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Find video protocols related to scientific articles indexed in Pubmed.
Pemetrexed is Mildly Active with Good Tolerability for Treatment of Patients with Colorectal Cancer.
Asian Pac. J. Cancer Prev.
PUBLISHED: 10-24-2014
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This systematic analysis was conducted to evaluate the efficacy and safety of pemetrexed based salvage chemotherapy for treatment of patients with metastatic colorectal cancer.
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Efficacy of Anti-RON Antibody Zt/g4-Drug Maytansinoid Conjugation (Anti-RON ADC) as a Novel Therapeutics for Targeted Colorectal Cancer Therapy.
Clin. Cancer Res.
PUBLISHED: 10-07-2014
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The receptor tyrosine kinase RON is critical in epithelial tumorigenesis and a drug target for cancer therapy. Here, we report the development and therapeutic efficacy of a novel anti-RON antibody Zt/g4-maytansinoid (DM1) conjugates for targeted colorectal cancer (CRC) therapy.
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Generation and characterization of a transgenic pig carrying a DsRed-monomer reporter gene.
PLoS ONE
PUBLISHED: 09-04-2014
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Pigs are an optimal animal for conducting biomedical research because of their anatomical and physiological resemblance to humans. In contrast to the abundant resources available in the study of mice, few fluorescent protein-harboring porcine models are available for preclinical studies. In this paper, we report the successful generation and characterization of a transgenic DsRed-Monomer porcine model.
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The Extract of Ziziphus jujuba Fruit (Jujube) Induces Expression of Erythropoietin Via Hypoxia-Inducible Factor-1? in Cultured Hep3B Cells.
Planta Med.
PUBLISHED: 09-03-2014
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The fruit of Ziziphus jujuba Mill., known as jujube or Chinese date, is commonly consumed as health supplement or herbal medicine worldwide. To study the beneficial role of jujube in enhancing hematopoietic function, we investigated its roles on the expression of erythropoietin in cultured Hep3B human hepatocellular carcinoma cells. Application of chemically standardized jujube water extract stimulated erythropoietin expression in a dose-dependent manner, with the highest response by ~?100?% of increase. A plasmid containing hypoxia response element, a critical regulator for erythropoietin transcription, was transfected into Hep3B cells. Application of jujube water extract onto the transfected cells induced the transcriptional activity of the hypoxia response element. To account for its transcriptional activation, the expression of hypoxia-inducible factor-1? was increased after treatment with jujube water extract: the increase was in both mRNA and protein levels. These results confirmed the hematopoietic function of jujube in the regulation of erythropoietin expression in liver cells.
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The sulfur-fumigation reduces chemical composition and biological properties of Angelicae Sinensis Radix.
Phytomedicine
PUBLISHED: 07-31-2014
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Angelica Sinensis Radix (roots of Angelica sinensis; ASR) is a popular herbal supplement in China for promoting blood circulation. Today, sulfur-fumigation is commonly used to treat ASR as a means of pest control; however, the studies of sulfur-fumigation on the safety and efficacy of ASR are very limited. Here, we elucidated the destructive roles of sulfur-fumigation on ASR by chemical and biological assessments. After sulfur-fumigation, the chemicals in ASR were significantly lost. The biological activities of anti-platelet aggregation, induction of NO production and estrogenic properties were compared between the water extracts of non-fumigated and sulfur-fumigated ASR. In all cases, the sulfur-fumigation significantly reduced the biological properties of ASR. In addition, application of water extract deriving from sulfur-fumigated ASR showed toxicity to cultured MCF-7 cells. In order to ensure the safety and to achieve the best therapeutic effect, it is recommended that sulfur-fumigation is an unacceptable approach for processing herbal materials.
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Rapid analysis of raw solution samples by C18 pipette-tip electrospray ionization mass spectrometry.
Anal. Chim. Acta
PUBLISHED: 07-16-2014
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A C18 pipette-tip electrospray ionization mass spectrometry technique was developed for rapid analysis of raw solution samples. In this technique, a C18 pipette tip was employed for rapid purification and enrichment of analytes in raw sample solutions. The adsorbed analytes were eluted by solvents supplied by a syringe and a syringe pump, and a high voltage was applied onto the syringe needle to induce electrospray ionization at the pipette tip end for mass spectrometric analysis. This technique is simple, easy to assemble, enables generation of stable and reproducible signals, and can be conveniently used for qualitative and quantitative analysis of raw solution samples. Analysis by the technique only involved simple sample preparation procedures followed by direct mass spectrometric detection, all of which could be completed within minutes, while the analytical performances of the technique, including the limit of detection, limit of quantitation, liner range, accuracy and precision, were comparable to those by conventional methods.
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Examining the Need Assessment Process by Identifying the Need Profiles of Elderly Care Recipients in the Ten-Year Long-Term Care Project (TLTCP) of Taiwan.
J Am Med Dir Assoc
PUBLISHED: 05-24-2014
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To deal with the increasing long-term care (LTC) needs of elderly people in Taiwan, the government launched the Ten-year Long-term Care Project (TLTCP) in 2007, and through the care management system, care plans for those in need were distributed and implemented by care managers according to the single assessment process. Based on the emphasis of linking the right need assessment to the care plan, this study aimed to explore the need profiles of LTC recipients with regard to their health indicators to serve as a validity check on the identified dependency levels and care plans in the current care management system.
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Identification of Angelica oil as a suppressor for the biological properties of Danggui Buxue tang: a Chinese herbal decoction composes of Astragali Radix and Angelica Sinensis Radix.
J Ethnopharmacol
PUBLISHED: 05-05-2014
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Danggui Buxue Tang (DBT), a Chinese herbal decoction commonly used in treating women?s ailments, contains two herbs: Angelica Sinensis Radix (ASR) and Astragali Radix (AR). Traditionally, ASR had to be pre-treated with yellow wine before the herbal preparation, which reduced the amount of volatile oil in water extract of ASR and DBT, and meanwhile the volatile oil-reduced DBT processed better bioactivities in cell cultures. The present study aimed to investigate the effect of volatile oil from ASR (Angelica oil) on the solubility of AR-derived ingredients and the biological properties of DBT.
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[Epigallocatechin gallate attenuates the expression of regulated upon activation normal T cell expressed and secreted induced by lipopolysaccharide in human retinal endothelial cells].
Sheng Li Xue Bao
PUBLISHED: 04-30-2014
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The present study was undertaken to determine the effect of epigallocatechin gallate (EGCG) on lipopolysaccharide (LPS)-induced production of inflammatory chemokine regulated upon activation normal T cell expressed and secreted (RANTES) in human retinal endothelial cells (HRECs) and to explore the underlying regulatory mechanism. HRECs were stimulated with LPS in the presence or absence of EGCG at various concentrations (100, 50, 25, 12.5, 6.25 ?mol/L). The optimum concentration of drug was determined by a real-time cell-electronic sensing (RT-CES) system, and MTS chromatometry was used to detect the toxicity of LPS and EGCG on HRECs. RANTES production in the culture supernatant was measured by ELISA. The expression levels of Akt and phosphorylated Akt were examined by Western blot assay. The result showed that LPS markedly stimulated RANTES secretion from HRECs. EGCG treatment significantly suppressed LPS-induced RANTES secretion in a dose-dependent manner. Furthermore, EGCG exhibited a dose-dependent inhibitory effect on LPS-induced phosphorylation of Akt. Taken together, our data suggest that EGCG suppresses LPS-induced RANTES secretion, possibly via inhibiting Akt phosphorylation in HRECs.
