted using a liquid-liquid extraction method with ethyl acetate. Chromatographic separation was achieved using a C18 column (3.0 × 50 mm, 2.7 µm) with a mobile phase consisting of 0.1% formic acid/acetonitrile adopting gradient elution at a flow rate of 0.4 mL/min. The mass spectrometer was operated in positive electrospray ionization mode. The precursor-product ion pairs used for multiple reaction monitoring were m/z 287→97 (androstenedione), m/z 271 → 159 (estrone), and m/z 361 → 163 (IS, cortisone). The developed method met the required criteria for the validation of bioanalytical methods. The validated method was successfully applied to evaluate aromatase inhibitory activity of plants extracts of Simaroubaceae.


Asunto(s)
Inhibidores de la Aromatasa/análisis , Aromatasa/química , Cromatografía Liquida/métodos , Espectrometría de Masas en Tándem/métodos , Cromatografía Líquida de Alta Presión , Cortisona/química , Relación Dosis-Respuesta a Droga , Ensayo de Inmunoadsorción Enzimática , Estrona/química , Humanos , Extracción Líquido-Líquido , Extractos Vegetales , Reproducibilidad de los Resultados , Simaroubaceae
13.
Bioorg Med Chem Lett ; 24(7): 1730-3, 2014 Apr 01.
Artículo en Inglés | MEDLINE | ID: mdl-24630560

RESUMEN

Rhus verniciflua Stokes has been used as a traditional herbal medicine in Asia. In this study, the effect of R. verniciflua extract on human aromatase (cytochrome P450 19, CYP19) activity was investigated to elucidate the mechanism for the effect of R. verniciflua extract on androgen hormone levels. Androstenedione was used as a substrate and incubated with R. verniciflua extract in cDNA-expressed CYP19 supersomes in the presence of NADPH, and estrone formation was measured using liquid chromatography-tandem mass spectrometry. R. verniciflua extract was assessed at concentrations of 10-1000 µg/mL. The resulting data showed that R. verniciflua extract inhibited CYP19-mediated estrone formation in a concentration-dependent manner with an IC50 value of 136 µg/mL. Subsequently, polyphenolic compounds from R. verniciflua extract were tested to identify the ingredients responsible for the aromatase inhibitory effects by R. verniciflua extract. As a result, butin showed aromatase inhibitory effect in a concentration-dependent manner with an IC50 value of 9.6 µM, whereas the inhibition by other compounds was negligible. These results suggest that R. verniciflua extract could modulate androgen hormone levels via the inhibition of CYP19 activity and butin is a major ingredient responsible for this activity.


Asunto(s)
Inhibidores de la Aromatasa/farmacología , Aromatasa/metabolismo , Benzopiranos/farmacología , Extractos Vegetales/farmacología , Estructuras de las Plantas/química , Rhus/química , Inhibidores de la Aromatasa/química , Inhibidores de la Aromatasa/aislamiento & purificación , Benzopiranos/química , Benzopiranos/aislamiento & purificación , Relación Dosis-Respuesta a Droga , Humanos , Medicina Tradicional , Estructura Molecular , Extractos Vegetales/química , Extractos Vegetales/aislamiento & purificación , Relación Estructura-Actividad
14.
Chem Res Toxicol ; 26(11): 1652-9, 2013 Nov 18.
Artículo en Inglés | MEDLINE | ID: mdl-24138086

