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1.
Biochem Pharmacol ; 155: 252-263, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-30009768

RESUMO

Estrogen plays a pivotal role in the pathological development of breast cancer. Resveratrol has chemo-preventive effects against breast cancer, whereas, the mechanism of antitumor activities of resveratrol remains unanswered. In this study, we showed that estrogen homeostasis profile was disturbed in both breast cancer patients and in experimental breast cancer model rats, with carcinogenic catechol estrogens significantly accumulated in the mammary tissues. UDP-glucuronosyltransferase 1A8 (UGT1A8) is an important phase II drug-metabolizing enzymes which involved in the metabolism of catechol estrogens. Here we found that the mammary nuclear factor erythroid 2-related factor 2 (NRF2) - UGT1A8 signaling was down-regulated in breast cancer rats, whereas treatment with resveratrol could upregulate the expression of NRF2 and UGT1A8, accelerate metabolic elimination of catechol estrogens, inhibit estrogen-induced DNA damage and suppress the pathological development of breast cancer. In addition, luciferase reporter assay suggested that resveratrol activated the expression of UGT1A8 by up-regulating the transcriptional activity of NRF2. Small-interfering RNA-mediated silencing of NRF2 abolished resveratrol-mediated preventive effects indicated that the antitumor effect of resveratrol is based on NRF2-UGT1A8-estrogen metabolism axis. Taken together, we established the resveratrol regulating potential on estrogen homeostasis based on NRF2-UGT1A8 signaling pathway, and also provided a novel link between estrogen glucuronidation metabolism and breast cancer pathological development.


Assuntos
Antineoplásicos Fitogênicos/uso terapêutico , Neoplasias da Mama/metabolismo , Estrogênios/metabolismo , Glucuronosiltransferase/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Resveratrol/uso terapêutico , Adulto , Animais , Antineoplásicos Fitogênicos/farmacologia , Neoplasias da Mama/tratamento farmacológico , Linhagem Celular , Estrogênios/análise , Feminino , Glucuronosiltransferase/análise , Humanos , Fator 2 Relacionado a NF-E2/análise , Ratos , Ratos Sprague-Dawley , Resveratrol/farmacologia , Espectrometria de Massas em Tandem/métodos
2.
Acta Biochim Pol ; 65(1): 35-41, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29281744

RESUMO

One of the earliest critical secondary complications of diabetes is the opacification of the eye lens - a condition strictly associated with diabetic cataract. The study presented here was designed to investigate the effect of Ginkgo biloba extract (GbE), rutin and quercetin on streptozotocin (STZ) induced diabetic cataract (DC) rats. Ten weeks after administration of GbE, rutin and quercetin, the opacity of diabetic rats' lenses was graded under a slit lamp. Then, the levels of malondialdehyde (MDA), reduced glutathione (GSH), advanced glycosylation end products (AGEs), and the activities of aldose reductase (AR) were estimated. The DC-induced rats produced less GSH, higher levels of MDA and AGEs as well as elevated AR activity when compared to the normal group. Administration of GbE, rutin and quercetin remarkably inhibited the AR activity, stimulated the production of glutathione, and decreased the levels of MDA and AGEs in the lenses of DC-induced rats, which eventually delayed the progression of lens opacification in diabetic rats to various degrees. Our results revealed that quercetin had the highest significant (P<0.05) potential to delay the progression of STZ-induced diabetic cataract when compared with rutin and GbE. The mechanism dictating this interesting prowess of quercetin might be attributed to its AR inhibitory strength, anti-lipid peroxidation potential and anti-AGEs activity.


Assuntos
Catarata/tratamento farmacológico , Complicações do Diabetes/tratamento farmacológico , Estresse Oxidativo/efeitos dos fármacos , Aldeído Redutase/efeitos dos fármacos , Animais , Catarata/etiologia , Catarata/prevenção & controle , Diabetes Mellitus Experimental , Cristalino/patologia , Extratos Vegetais/uso terapêutico , Polímeros/metabolismo , Quercetina/uso terapêutico , Ratos , Rutina/uso terapêutico
3.
J Pharm Sci ; 106(8): 2152-2162, 2017 08.
Artigo em Inglês | MEDLINE | ID: mdl-28479355