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Leucine facilitates the insulin-stimulated glucose uptake and insulin signaling in skeletal muscle cells: involving mTORC1 and mTORC2.
Amino Acids
PUBLISHED: 04-16-2014
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Leucine, a branched-chain amino acid, has been shown to promote glucose uptake and increase insulin sensitivity in skeletal muscle, but the exact mechanism remains unestablished. We addressed this issue in cultured skeletal muscle cells in this study. Our results showed that leucine alone did not have an effect on glucose uptake or phosphorylation of protein kinase B (AKT), but facilitated the insulin-induced glucose uptake and AKT phosphorylation. The insulin-stimulated glucose uptake and AKT phosphorylation were inhibited by the phosphatidylinositol 3-kinase inhibitor, wortmannin, but the inhibition was partially reversed by leucine. The inhibitor of mammalian target of rapamycin complex 1 (mTORC1), rapamycin, had no effect on the insulin-stimulated glucose uptake, but eliminated the facilitating effect of leucine in the insulin-stimulated glucose uptake and AKT phosphorylation. In addition, leucine facilitation of the insulin-induced AKT phosphorylation was neutralized by knocking down the core component of the mammalian target of rapamycin complex 2 (mTORC2) with specific siRNA. Together, these findings show that leucine can facilitate the insulin-induced insulin signaling and glucose uptake in skeletal muscle cells through both mTORC1 and mTORC2, implicating the potential importance of this amino acid in glucose homeostasis and providing new mechanistic insights.
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A Chemically Standardized Extract of Ziziphus jujuba Fruit (Jujube) Stimulates Expressions of Neurotrophic Factors and Anti-oxidant Enzymes in Cultured Astrocytes.
Phytother Res
PUBLISHED: 04-15-2014
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The fruit of Ziziphus jujuba Mill., known as jujube or Chinese date, is commonly consumed as a health supplement worldwide. To study the role of jujube in brain benefits, the expression of neurotrophic factors and anti-oxidant enzymes in the jujube-treated cultured astrocytes was determined. Application of a chemical standardized water extract of jujube in cultured astrocytes for 24?h stimulated the expressions of nerve growth factor, brain-derived neurotrophic factor and glial cell line-derived neurotrophic factor in a concentration-dependent manner. The pre-treatment with H89, a protein kinase A inhibitor, attenuated the jujube-induced expression of neurotrophic factors. In parallel, the treatment of jujube water extract induced the transcriptional expressions of the enzymes responsible for anti-oxidation, i.e.
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Comparative expression profiles of microRNA in left and right atrial appendages from patients with rheumatic mitral valve disease exhibiting sinus rhythm or atrial fibrillation.
J Transl Med
PUBLISHED: 04-02-2014
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The atrial fibrillation (AF) associated microRNAs (miRNAs) were found in the right atrium (RA) and left atrium (LA) from patients with rheumatic mitral valve disease (RMVD). However, most studies only focus on the RA; and the potential differences of AF-associated miRNAs between the RA and LA are still unknown. The aim of this study was to perform miRNA expression profiles analysis to compare the potential differences of AF-associated miRNAs in the right atrial appendages (RAA) and left atrial appendages (LAA) from RMVD patients.
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Is the hospital's magnet status linked to HCAHPS scores?
J Nurs Care Qual
PUBLISHED: 04-02-2014
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This study identified a significant link between Magnet hospitals and higher HCAHPS (Hospital Consumer Assessment of Healthcare Providers and Systems) scores across 110 Illinois hospitals. Compared with registered nurse nursing hours per patient-day and registered nurse turnover rate, Magnet status was a stronger contributor to the HCAHPS scores. A moderate to strong, reverse relationship between hospital's percentage of African American patients and HCAHPS scores suggests a need for strengthening culturally sensitive nurse-patient communications.
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Passive smoke exposure was related to mean platelet volume in never-smokers.
Am J Health Behav
PUBLISHED: 03-19-2014
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To investigate the effect of passive smoking on the changes in mean platelet volume (MPV) in healthy adults.
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Is selective antegrade cerebral perfusion superior to retrograde cerebral perfusion for brain protection during deep hypothermic circulatory arrest? Metabolic evidence from microdialysis.
Crit. Care Med.
PUBLISHED: 02-25-2014
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This study aimed to investigate whether selective antegrade cerebral perfusion or retrograde cerebral perfusion is a better technique for brain protection in deep hypothermic circulatory arrest by obtaining metabolic evidence from microdialysis.
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Telomerase and hTERT: can they serve as markers for gastric cancer diagnosis?
World J. Gastroenterol.
PUBLISHED: 02-23-2014
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To investigate telomerase activity and human telomerase reverse transcriptase (hTERT) expression in normal human gastric mucosal epithelial cells (nhGMECs) and fibroblasts (nhGMFs).
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The standardized extract of Ziziphus jujuba fruit (jujube) regulates pro-inflammatory cytokine expression in cultured murine macrophages: suppression of lipopolysaccharide-stimulated NF-?B activity.
Phytother Res
PUBLISHED: 02-15-2014
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The fruit of Ziziphus jujuba Mill., known as jujube or Chinese date, is commonly consumed as a health supplement or herbal medicine worldwide. To study the beneficial role of jujube in regulating immune response, we investigated its roles on the expressions of pro-inflammatory cytokines in cultured macrophages. Application of chemically standardized jujube water extract for 24?h stimulated the transcriptional expression of interleukin (IL)-1?, IL-6, and tumor necrosis factor (TNF)-? in cultured RAW 264.7 macrophages. In contrast, the pretreatment with jujube water extract suppressed the expression of IL-1? and IL-6, but not for TNF-? in lipopolysaccharide (LPS)-stimulated macrophages. The IL-1? and IL-6 cytokines in LPS-induced macrophages were suppressed by jujube water extract in both mRNA and protein levels. In parallel, the inhibition of jujube water extract on the transcriptional activity of nuclear factor-kappa B was revealed in LPS-induced macrophages. These results verified the bidirectional immune-modulatory roles of jujube by regulating the expressions of pro-inflammatory cytokines in macrophages. Copyright © 2014 John Wiley & Sons, Ltd.
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Selective antegrade cerebral perfusion attenuating the TLR4/NF-?B pathway during deep hypothermia circulatory arrest in a pig model.