RESUMEN

The kidney is the most important organ for the excretion of pharmaceuticals and their metabolites. Among the complex structures of the kidney, the proximal tubule and renal interstitium are major targets of nephrotoxins. Despite its importance, there are only a few in silico models for predicting human nephrotoxicity for drug candidates. Here, we present quantitative structure-activity relationship (QSAR) models for three common patterns of drug-induced kidney injury, i.e., tubular necrosis, interstitial nephritis, and tubulo-interstitial nephritis. A support vector machine (SVM) was used to build the binary classification models of nephrotoxin versus non-nephrotoxin with eight fingerprint descriptors. To build the models, we constructed two types of data sets, i.e., parent compounds of pharmaceuticals (251 nephrotoxins and 387 non-nephrotoxins) and their major urinary metabolites (307 nephrotoxins and 233 non-nephrotoxins). Information on the nephrotoxicity of the pharmaceuticals was taken from clinical trial and postmarketing safety data. Though the mechanisms of nephrotoxicity are very complex, by using the metabolite information, the predictive accuracies of the best models for each type of kidney injury were better than 83% for external validation sets. Software to predict nephrotoxicity is freely available from our Web site at http://bmdrc.org/DemoDownload .


Asunto(s)
Riñón/lesiones , Modelos Biológicos , Preparaciones Farmacéuticas/metabolismo , Simulación por Computador , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos , Humanos , Internet , Riñón/efectos de los fármacos , Riñón/metabolismo , Preparaciones Farmacéuticas/orina , Relación Estructura-Actividad Cuantitativa , Programas Informáticos , Máquina de Vectores de Soporte , Interfaz Usuario-Computador
15.
Food Chem ; 141(4): 3813-9, 2013 Dec 15.
Artículo en Inglés | MEDLINE | ID: mdl-23993553

RESUMEN

A simple, sensitive, and precise reversed-phase liquid chromatographic method was developed for the quantitative determination of 4 bioactive phenolic compounds (gallic acid, fustin, fisetin, and sulfuretin) from the stem extract of Rhus verniciflua stokes. Chromatographic analysis was performed on a Capcell Pak C18 column (150 × 4.6 mm, 3 µm) with a mobile phase consisting of 0.1% formic acid and 90% acetonitrile at a flow rate of 1 mL/min. Quantitation was performed using a UV-vis detector at 260 nm. The method was validated in terms of selectivity, linearity, accuracy, precision, and recovery. Excellent linear behavior was observed over the investigated concentration range (10-500 µg/mL for gallic acid, fustin, and fisetin; 0.5-100 µg/mL for sulfuretin) with correlation coefficient (r(2)) values >0.99. The intra- and inter-day precision over the concentration range of compounds was less than 6.65% (relative standard deviation) and the accuracy was between 92.42% and 103.62%. The mean recoveries for all the analytes were more than 92.18%. This method was successfully applied for the analysis of bioactive phenolic compounds in the R. verniciflua extracts.


Asunto(s)
Cromatografía Líquida de Alta Presión/métodos , Fenoles/análisis , Extractos Vegetales/análisis , Rhus/química , Tallos de la Planta/química
16.
Am J Chin Med ; 41(4): 945-55, 2013.
Artículo en Inglés | MEDLINE | ID: mdl-23895162

RESUMEN

Hovenia dulcis (H. dulcis) Thunb., which is distributed in Korea, China, and Japan, has been known to show hepatoprotective and free radical scavenging effects and enhance physical activity. Therefore, the objectives of this present study were to determine the anti-fatigue activity of hot-water extract from H. dulcis peduncle, and to find the reason why H. dulcis extract (HDE)-ingested mice had enhanced physical activity against swimming performance. The mice orally administrated with HDE (HDE-mice) dramatically enhanced their swimming time compared to the control mice. HDE significantly decreased serum levels of stress hormones, such as cortisol and adrenocorticotropic hormone (ACTH) in mice. The levels of thiobarbituric acid reactive substances (TBARS) were dramatically decreased in gastrocnemius muscle from both 100 mg/kg of HDE (LHDE) and 200 mg/kg of HDE (HHDE)-ingested mice compared to the control mice. The liver activities of superoxide dismutase (SOD) were significantly increased in HHDE-mice with increasing tendency in LHDE-mice. In addition, HHDE-mice significantly decreased the levels of blood glucose, total cholesterol (T-Chol), and triglyceride (TG). These results suggest that HDE had a significant anti-fatigue effect via its anti-stress and antioxidant activities, and thereby enhanced physical activity in swimming performance.