RESUMO

The progression of breast cancer is closely related to the levels of estrogens within the body. UDP-glucuronosyltransferase (UGT) is an important class of phase II metabolizing enzymes, playing a pivotal role in detoxifying steroid hormone. In the present study, we aim at uncovering the potential dysregulation pattern of UGT and its role in estrogen metabolism and in the pathogenesis of breast cancer. Female Sprague-Dawley rats were treated with 100 mg/kg dimethylbenz(a)anthracene (DMBA) to induce breast cancer. Our results showed that the expression and activity of UGT in mammary tissues were downregulated significantly in DMBA rats. Consistent with this, levels of estradiol, 4-hydroxylated estradiol, and 2-hydroxylated estradiol were increased in both mammary tissues and serum, supporting a notable accumulation of toxic estrogen species in the target tissue of breast cancer. In addition, we also observed the decreased cell migration, cell proliferation, and DNA damage in UGT-transfected MCF-7 cells, suggesting a protective role of UGT against estrogen-induced mammary carcinogenesis. Taken together, these results indicated that accumulation of estrogens induced by UGT deficiency is a critical factor to induce the development of breast cancer. UGT contributes to estrogen elimination, and its glucuronidation capacity influences the estrogen signaling pathway and the pathogenesis of breast cancer.


Assuntos
Neoplasias da Mama/metabolismo , Mama/metabolismo , Estrogênios/metabolismo , Glucuronosiltransferase/metabolismo , Animais , Mama/patologia , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Regulação para Baixo , Estradiol/análise , Estradiol/metabolismo , Estrogênios/análise , Feminino , Regulação Neoplásica da Expressão Gênica , Glucuronosiltransferase/genética , Humanos , Células MCF-7 , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , Ratos , Ratos Sprague-Dawley
4.
J Chromatogr Sci ; 55(8): 839-845, 2017 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-28505281

RESUMO

A new type of partially substituted 3,5-dimethylphenylcarbamate-(3-(2-O-ß-cyclodextrin)-2-hydroxypropoxy)-propylsilyl-appended silica particles (MP-CD-HPS) have been prepared by a convenient post-immobilization derivazition procedure. The MP-CD-HPS has been successfully used as chiral stationary phase (CSP) for high-performance liquid chromatography (HPLC) under normal phase, reversed phase and polar organic mobile phase conditions. The chromatographic evaluation results show that the MP-CD-HPS has excellent selectivity for the separation of aromatic positional isomers and enantiomers of some chiral compounds. The multi-mode HPLC separation results also indicate that both the stable ether spacer linking to the wider torus rim of ß-cyclodextrin in the MP-CD-HPS phase and the hydroxyl residues in the partially substituted ß-cyclodextrin have important contributions to chiral recognitions and chromatographic separations.

5.
Neural Regen Res ; 10(7): 1120-4, 2015 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-26330837

RESUMO

Necroptosis is characterized by programmed necrotic cell death and autophagic activation and might be involved in the death process of dopaminergic neurons in Parkinson's disease. We hypothesized that necrostatin-1 could block necroptosis and give protection to dopaminergic neurons. There is likely to be crosstalk between necroptosis and other cell death pathways, such as apoptosis and autophagy. PC12 cells were pretreated with necroststin-1 1 hour before exposure to 6-hydroxydopamine. We examined cell viability, mitochondrial membrane potential and expression patterns of apoptotic and necroptotic death signaling proteins. The results showed that the autophagy/lysosomal pathway is involved in the 6-hydroxydopamine-induced death process of PC12 cells. Mitochondrial disability induced overactive autophagy, increased cathepsin B expression, and diminished Bcl-2 expression. Necrostatin-1 within a certain concentration range (5-30 µM) elevated the viability of PC12 cells, stabilized mitochondrial membrane potential, inhibited excessive autophagy, reduced the expression of LC3-II and cathepsin B, and increased Bcl-2 expression. These findings suggest that necrostatin-1 exerted a protective effect against injury on dopaminergic neurons. Necrostatin-1 interacts with the apoptosis signaling pathway during this process. This pathway could be a new neuroprotective and therapeutic target in Parkinson's disease.