Cardiology
PUBLISHED: 02-14-2014
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The alteration of the Toll-like receptor/nuclear factor-kappa B (TLR4/NF-?B) signaling pathway during deep hypothermia circulatory arrest (DHCA) has not yet been defined. The aim of this study was to explore the expression of the TLR4/NF-?B pathway cytokine in cerebral injury resulting from DHCA as well as the effect of selective antegrade cerebral perfusion (SACP) on TLR4/NF-?B pathway expression.
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A standardized extract of the fruit of Ziziphus jujuba (Jujube) induces neuronal differentiation of cultured PC12 cells: a signaling mediated by protein kinase A.
J. Agric. Food Chem.
PUBLISHED: 02-12-2014
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The fruit of Ziziphus jujuba Mill., known as Chinese date or jujube, is consumed as a health supplement worldwide. To study the role of jujube in brain benefits, its effects on neuronal differentiation of PC12 cells were studied. Application of jujube water extract induced neurite outgrowth of PC12 cells, >25% of which were differentiated; this effect was similar to that of nerve growth factor. In parallel, the expressions of neurofilaments (NFs) in jujube-treated cultures showed a dose-dependent increase, with the highest inductions by ?150% for NF68 and NF160 and by ?100% for NF200. Application of H89, a protein kinase A inhibitor, attenuated jujube-induced neurite outgrowth of the cultures. Besides, using jujube extract induced the phosphorylation of cAMP responsive element binding protein on PC12 cells, which was blocked by H89. These results support the use of jujube as a food supplement for the prevention of neurodegenerative diseases in which neurotrophin deficiency is involved.
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Quinocetone-induced Nrf2/HO-1 pathway suppression aggravates hepatocyte damage of Sprague-Dawley rats.
Food Chem. Toxicol.
PUBLISHED: 02-10-2014
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Quinocetone (3-methyl-2-quinoxalin benzenevinylketo-1,4-dioxide, QCT) is a widely used veterinary drug in PR China that promotes feed efficiency and growth of various animals. However, its potential toxicity has been concerned recently. In the present study, we investigated QCT-induced hepatocyte changes and its related mechanism, especially the expression of Nrf2/HO-1 pathway. Oxidative stress induced by QCT in hepatocyte led to DNA damage, inflammation and apoptosis. Nevertheless, hepatocyte has a self-repair system to protect itself from oxidative stress. In the 50 mg/kg/day QCT group, the morphology and function of liver were approximately maintained on normal level, which indicated that the damaged cell might have a self-repair mechanism. Notably, nuclear factor-erythroid 2-related factor 2/heme oxygenase-1 (Nrf2/HO-1) pathway plays a critical role in protecting cells against reactive oxygen species (ROS) generation. However, higher doses of QCT (800 mg/kg/day and 2400 mg/kg/day) inhibited the expression of Nrf2/HO-1 pathway, which resulted in excessive ROS generation and irreversible oxidative DNA damage, inflammation and apoptosis. In conclusion, although QCT-induced oxidative stress activates the expression of Nrf2/HO-1 pathway initially, persistent QCT exposure will inhibit this expression and aggravate hepatocyte damage. Simultaneously, inflammation and apoptosis continues to progress, liver dysfunction and tissue damage will be occurred eventually.
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Quercetin prevents ethanol-induced iron overload by regulating hepcidin through the BMP6/SMAD4 signaling pathway.
J. Nutr. Biochem.
PUBLISHED: 02-09-2014
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Emerging evidence has demonstrated that chronic ethanol exposure induces iron overload, enhancing ethanol-mediated liver damage. The purpose of this study was to explore the effects of the naturally occurring compound quercetin on ethanol-induced iron overload and liver damage, focusing on the signaling pathway of the iron regulatory hormone hepcidin. Adult male C57BL/6J mice were pair-fed with isocaloric-Lieber De Carli diets containing ethanol (accounting for 30% of total calories) and/or carbonyl iron (0.2%) and treated with quecertin (100 mg/kg body weight) for 15 weeks. Mouse primary hepatocytes were incubated with ethanol (100 mM) and quercetin (100 ?M) for 24 h. Mice exposed to either ethanol or iron presented significant fatty infiltration and iron deposition in the liver; these symptoms were exacerbated in mice cotreated with ethanol and iron. Quercetin attenuated the abnormity induced by ethanol and/or iron. Ethanol suppressed BMP6 and intranuclear SMAD4 as well as decreased hepcidin expression. These effects were partially alleviated by quercetin supplementation in mice and hepatocytes. Importantly, ethanol caused suppression of SMAD4 binding to the HAMP promoter and of hepcidin messenger RNA expression. These effects were exacerbated by anti-BMP6 antibody and partially alleviated by quercetin or human recombinant BMP6 in cultured hepatocytes. In contrast, co-treatment with iron and ethanol, especially exposure of iron alone, activated BMP6/SMAD4 pathway and up-regulated hepcidin expression, which was also normalized by quercetin in vivo. Quercetin prevented ethanol-induced hepatic iron overload different from what carbonyl iron diet elicited in the mechanism, by regulating hepcidin expression via the BMP6/SMAD4 signaling pathway.
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Quercetin attenuates chronic ethanol hepatotoxicity: implication of "free" iron uptake and release.
Food Chem. Toxicol.
PUBLISHED: 02-09-2014
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Emerging evidence has displayed that oxygen free radicals especially ones promoted by "free" iron play an important role in the development of alcoholic liver disease (ALD). Naturally-occurring quercetin has been reported to prevent ALD and iron overload-induced damage aside from the "free" iron. The purpose was to explore the potential mechanisms by which quercetin arrests alcohol-induced "free" iron disorder. Chronic alcohol (30% of total calories) or iron (0.2%)-fed adult male C57BL/J mice for 15 weeks resulted in significantly elevated levels of hepatic iron, labile iron pool-Fe and serum non-transferrin bound iron, accompanied with sustained oxidative damage. The hepatotoxicity was further exacerbated by ethanol and iron. Quercetin (100 mg/kg. body weight) alleviated the detrimental effects induced by ethanol and/or iron. The expressions of divalent metal transporter 1, zinc transporter member 14, mucolipin 1, transferrin receptor 1 (TfR1) and ferritin were up-regulated by ethanol and/or iron, which were partially normalized by quercetin. Quercetin prevented ethanol-induced hepatotoxicity, which may be partially attributed to the alleviated disorder of bound iron and "free" iron. The significant suppression of ethanol-stimulated molecules for "free" iron uptake and release may contribute to the hepatoprotective effect of quercetin, although TfR1-mediated physiological pathway of iron uptake also played a role.
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Hydrolysis of Glycosidic Flavonoids during the Preparation of Danggui Buxue Tang: An Outcome of Moderate Boiling of Chinese Herbal Mixture.