Asunto(s)
Hormona Adrenocorticotrópica/efectos de los fármacos , Antioxidantes/farmacología , Fatiga/metabolismo , Actividad Motora/efectos de los fármacos , Extractos Vegetales/farmacología , Rhamnaceae , Hormona Adrenocorticotrópica/sangre , Animales , Modelos Animales de Enfermedad , Fatiga/sangre , Hidrocortisona/sangre , Hígado/efectos de los fármacos , Hígado/metabolismo , Masculino , Ratones , Superóxido Dismutasa/efectos de los fármacos , Superóxido Dismutasa/metabolismo , Superóxido Dismutasa-1 , Natación , Sustancias Reactivas al Ácido Tiobarbitúrico/metabolismo
17.
Protein Expr Purif ; 89(1): 44-50, 2013 May.
Artículo en Inglés | MEDLINE | ID: mdl-23459292

RESUMEN

CYP3A4 is the most abundant cytochrome P450 in the human liver. The expression level of CYP3A4 when coexpressed with cytochrome b(5) (cyt b(5)) in Escherichia coli was 20-60% higher than that when it was expressed alone over an extended period (48-72 h). This time-dependent elevation in coexpression with cyt b(5) was a result of an increase in CYP3A4 mRNA half-life; no significant change in CYP3A4 degradation was seen in the bacterial protease fraction. These results suggest that the higher CYP3A4 levels observed upon coexpression with cyt b(5) primarily resulted from CYP3A4 mRNA stabilization by cyt b(5).


Asunto(s)
Citocromo P-450 CYP3A/biosíntesis , Citocromos b5/biosíntesis , Hígado/enzimología , Oxidación-Reducción , Citocromo P-450 CYP3A/genética , Citocromos b5/genética , Escherichia coli , Regulación Bacteriana de la Expresión Génica , Humanos , Cinética , ARN Mensajero/genética , ARN Mensajero/metabolismo
18.
Toxicol Mech Methods ; 23(6): 437-48, 2013 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-23517440

RESUMEN

The specific properties of silver nanoparticles (AgNPs), such as antimicrobial activity and electrical conductivity, allow them to be used in many fields. However, their expanding application is also raising health, environmental and safety concerns. Previous in vivo AgNP toxicity studies have indicated a gender-different accumulation of silver in the kidneys, with 2-3 times more silver in female kidneys compared to male kidneys. However, no other studies have further addressed this gender difference. Accordingly, the current study investigated the gender-dependent effect of AgNPs on the kidney gene level based on toxicogenomic studies of kidneys obtained from rats exposed to AgNPs via inhalation for 12 weeks. When compared with the fresh air control, the silver nanoparticle-exposed kidneys included 104 genes with a more than 1.3-fold expression increase. For the male rat kidneys exposed to a low or high dose of silver nanoparticles, 96 genes exhibited expression changes, where six genes changed with both the low and high dose; four increased and two decreased. Meanwhile, for the female rat kidneys exposed to a low or high dose of silver nanoparticles, 66 genes exhibited expression changes, where 11 genes changed with both the low and high dose; nine increased and two decreased. Gender-dependent gene expression changes of more than 2-fold were linked to 163 genes, with 79 genes in the male kidneys and 84 genes in the female kidneys, plus gender-dependent gene expression changes of more than 5-fold were linked to 21 genes. However, no genes involved in apoptosis or the cell cycle were activated by the 12-week silver nanoparticle inhalation exposure. Overall, the male rat kidneys showed a higher expression of genes involved in xenobiotic metabolism, while the female rat kidneys showed a higher expression of genes involved in extracellular signaling.