6.
Eur J Pharmacol ; 721(1-3): 355-64, 2013 Dec 05.
Artigo em Inglês | MEDLINE | ID: mdl-24036348

RESUMO

Advanced glycation endproducts (AGEs) and its precursor methylglyoxal are associated with diabetic nephropathy (DN). Mangiferin has many beneficial biological activities, including anti-inflammatory, anti-oxidative and anti-diabetic effects. We investigated the effect of mangiferin on DN and its potential mechanism associated with glyoxalase 1 (Glo-1), a detoxifying enzyme of methylglyoxal, in streptozotocin-induced rat model of DN. Diabetic rats were treated orally with mangiferin (15, 30, and 60 mg/kg) or distilled water for 9 weeks. Kidney tissues were collected for morphologic observation and the determination of associated biochemical parameters. The cultured mesangial cells were used to measure the activity of Glo-1 in vitro. Chronic treatment with mangiferin significantly ameliorated renal dysfunction in diabetic rats, as evidenced by decreases in albuminuria, blood urea nitrogen, kidney weight index, periodic acid-schiff stain positive mesangial matrix area, glomerular extracellular matrix expansion and accumulation, and glomerular basement membrane thickness. Meanwhile, mangiferin treatment caused substantial increases in the enzymatic activity of Glo-1 in vivo and in vitro, and protein and mRNA expression of Glo-1, reduced levels of AGEs and the protein and mRNA expression of their receptor (RAGE) in the renal cortex of diabetic rats. Moreover, mangiferin significantly attenuated oxidative stress damage as reflected by the lowered malondialdehyde and the increased glutathione levels in the kidney of diabetic rats. However, mangiferin did not affect the blood glucose and body weight of diabetic rats. Therefore, mangiferin can remarkably ameliorate DN in rats through inhibiting the AGEs/RAGE aix and oxidative stress damage, and Glo-1 may be a target for mangiferin action.


Assuntos
Diabetes Mellitus Experimental/complicações , Nefropatias Diabéticas/genética , Nefropatias Diabéticas/prevenção & controle , Progressão da Doença , Lactoilglutationa Liase/genética , Regulação para Cima/efeitos dos fármacos , Xantonas/farmacologia , Animais , Glicemia/metabolismo , Peso Corporal/efeitos dos fármacos , Nefropatias Diabéticas/sangue , Nefropatias Diabéticas/metabolismo , Jejum/sangue , Produtos Finais de Glicação Avançada/metabolismo , Masculino , Estresse Oxidativo/efeitos dos fármacos , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ratos , Ratos Sprague-Dawley , Receptor para Produtos Finais de Glicação Avançada , Receptores Imunológicos/genética , Receptores Imunológicos/metabolismo
7.
Psychopharmacology (Berl) ; 228(4): 585-94, 2013 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-23529380

RESUMO

RATIONALE: Evidences indicate that methylglyoxal, a highly reactive metabolite of hyperglycemia, can enhance protein glycation, oxidative stress, or inflammation. Mangiferin, a polyphenol compound of C-glucoside, has many beneficial biological activities, including anti-inflammation, anti-oxidation, neuroprotection, cognitive enhancement, etc. Whether mangiferin alleviates diabetes-associated cognitive impairment is still unclear. OBJECTIVES: The present study was designed to investigate the effects of mangiferin on the behavioral deficits of diabetic rats induced by streptozotocin; the mechanisms associated with methylglyoxal toxicity are especially investigated. METHODS: Diabetic rats were treated with mangiferin (15, 30, and 60 mg/kg, p.o.) for 9 weeks. Cognitive performances were evaluated with the Morris water maze. Hippocampus and blood were obtained for evaluation of the effects of mangiferin on protein glycation, oxidative stress, and inflammation in diabetic state. RESULTS: Mangiferin significantly improved the behavioral performances of diabetic rats, evidenced by a decrease in escape latency as well as increases in numbers of crossing the platform and percentage of time spent in the target quadrant, which were accompanied by decreases in the levels of advanced glycation end-products and their receptor (RAGE), interleukin-1ß, TNF-α, and malondialdehyde and increases in the activity and expression of glyoxalase 1 as well as glutathione level in the hippocampus of diabetic rats. Furthermore, mangiferin produced a significant decrease in malondialdehyde level and increased glutathione level and superoxide dismutase activity in the serum of diabetic rats. CONCLUSIONS: This study demonstrates that mangiferin can markedly ameliorate diabetes-associated cognitive decline in rats, which is done likely through suppressing methylglyoxal hyperactivity (promoting protein glycation, oxidative stress, and inflammation) mediated noxious effects.