Evid Based Complement Alternat Med
PUBLISHED: 02-07-2014
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Chemical change during boiling of herbal mixture is a puzzle. By using Danggui Buxue Tang (DBT), a herbal decoction that contains Astragali Radix (AR) and Angelicae Sinensis Radix (ASR), we developed a model in analyzing the hydrolysis of flavonoid glycosides during the boiling of herbal mixture in water. A proper preparation of DBT is of great benefit to the complete extraction of bioactive ingredients. Boiling of DBT in water increased the solubility of AR-derived astragaloside IV, calycosin, formononetin, calycosin-7-O- ? -D-glucoside, and ononin in a time- and temperature-dependent manner: the amounts of these chemicals reached a peak at 2?h. The glycosidic resides of AR, calycosin-7-O- ? -D-glucoside, and ononin could be hydrolyzed during the moderate boiling process to form calycosin and formononetin, respectively. The hydrolysis efficiency was strongly affected by pH, temperature, and amount of herbs. Interestingly, the preheated herbs were not able to show this hydrolytic activity. The current results supported the rationality of ancient preparation of DBT in boiling water by moderate heat.
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Atrial fibrillation alters the microRNA expression profiles of the left atria of patients with mitral stenosis.
BMC Cardiovasc Disord
PUBLISHED: 01-22-2014
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Structural changes of the left and right atria associated with atrial fibrillation (AF) in mitral stenosis (MS) patients are well known, and alterations in microRNA (miRNA) expression profiles of the right atria have also been investigated. However, miRNA changes in the left atria still require delineation. This study evaluated alterations in miRNA expression profiles of left atrial tissues from MS patients with AF relative to those with normal sinus rhythm (NSR).
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Altered expression of ETV1 and its contribution to tumorigenic phenotypes in gastrointestinal stromal tumors.
Oncol. Rep.
PUBLISHED: 01-17-2014
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Gastrointestinal stromal tumor (GIST) is the most common mesenchymal neoplasm of the gastrointestinal tract. ETV1 is a unique transcription factor specific to GIST that has been reported to date. The present study aimed to determine aberrant ETV1 expression and its contribution to tumorigenesis in GISTs. Altered expression levels of ETV1 and its relevant signaling pathways were assessed using western blotting and quantitative real-time PCR in 72 paired patient tissue samples. In addition, immunochemistry was performed on 156 GISTs using tissue microarray to analyze the correlation between ETV1 and clinical parameters. The results revealed that ETV1 was highly expressed in the GISTs at both the transcription and protein levels. Immunochemical analysis revealed that increased expression of ETV1 was correlated with KIT in the 156 patients. In addition, the frequency of ETV1 positivity was higher when compared with KIT [50.0% (9/18) vs 38.9% (7/18)] particularly in high-risk GISTs. Analysis of western blotting data showed that total protein isoforms of Raf, MEK and ERK were similar in the GIST tissues as well as in the uninvolved normal tissues. In contrast, the level of phospho-Raf, phospho-MEK and phospho?ERK were decreased in the tumor group. Moreover, enhanced signaling molecules such as Bcl-2 and Dvl2/GSK-3?/?-catenin/Smad2 were detected, showing a significant difference in comparison with the uninvolved normal cases. We conclude that ETV1, a member of the ETS family, is upregulated in GISTs, and its signaling is integrated into a cellular signaling network for resistance to apoptosis, tumor cell invasion and survival.
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Requirement and epigenetics reprogramming of Nrf2 in suppression of tumor promoter TPA-induced mouse skin cell transformation by sulforaphane.
Cancer Prev Res (Phila)
PUBLISHED: 01-17-2014
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Nrf2 is a transcription factor that plays critical roles in regulating the expression of cellular defensive antioxidants and detoxification enzymes. However, the role of Nrf2 and Nrf2's epigenetics reprogramming in skin tumor transformation is unknown. In this study, we investigated the inhibitory role and epigenetics of Nrf2 on tumor transformation induced by 12-O-tetradecanoylphorbol-13-acetate (TPA) in mouse skin epidermal JB6 (JB6 P+) cells and the anticancer effect of sulforaphane (SFN), an isothiocyanate found in cruciferous vegetables. After five days of treatment, SFN significantly inhibited TPA-induced JB6 cellular transformation and SFN enhanced the nuclear translocation of Nrf2 and increased the mRNA and protein levels of the Nrf2 target genes HO-1, NQO1 and UGT1A1. Knockdown of Nrf2 attenuated the induction of Nrf2, HO-1 and NQO1 by SFN, enhanced TPA-induced colony formation and dampened the inhibitory effect of SFN on TPA-induced JB6 transformation. Epigenetics investigation using bisulfite genomic sequencing showed that SFN decreased the methylation ratio of the first 15 CpGs of the Nrf2 gene promoter, which was corroborated by increased Nrf2 mRNA expression. Furthermore, SFN strongly reduced the protein expression of DNA methyltransferases (DNMT1, DNMT3a and DNMT3b). SFN also inhibited the total histone deacetylase (HDAC) activity and decreased the protein expression of HDAC1, HDAC2, HDAC3 and HDAC4. Collectively, these results suggest that the anti-cancer effect of SFN against TPA-induced neoplastic transformation of mouse skin could involve the epigenetic reprogramming of anti-cancer genes such as Nrf2, leading to the epigenetic reactivation of Nrf2 and the subsequent induction of downstream target genes involved in cellular protection.
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Direct analysis of herbal powders by pipette-tip electrospray ionization mass spectrometry.
Anal. Chim. Acta
PUBLISHED: 01-15-2014
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Conventional electrospray ionization mass spectrometry (ESI-MS) is widely used for analysis of solution samples. The development of solid-substrate ESI-MS allows direct ionization analysis of bulky solid samples. In this study, we developed pipette-tip ESI-MS, a technique that combines pipette tips with syringe and syringe pump, for direct analysis of herbal powders, another common form of samples. We demonstrated that various herbal powder samples, including herbal medicines and food samples, could be readily online extracted and analyzed using this technique. Various powder samples, such as Rhizoma coptidis, lotus plumule, great burdock achene, black pepper, Panax ginseng, roasted coffee beans, Fructus Schisandrae Chinensis and Fructus Schisandrae Sphenantherae, were analyzed using pipette-tip ESI-MS and quality mass spectra with stable and durable signals could be obtained. Both positive and negative ion modes were attempted and various compounds including amino acids, oligosaccharides, glycosides, alkaloids, organic acids, ginosensides, flavonoids and lignans could be detected. Principal component analysis (PCA) based on the acquired mass spectra allowed rapid differentiation of closely related herbal species.
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Prevention of BMS-777607-induced polyploidy/senescence by mTOR inhibitor AZD8055 sensitizes breast cancer cells to cytotoxic chemotherapeutics.