Asunto(s)
Exposición por Inhalación/efectos adversos , Riñón/efectos de los fármacos , Nanopartículas del Metal/toxicidad , Caracteres Sexuales , Plata/toxicidad , Transcriptoma/efectos de los fármacos , Animales , Relación Dosis-Respuesta a Droga , Femenino , Perfilación de la Expresión Génica , Riñón/metabolismo , Masculino , Nanopartículas del Metal/química , Análisis de Secuencia por Matrices de Oligonucleótidos , Tamaño de la Partícula , Ratas , Ratas Sprague-Dawley , Plata/química , Pruebas de Toxicidad Subcrónica
19.
Biochem Biophys Res Commun ; 431(4): 746-52, 2013 Feb 22.
Artículo en Inglés | MEDLINE | ID: mdl-23348226

RESUMEN

GDK-100017, a 2,3,6-trisubstituted quinoxaline derivative, reduced ß-catenin-T-cell factor/lymphoid enhancer factor (TCF/LEF)-dependent transcriptional activity and inhibited cell proliferation in a dose-dependent manner with an IC50 value of about 10 µM in A549/Wnt2 cells. GDK-100017 down-regulated the expression of Wnt/ß-catenin pathway target genes such as cyclin D1 and Dkk1 but not c-myc or survivin. GDK-100017 inhibited cell proliferation by arresting the cell cycle in the G1 phase not only in A549/wnt2 cells but also in SW480 colon cancer cells. In addition to its wnt signaling inhibitory properties, GDK-100017 also enhanced the radiosensitivity of the A549 human NSCLC line. These results suggest that GDK-100017 possesses potential anti-cancer activity by inhibiting the Wnt/ß-catenin signal pathway, blocking the ß-catenin-TCF/LEF interaction, and enhancing radiosensitivity.


Asunto(s)
Antineoplásicos/farmacología , Proliferación Celular/efectos de los fármacos , Quinoxalinas/farmacología , Tolerancia a Radiación/efectos de los fármacos , Fármacos Sensibilizantes a Radiaciones/farmacología , Proteínas Wnt/antagonistas & inhibidores , beta Catenina/antagonistas & inhibidores , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Ciclo Celular/efectos de los fármacos , Línea Celular Tumoral , Neoplasias del Colon/metabolismo , Ciclina D1/metabolismo , Humanos , Neoplasias Pulmonares/metabolismo , Quinoxalinas/química , Mucosa Respiratoria/efectos de los fármacos , Vía de Señalización Wnt/efectos de los fármacos
20.
Biosci Biotechnol Biochem ; 76(5): 923-7, 2012.
Artículo en Inglés | MEDLINE | ID: mdl-22738960

RESUMEN

This study characterizes the correlation between the chemical fingerprint and estrogenic activity of an Epimedium koreanum extract. The estrogenic activity of 31 E. koreanum extract samples was evaluated by a luciferase reporter gene assay, and the samples were classified into 3 groups based on their bioactivity. A chemical fingerprint analysis was performed on each sample by high-performance liquid chromatography (HPLC), and 44 common peaks were selected from the chromatogram and used as a dataset for a pattern recognition analysis. A canonical discriminant analysis performed on this dataset determined a distinct distribution of the samples according to their estrogenic activity on the scoring plot. The classification results showed that 90.3% of the original grouped cases had been correctly classified. The total content of the 4 major extract compounds, epimedin A, epimedin B, epimedin C, and icariin, exhibited good correlation (r=0.784) with the estrogenic activities of the respective extracts. This chromatographic fingerprint-chemometric analysis system could be useful for predicting the E. koreanum pharmacological activity and consequent biological activity-relevant quality control assessment.


Asunto(s)
Epimedium/química , Estrógenos/biosíntesis , Estrógenos/farmacología , Extractos Vegetales/farmacología , Hojas de la Planta/química , Línea Celular Tumoral , Cromatografía Líquida de Alta Presión , Análisis Discriminante , Estrógenos/aislamiento & purificación , Estrógenos/metabolismo , Flavonoides/aislamiento & purificación , Flavonoides/farmacología , Genes Reporteros , Humanos , Luciferasas , Extractos Vegetales/química
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