Assuntos
Transtornos Cognitivos/tratamento farmacológico , Diabetes Mellitus Experimental/complicações , Aldeído Pirúvico/metabolismo , Xantonas/farmacologia , Animais , Comportamento Animal/efeitos dos fármacos , Transtornos Cognitivos/etiologia , Diabetes Mellitus Experimental/fisiopatologia , Relação Dose-Resposta a Droga , Glutationa/efeitos dos fármacos , Glutationa/metabolismo , Produtos Finais de Glicação Avançada/efeitos dos fármacos , Hipocampo/metabolismo , Inflamação/tratamento farmacológico , Inflamação/etiologia , Masculino , Malondialdeído/metabolismo , Aprendizagem em Labirinto/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Estreptozocina , Superóxido Dismutase/efeitos dos fármacos , Superóxido Dismutase/metabolismo , Xantonas/administração & dosagem
8.
Artigo em Inglês | MEDLINE | ID: mdl-23396113

RESUMO

The cytotoxic agent Gemcitabine (2',2'-difluoro-2'-deoxycytidine) has been proved to be effective in the treatment of malignant gliomas. A rapid, sensitive and specific ultra performance liquid chromatography with tandem mass spectrometry (UPLC-MS/MS) assay using microdialysis sampling was developed and validated to quantify gemcitabine and its major metabolite 2',2'-difluoro-2'-deoxyuridine (dFdU) in Sprague-Dawley rat bearing 9L glioma. Microdialysis probes were surgically implanted into the area of rat brain tumor in the striatal hemisphere, and artificial cerebrospinal fluid was used as a perfusion medium. The samples were analyzed directly by UPLC-MS/MS after the addition of 5-bromouracil as an internal standard (IS). Separation was achieved on Agilent SB-C(18) (50 mm × 2.1mm I.D., 1.8 µm) column at 40 °C using an isocratic elution method with acetonitrile and 0.1% formic acid (4:96, v/v) at a flow rate of 0.2 mL/min. Detection was performed using electrospray ionization in positive ion selected reaction monitoring mode by monitoring the following ion transitions m/z 264.0→112.0 (gemcitabine), m/z 265.1→113.0 (dFdU) and m/z 190.9→173.8 (IS). The calibration curves of gemcitabine and dFdU were linear in the concentration range of 0.66-677.08 ng/mL and 0.31-312.00 ng/mL, respectively. The lower limit of quantification of gemcitabine and dFdU were 0.66 ng/mL and 0.31 ng/mL, respectively. The lower limit of detection of gemcitabine and dFdU were calculated to be 0.2 ng/mL and 0.1 ng/mL, respectively. All the validation data, such as intra- and inter-day precision, accuracy, selectivity and stability, were within the required limits. The validated method was simple, precise and accurate, which was successfully employed to determinate the concentrations of gemcitabine and dFdU in the extracellular fluid of rat brain tumor.


Assuntos
Neoplasias Encefálicas/química , Cromatografia Líquida de Alta Pressão/métodos , Desoxicitidina/análogos & derivados , Floxuridina/análogos & derivados , Glioma/química , Microdiálise/métodos , Espectrometria de Massas em Tandem/métodos , Animais , Antimetabólitos Antineoplásicos/análise , Antimetabólitos Antineoplásicos/química , Antimetabólitos Antineoplásicos/farmacocinética , Antimetabólitos Antineoplásicos/uso terapêutico , Química Encefálica , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/metabolismo , Desoxicitidina/análise , Desoxicitidina/farmacocinética , Desoxicitidina/farmacologia , Estabilidade de Medicamentos , Floxuridina/análise , Floxuridina/farmacocinética , Glioma/tratamento farmacológico , Glioma/metabolismo , Limite de Detecção , Modelos Lineares , Masculino , Ratos , Ratos Sprague-Dawley , Reprodutibilidade dos Testes
9.
Zhongguo Zhong Yao Za Zhi ; 34(11): 1410-4, 2009 Jun.
Artigo em Chinês | MEDLINE | ID: mdl-19771874