Mol Oncol
PUBLISHED: 01-02-2014
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Targeted inhibition of MET/RON signaling by tyrosine kinase inhibitor BMS-777607 for cancer treatment is currently under clinical trials. We have previously shown that BMS-777607 induces chemoresistance in vitro by causing polyploidy, which hampers therapeutic efficacy. Here, we studied polyploidy-associated senescence induced by BMS-777607 in breast cancer cells and its prevention by mTOR inhibitor AZD8055, leading to increased chemosensitivity. In breast cancer T-47D and ZR-75-1 cells, BMS-777607 induced phenotypic changes including enlarged cellular size, flattened morphology, increased DNA content, and activity of senescence-associated ?-galactosidase. These changes were accompanied by increased p21/WAF1 expression and decreased Retinoblastoma Ser(780) phosphorylation, indicating that BMS-777607 induces not only polyploidy but also senescence. The appearance of senescence was associated with polyploidy in which ?-galactosidase is exclusively expressed in polyploid cells. Survivin expression was increased in polyploid/senescent cells as analyzed by Western blotting. Increased survivin accumulated both in the nucleus and cytoplasm and dissociated with condensed DNA and mitotic spindle at the metaphase. Abnormal accumulation of survivin also rendered polyploid/senescent cells insensitive to cytotoxic activities of YM155, a DNA damaging agent with a suppressive effect on survivin gene transcription. AZD8055, a specific mTOR inhibitor, effectively prevented BMS-777607-induced polyploidy and senescence and restored survivin expression and its nuclear localization to normal levels. Although a synergism was not observed, BMS-777607 plus AZD8055 increased cancer cell sensitivity toward different cytotoxic chemotherapeutics. In conclusion, BMS-777607-induced chemoresistance is associated with cell polyploidy and senescence. Inhibition of mTOR signaling by AZD8055 prevents BMS-777607-induced polyploidy/senescence and increases breast cancer cell chemosensitivity.
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PDE2 Is a Novel Target for Attenuating Tumor Formation in a Mouse Model of UVB-Induced Skin Carcinogenesis.
PLoS ONE
PUBLISHED: 01-01-2014
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Our previous studies demonstrated that the topical application of caffeine is a potent inhibitor of UVB-induced carcinogenesis and selectively increases apoptosis in tumors but not in non-tumor areas of the epidermis in mice that are at a high risk for developing skin cancer. While this effect is mainly through a p53 independent pathway, the mechanism by which caffeine inhibits skin tumor formation has not been fully elucidated. Since caffeine is a non-specific phosphodiesterase inhibitor, we investigated the effects of several PDE inhibitors on the formation of sunburn cells in mouse skin after an acute exposure to ultraviolet light B (UVB). The topical application of a PDE2 inhibitor, erythro-9-(2-hydroxy-3-nonyl) adenine hydrochloride (EHNA hydrochloride), stimulated epidermal apoptosis compared to control (P<0.01) and to a greater extent than caffeine whereas a PDE4 inhibitor attenuated the epidermal apoptosis compared to control (P<0.01). Since PDE2 hydrolyzes cyclic nucleotides, mainly cGMP, the effects of EHNA hydrochloride on epidermal apoptosis following UVB exposure may be mediated, in part, by increased cGMP signaling. Data demonstrated that the topical application of dibutyryl cGMP stimulated epidermal apoptosis (P<0.01) following an acute exposure to UVB. Treating UVB-pretreated mice topically with 3.1 µmole or 0.8 µmole of EHNA hydrochloride attenuated tumor formation to a greater extent than treating with 6.2 µmole caffeine when these compounds were applied once a day, five days a week for 18 weeks. These observations suggest a novel role for PDE2 in UVB-induced tumorigenesis and that PDE2 inhibitors that mediate cGMP signaling may be useful for the prevention and treatment of skin cancer.
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Development of two barthel index-based supplementary scales for patients with stroke.
PLoS ONE
PUBLISHED: 01-01-2014
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The Barthel Index (BI) assesses actual performance of activities of daily living (ADL). However, comprehensive assessment of ADL functions should include two other constructs: self-perceived difficulty and ability.
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Epigallocatechin-3-gallate attenuates lipopolysaccharide-induced inflammation in human retinal endothelial cells.
Int J Ophthalmol
PUBLISHED: 01-01-2014
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To investigate the mechanism underlying the anti-inflammatory effects of epigallocatechin-3-gallate (EGCG) in lipopolysaccharide (LPS)-stimulated human retinal endothelial cells (HRECs).
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[Potential molecular mechanisms of quercetin-induced heme oxygenase-1 in rat primary hepatocytes].
Zhonghua Gan Zang Bing Za Zhi
PUBLISHED: 12-17-2013
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To investigate the possible molecular mechanisms of heme oxygenase-1 (HO-1) induction by quercetin using rat primary hepatocytes.
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Interactions between Zinc Transporter-8 Gene (SLC30A8) and Plasma Zinc Concentrations for Impaired Glucose Regulation and Type 2 Diabetes.
Diabetes
PUBLISHED: 12-04-2013
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Though both SLC30A8 rs13266634 SNP and plasma zinc concentrations have been associated with impaired glucose regulation (IGR) and type 2 diabetes (T2D), their interactions for IGR and T2D remain unclear. Therefore, to assess zinc-SLC30A8 interactions, we performed a case-control study in 1,796 participants: 218 newly diagnosed IGR patients, 785 newly diagnosed T2D patients, and 793 individuals with normal glucose tolerance (NGT). After adjustment for age, sex, BMI, family history of diabetes and hypertension, the multivariable OR of T2D associated with a 10-µg/dl higher plasma zinc level was 0.87 (0.85-0.90). Meanwhile, the OR of SLC30A8 rs13266634 homozygous genotypes CC compared with TT was 1.53 (1.11-2.09) for T2D. Similar associations were found in IGR and IGR&T2D groups. Each 10-µg/dl increment of plasma zinc was associated with 22% (OR, 0.78; 95% CI, 0.72-0.85) lower odds of T2D in TT genotype carriers, 17% (0.83; 0.80-0.87) lower odds in CT genotype carriers, and 7% (0.93; 0.90-0.97) lower odds in CC genotype carriers (P for interaction = 0.01). Our study suggested that the C allele of rs13266634 was associated with higher odds of T2D, and higher plasma zinc was associated with lower odds. The inverse association of plasma zinc concentrations with T2D was modified by SLC30A8 rs13266634. Further studies are warranted to confirm our findings and clarify the mechanisms underlying the interaction between plasma zinc and the SLC30A8 gene in relation to T2D.
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[Study of RON mediated invasion of Raji cell line and drug-target effects].
Zhonghua Xue Ye Xue Za Zhi
PUBLISHED: 12-04-2013
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To study the proto-oncogene RON mediated aggression of Raji cells and the inhibitory effects by monoclonal antibody Zt/f2 (2f2).
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Synergistic Activities of MET/RON Inhibitor BMS-777607 and mTOR Inhibitor AZD8055 to Polyploid Cells Derived from Pancreatic Cancer and Cancer Stem Cells.
Mol. Cancer Ther.
PUBLISHED: 11-14-2013
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Tyrosine kinase inhibitor BMS-777067 is an inhibitor of RON/MET receptor tyrosine kinases currently under clinical trials. Here, we report the synergistic activity of BMS-777607 in combination with mTOR inhibitor AZD8055 in killing chemoresistant pancreatic cancer and cancer stem cells. Treatment of pancreatic cancer L3.6pl cells with BMS-777607 alone inhibited clonogenic growth and moderately induced apoptotic death. However, BMS-777607 caused extensive polyploidy in L3.6pl cells through inhibition of aurora kinase B activity, independent of RON expression. In contrast, L3.6pl-derived cancer stem cells were highly resistant to BMS-777607-induced growth inhibition and apoptosis. The effect of BMS-777607 on induction of cancer stem cell polyploidy was also weak. BMS-777607-induced polyploidy features a predominant cell population with 8N chromosome content in both L3.6pl and cancer stem cells. These cells also showed decreased sensitivity toward chemotherapeutics by increased survival of IC50 values in response to doxorubicin, cisplatin, methotrexate, 5-fluorouracial, and gemcitabine. Among a panel of chemical inhibitors that target different signaling proteins, we found that BMS-777607 in combination with mTOR inhibitor AZD8055 exerted synergistic effects on L3.6pl and cancer stem cells. More than 70% of L3.6pl and cancer stem cells lost their viability when both inhibitors were used. Specifically, BMS-777607 in combination with inhibition of mTORC2, but not mTORC1, was responsible for the observed synergism. Our findings demonstrate that BMS-777607 at therapeutic doses exerts inhibitory activities on pancreatic cancer cells but also induces polyploidy insensitive to chemotherapeutics. Combination of BMS-777607 with AZD8055 achieves the maximal cytotoxic effect on pancreatic cancer and cancer stem cells. Mol Cancer Ther; 13(1); 1-12. ©2013 AACR.
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[Preparation of anti-B7-H4 monoclonal antibody to investigate B7-H4 expression in pancreatic cancer].
Zhejiang Da Xue Xue Bao Yi Xue Ban
PUBLISHED: 10-30-2013
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To prepare a monoclonal antibody (mAb) against extracellular domain of B7-H4 and to investigate the expression of B7-H4 in pancreatic cancer tissue with the prepared mAb.
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The heterogeneous health latent classes of elderly people and their socio-demographic characteristics in Taiwan.
Arch Gerontol Geriatr
PUBLISHED: 10-28-2013
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The health care needs of elderly people were influenced by their heterogeneity. This study aimed to identify the health latent classes of elderly people by using latent class analysis to deal with heterogeneity and examine their socio-demographic characteristics. Data came from the 2005 National Health Interview Survey (NHIS) in Taiwan. In total, 2449 elderly individuals with available health indicators were examined in latent class analysis (LCA), and 2217 elderly community-dwellings with complete socio-demographic data were analyzed by multinomial logistic regression. Four health latent classes were identified which included 1066 (43.5%) people in the High Comorbidity (HC), 152 (6.2%) in the Functional Impairment (FI), 252 (10.3%) in the Frail (FR), and 979 (40.0%) in the Relatively Healthy (RH) group. Multinomial logistic regressions revealed socio-demographic characteristics among health classes. The variables associated with an increased likelihood of being in the FR group were age, female, and living with families. They were also correlated to ethnicity and educations. Apart from age and gender, the Functional Impairment group was less likely to be ethnicity of Hakka, more likely to live with others than were the RH group. The HC group tended to be younger, with higher educations, and more likely to live in urban area than the Functional Impairment group. The correlations between health classes and socio-demographic factors were discussed. The health status of elderly people includes a variety of health indicators. A person-centered approach is critical to identify the health heterogeneity of elderly people and manage their care needs by targeting differential aging.
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Inverse relationship between p53 and phospho-Chk1 (Ser317) protein expression in UVB-induced skin tumors in SKH-1 mice.
Exp. Mol. Pathol.
PUBLISHED: 10-15-2013
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Immunohistochemical evaluation of serial stored paraffin sections from 42 keratoacanthomas and 11 squamous cell carcinomas demonstrated that skin tumors from UVB-exposed mice showed an inverse relationship (>95%) between p53 protein expression and phospho-Chk1 (Ser317), but not phospho-Chk1 (Ser345) protein expression. Tumors expressing high levels and large areas of p53 protein had no detectable phospho-Chk1 (Ser317), whereas tumors expressing high levels and large areas of phospho-Chk1 (Ser317) protein had no detectable p53. Squamous cell carcinomas that demonstrated heterogeneous p53 and phospho-Chk1 (Ser317) protein expression within the same tumor showed that areas expressing p53 were negative for phospho-Chk1 (Ser317) immunostaining while areas expressing phospho-Chk1 (Ser317) were negative for p53. Similar patterns were observed for keratoacanthomas. These findings were also observed in epidermal areas distant from tumors that demonstrated no detectable phospho-Chk1 (Ser317), but appreciable p53 protein in the basal layer. Tumors from congenic hairless p53 knockout mice had elevated levels of phospho-Chk1 (Ser317) compared to tumors from p53 wild-type SKH-1 controls. After a single acute exposure to UVB, normal epidermal cells from a p53 knockout mouse expressed a relatively high level of phospho-Chk1 (Ser317) whereas epidermal cells from a p53 wild-type littermate induced p53 protein and expressed a relatively low level of phospho-Chk1 (Ser317). These data illustrate the dynamic regulation of checkpoint function, suggesting that phosphorylation of Chk1 on Serine 317 is regulated by p53 status and that p53 may act as a molecular on/off switch for phosphorylation at this site.
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Erythropoiesis-stimulating agents in chronic kidney disease: What have we learned in 25 years?
J. Formos. Med. Assoc.
PUBLISHED: 08-22-2013
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Since the pioneering studies by Eschbach et al in 1987, erythropoiesis-stimulating agents (ESAs) have become the mainstay of anemia therapy in chronic kidney disease (CKD) patients. The introduction of ESAs 25 years ago markedly improved the lives of many patients with CKD, who until then had severe, often transfusion-dependent anemia. However, randomized controlled trials demonstrate an increased risk for cardiovascular events such as stroke, thrombosis, and death at nearly normal hemoglobin concentrations and higher ESA doses in CKD. By contrast, kidney transplant recipients may represent a unique population of CKD patients who may benefit from ESA therapy. This review discusses potential mechanisms involving the erythropoietic and nonerythropoietic effects of ESA treatment and ESA resistance. Further research aimed at elucidating the causal pathways is strongly recommended. Given current knowledge, however, clinical practice should avoid disproportionately high dosages of ESAs to achieve recommended hemoglobin targets, particularly in those with significant cardiovascular morbidity or ESA resistance. The key to CKD anemia management will be individualization of the potential benefits of reducing blood transfusions and anemia-related symptoms against the risks of harm.
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Deoxynivalenol induced oxidative stress and genotoxicity in human peripheral blood lymphocytes.
Food Chem. Toxicol.