RESUMO

OBJECTIVE: To observe the inhibitory effect of citrus extract nobiletin on K562 cells xenograft in nude mice and discuss its anticancer activity and mechanism. METHOD: The model of K562 cells xenograft was established in nude mice. Twenty-five nude mice were divided to five groups. After 24 hrs of inoculation with K562 tumor cells subcutaneously, 1% CMC-Na in the nude mice of model control group, nobiletin (12.5, 25, 50 mg x kg(-1)) in the nude mice of nobiletin groups and CTX (20 mg x kg(-1)) in positive control group were administered once every day. The nude mice were killed at 18th day-point of administration. The inhibitory rate of nobiletin on tumor was calculated according to the measured tumor weight. Immunohistochemistry assay was used to determine the effect of nobiletin on VEGF expression and MVD, and CAM assay was used to detect the effect of nobiletin on vessel regeneration. RESULT: Nobiletin have notable inhibition on K562 cells xenograft in nude mice comparing with model control group (P < 0.01), the inhibitory rate of nobiletin groups were 36% -58%. The results of immunohistochemical technology showed that the expression of VEGF in nobiletin groups decreased significantly comparing with the model control group (P < 0.05, P < 0.01, P < 0.01). Nobiletin could remarkably decrease the angiogenesis within tumor tissues. The expression of CD34 in nobiletin low dose group and high dose group was lower than that in model control group (P < 0.05, P < 0.01). The result of CAM indicated that 4 microg and 2 microg nobiletin could inhibit the new blood vessels of CAM (P < 0.01). CONCLUSION: Nobiletin inhibited the tumor growth and angiogenesis by reducing the VEGF expression of K562 cells xenograft in nude mice.


Assuntos
Inibidores da Angiogênese/farmacologia , Antineoplásicos/farmacologia , Citrus/química , Flavonas/farmacologia , Neoplasias/tratamento farmacológico , Animais , Modelos Animais de Doenças , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Células K562 , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Transplante de Neoplasias , Neoplasias/genética , Neoplasias/metabolismo , Transplante Heterólogo , Fatores de Crescimento do Endotélio Vascular/genética , Fatores de Crescimento do Endotélio Vascular/metabolismo
10.
Zhongguo Zhong Yao Za Zhi ; 32(23): 2511-4, 2007 Dec.
Artigo em Chinês | MEDLINE | ID: mdl-18330246

RESUMO

OBJECTIVE: To study the effect of C21 steroidal glycoside (CSG) from the root of Cynanchum auriculatum from Jiangsu on D-galactose (D-gal) induced aging model mice. METHOD: D-gal aging mouse model was established by cervicodorsal region subcutaneous injection with D-gal once a day for eight successive weeks. The mice in the normal control group (NCG, non-modeled) and the model control group (MCG, modeled but untreated) were treated with 1% CMC-Na. The model mice in the low, middle and high-dose CSG and Vitamin E treated groups were treated with a dose of (10, 20, 40, 100 mg x kg(-1) per day, respectively. The SOD activity, MDA content and telomerase activity in serum, heart, liver and brain tissues of mice were measured. RESULT: CSG could obviously increase the SOD activity and decrease the MDA level in serum, heart, liver and brain tissues in D-gal aging mice (P < 0.01). There was no significant difference between three CSG treated groups and Vitamin E treated groups. In comparison of telomerase activity between MCG and the treated groups, it was shown that there was a significant increase in serum in middle and high dose group, and in heart tissues in CSG and Vit E treated groups, but was not in liver and brain tissue. CONCLUSION: This study demonstrates that CSG can antagonize free radical injury, increase the SOD activity and decrease the MDA content of serum, heart, liver and brain in D-gal aging mice, and increase the telomerase activity in serum and heart tissues but not in liver and brain tissue.


Assuntos
Envelhecimento/efeitos dos fármacos , Cynanchum/química , Medicamentos de Ervas Chinesas/farmacologia , Raízes de Plantas/química , Envelhecimento/metabolismo , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Medicamentos de Ervas Chinesas/isolamento & purificação , Feminino , Galactose/toxicidade , Glicosídeos/isolamento & purificação , Glicosídeos/farmacologia , Fígado/efeitos dos fármacos , Fígado/metabolismo , Masculino , Malondialdeído/sangue , Malondialdeído/metabolismo , Camundongos , Camundongos Endogâmicos ICR , Miocárdio/metabolismo , Plantas Medicinais/química , Distribuição Aleatória , Esteroides/isolamento & purificação , Esteroides/farmacologia , Superóxido Dismutase/sangue , Superóxido Dismutase/metabolismo , Telomerase/metabolismo
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