PUBLISHED: 08-21-2013
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Deoxynivalenol (DON) is one of the most common mycotoxins. The aim of this study consists in using diverse cellular and molecular assays to evaluate cytotoxicity, genotoxicity as well as oxidative damage and to investigate their mechanisms in human peripheral blood lymphocytes. The human lymphocytes were cultured in eight different doses of DON (0, 6.25, 12.5, 25, 50, 100, 250 and 500ng/mL) during 6; 12; and 24h. DON was able to decrease cell viability and cause damage to the membrane, the chromosomes or the DNA at all times of culture. It was also able to induce lipid peroxidation and raise the levels of 8-OHdG and ROS in 6, 12 and 24h. The results of the RT-PCR and the Western Blot indicated that DON is able to enhance mRNA or protein expressions of DNA repair genes and HO-1 in 6h and to inhibit these expressions in 24h. DON potentially triggers genotoxicity in human lymphocytes. This mechanism is probably related to depletion of antioxidase and oxidative damage to the DNA that reduced expression of HO-1, thereby inhibiting the ability of DNA repair.
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Characterization and biodistribution in vivo of quercetin-loaded cationic nanostructured lipid carriers.
Colloids Surf B Biointerfaces
PUBLISHED: 08-18-2013
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Nanobiotechnology has been recently viewed as a promising strategy to improve therapy efficacy by promoting the accumulation of hydrophobic bioactive compounds in tissues. The aim of present study was to formulate a novel quercetin-loaded cationic nanostructured lipid carriers (QR-CNLC) and to evaluate its biodistribution in vivo after oral administration. QR-CNLC were prepared by emulsifying at high temperature and subsequent solidifying at low temperature using various functional ingredients, and its characteristics, including physical index, release profile in vitro, and tissue distribution in vivo, were investigated. The results demonstrated that QR-CNLC exhibited an average particle size 126.6nm, a zeta potential of 40.5mV and 89.3% entrapment efficiency. QR-CNLC performed slower release compared with quercetin solution in vitro. QR-CNLC showed higher AUC (area under tissue concentration-time curve) value and higher Cmax value in lung, liver and kidney compared with control group. The value of relative intake rate (re) for lung, liver and kidney was 1.57, 1.51 and 1.68, respectively, which revealed that quercetin can be significantly accumulated in lung, kidney and liver after oral administration of QR-CNLC compared with quercetin suspension. In conclusion, cationic nanostructured lipid carriers may be an attractive nanocarrier system for oral delivery of hydrophobic functional components.
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Myocardial mitochondrial oxidative stress and dysfunction in intense exercise: regulatory effects of quercetin.
Eur. J. Appl. Physiol.
PUBLISHED: 08-06-2013
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Oxidative stress plays a pivotal role in the intense exercise-induced myocardium injury, and mitochondrial compartment is presumed as the main source and susceptible target of intracellular reactive oxygen species (ROS).
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Chemical and biological assessment of Ziziphus jujuba fruits from China: different geographical sources and developmental stages.
J. Agric. Food Chem.
PUBLISHED: 07-22-2013
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Chinese date, the fruit of Ziziphus jujuba Mill., has thousands of years cultivation history, and about 700 cultivars of dates in China. Two types of dates are commonly found in the market: (i) fresh immature dates consumed as fruits, and (ii) dried mature dates used as Chinese medicines. Here, chemical and biological properties of these dates were revealed. Different sources of dates showed similar chemical profiles; however, the amounts of identified chemicals showed a great variation. The amount of nucleotides, flavonoids and polysaccharides in dates could be affected by its maturity and drying process. In parallel, the antioxidative functions of their extracts were compared. The date extracts protected PC12 cells against tBHP-induced cytotoxicity, and which also stimulated the transcriptional activity of antioxidant response element. The antioxidative effects were varied among different dates. The current results suggested the optimization of sources and specific usage of different maturity dates.
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Association between serum uric acid and the metabolic syndrome among a middle- and old-age Chinese population.
Eur. J. Epidemiol.
PUBLISHED: 07-10-2013
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Our aim was to study whether there is causal association between serum uric acid and metabolic syndrome (MetS). A cross-sectional study was performed, including a total of 27,009 subjects (23,345 subjects having uric acid data) from the Dongfeng-Tongji Cohort study. The MetS was defined by the International Diabetes Foundation criteria of 2005. Association analysis was performed by logistic regression. A genetic risk score was calculated by adding the uric acid increasing alleles in two SNPs (rs11722228 in SLC2A9 and rs2231142 in ABCG2) which were identified from our genome-wide association study on uric acid levels. The causal association was examined by mendelian randomization analysis. Among a middle- and old-age Chinese population, serum uric acid concentrations were strongly associated with the risk of MetS and its several components (P < 0.0001). The effects were stronger in women than in men. Despite the lack of statistical significance, both SNPs exhibited a trend with increased MetS risk (rs11722228, OR = 1.06, 95 % CI 0.99-1.14; rs2231142, OR = 1.02, 95 % CI 0.95-1.10), consistent with their increasing uric acid effects. Each additional uric acid increasing allele in the genetic risk score was associated with 3 % increased MetS risk (OR = 1.03, 95 % CI 0.98-1.09; P = 0.23). Further adjustment for serum uric acid attenuated the trend of individual SNP and genetic risk score with increased MetS risk (all OR < 1.0). These findings suggested that serum uric acid was associated with MetS risk in a middle- and old-age Chinese population. Whether this association was causal remained to be investigated in the future studies.
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Soy protein/soy polysaccharide complex nanogels: folic acid loading, protection, and controlled delivery.
Langmuir
PUBLISHED: 06-26-2013
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In this study, we developed a facile approach to produce nanogels via self-assembly of folic acid, soy protein, and soy polysaccharide. High-pressure homogenization was introduced to break down the original aggregates of soy protein, which benefits the binding of soy protein with soy polysaccharide and folic acid at pH 4.0. After a heat treatment that causes the soy protein denaturation and gelation, folic acid-loaded soy protein/soy polysaccharide complex nanogels were fabricated. The nanogels have a polysaccharide surface that makes the nanogels dispersible in acidic conditions where folic acid is insoluble and soy protein forms precipitates after heating. More importantly, the protein and polysaccharide can inhibit the reactions between dissolved oxygen and folic acid during UV irradiation. After the preparation and storage of the nanogels in the presence of heat, oxygen, and light in acidic conditions, most of the folic acid molecules in the nanogels remain in their natural structure and can be released rapidly at neutral pH, that is, in the intestine. Because most food and beverages are acidic, the nanogels are a suitable delivery system of folic acid in food and beverages.
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MSP-RON signalling in cancer: pathogenesis and therapeutic potential.
Nat. Rev. Cancer
PUBLISHED: 06-25-2013
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Since the discovery of MSP (macrophage-stimulating protein; also known as MST1 and hepatocyte growth factor-like (HGFL)) as the ligand for the receptor tyrosine kinase RON (also known as MST1R) in the early 1990s, the roles of this signalling axis in cancer pathogenesis has been extensively studied in various model systems. Both in vitro and in vivo evidence has revealed that MSP-RON signalling is important for the invasive growth of different types of cancers. Currently, small-molecule inhibitors and antibodies blocking RON signalling are under investigation. Substantial responses have been achieved in human tumour xenograft models, laying the foundation for clinical validation. In this Review, we discuss recent advances that demonstrate the importance of MSP-RON signalling in cancer and its potential as a therapeutic target.
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[Costimulatory molecule CD40 expression in thyroid tissue of Graves disease patients and its immune pathogenetic significance].
Zhonghua Yi Xue Za Zhi
PUBLISHED: 06-13-2013
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To explore the expression of costimulatory molecule CD40 in thyroid tissue of Graves disease patients and understand its immune pathogenetic significance.
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Inflammatory markers and risk of type 2 diabetes: a systematic review and meta-analysis.
Diabetes Care
PUBLISHED: 06-07-2013
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There has been growing evidence that inflammatory markers play a role in the development of type 2 diabetes. We aimed to systematically review prospective studies on the associations of elevated levels of interleukin-6 (IL-6) and C-reactive protein (CRP) with increased risk of type 2 diabetes by conducting a meta-analysis.
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Oncogenic variant RON160 expression in breast cancer and its potential as a therapeutic target by small molecule tyrosine kinase inhibitor.
Curr Cancer Drug Targets
PUBLISHED: 06-02-2013
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Aberrant expression of the RON receptor tyrosine kinase contributes to breast cancer malignancy. Although clinical trials of RON targeting are underway, the intriguing issue is the diversity of RON expression as evident by cancer cells expressing different variants including oncogenic RON160. The current study determines aberrant RON160 expression in breast cancer and its potential as a target for breast cancer therapy. Using mouse monoclonal antibody Zt/h12 in immunohistochemical staining of breast cancer tissue microarray, we observed that RON160 was expressed in high frequency in primary invasive ductal (77.2%, 61/79 cases), lobular (42.5%, 34/80 cases), and lymph node-involved (63.9%, 26/36 cases) breast cancer samples. Moreover, RON160 overexpression was predominantly observed in invasive ductal (26.6%, 21/79 cases) and lymph node-involved (33.3%, 12/36) cases. Among a panel of breast cancer cell lines analyzed, Du4475 cells naturally expressed RON160. Silencing RON160 expression by siRNA reduced Du4475 cell viability. Inhibition of RON160 signaling by tyrosine kinase inhibitor PHA665752 also suppressed Du4475 cell anchorage-independent growth and induced apoptotic cell death. Studies in vivo revealed that PHA665752 inhibited 3T3- RON160 and Du4475 cell-mediated tumor growth in mouse mammary fat pad. A 60% reduction in tumor volume compared to controls was achieved after a 13-day treatment. We conclude from these studies that RON160 is highly expressed in breast cancer and its signaling is integrated into cellular signaling network for tumor cell growth and survival. Experimental treatment by PHA665752 in Du4475 breast cancer xenograft model highlights the significance of RON160 as a drug target in molecular-targeted breast cancer therapy.
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Carbon monoxide alleviates ethanol-induced oxidative damage and inflammatory stress through activating p38 MAPK pathway.
Toxicol. Appl. Pharmacol.
PUBLISHED: 05-10-2013
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Stress-inducible protein heme oxygenase-1(HO-1) is well-appreciative to counteract oxidative damage and inflammatory stress involving the pathogenesis of alcoholic liver diseases (ALD). The potential role and signaling pathways of HO-1 metabolite carbon monoxide (CO), however, still remained unclear. To explore the precise mechanisms, ethanol-dosed adult male Balb/c mice (5.0g/kg.bw.) or ethanol-incubated primary rat hepatocytes (100mmol/L) were pretreated by tricarbonyldichlororuthenium (II) dimmer (CORM-2, 8mg/kg for mice or 20?mol/L for hepatocytes), as well as other pharmacological reagents. Our data showed that CO released from HO-1 induction by quercetin prevented ethanol-derived oxidative injury, which was abolished by CO scavenger hemoglobin. The protection was mimicked by CORM-2 with the attenuation of GSH depletion, SOD inactivation, MDA overproduction, and the leakage of AST, ALT or LDH in serum and culture medium induced by ethanol. Moreover, CORM-2 injection or incubation stimulated p38 phosphorylation and suppressed abnormal Tnfa and IL-6, accompanying the alleviation of redox imbalance induced by ethanol and aggravated by inflammatory factors. The protective role of CORM-2 was abolished by SB203580 (p38 inhibitor) but not by PD98059 (ERK inhibitor) or SP600125 (JNK inhibitor). Thus, HO-1 released CO prevented ethanol-elicited hepatic oxidative damage and inflammatory stress through activating p38 MAPK pathway, suggesting a potential therapeutic role of gaseous signal molecule on ALD induced by naturally occurring phytochemicals.
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Analysis of a novel cathepsin B circulating antigen and its response to drug treatment in Trichinella-infected mice.
Parasitol. Res.
PUBLISHED: 04-16-2013
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In this paper, we cloned a novel full-length cDNA that encodes a Trichinella spiralis cathepsin B-like protease gene (TsCPB) using 3-RACE PCR. The recombinant mature TsCPB protein (rTsCPB) was then expressed in an Escherichia coli expression system and purified with Ni-affinity chromatography. Real-time quantitative PCR revealed that TsCPB was expressed across all development stages of the parasite but had the highest expression level during the adult stage. Furthermore, rTsCPB was detected in Trichinella excretory-secretory products with anti-rTsCPB rabbit polyclonal antibodies. Interestingly, rTsCPB was strongly recognized by the T. spiralis-infected sera in Western blotting, implying that TsCPB protein appeared in the peripheral blood of Trichinella-infected mice as circulating antigens (CAg). We then analyzed the dynamic levels of TsCPB CAg and its antibodies in T. spiralis-infected sera by using an improved double-antibody sandwich enzyme-linked immunosorbent assay (ELISA) and indirect ELISA, respectively. The results showed that TsCPB CAg can be detected much earlier compared to antibody detection in Trichinella-infected mice. In addition, we monitored the effects of albendazole drug therapy (a dosage of 370 mg/kg body weight, twice a day) on T. spiralis-infected mice by detecting the levels of TsCPB CAg and its antibody in the sera of drug-treated mice. The results showed that the levels of CAg dramatically decreased after successful drug treatment, while the antibody level remained unchanged. Overall, the novel Trichinella antigen TsCPB could be a promising novel circulating antigen molecule for the detection of Trichinella infection and for monitoring the efficacy of drug treatment of trichinellosis.
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Cholic acid modified N-(2-hydroxy)-propyl-3-trimethylammonium chitosan chloride for superoxide dismutase delivery.
Int J Pharm
PUBLISHED: 04-02-2013
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A series of novel amphiphilic chitosan derivatives, cholic acid modified N-(2-hydroxy)-propyl-3-trimethylammonium chitosan chloride (HTCC-CA) with different quaternization degrees and cholic acid substitutions were synthesized in this study. HTCC-CA is biocompatible and forms particles in aqueous solution. The binding with superoxide dismutase (SOD) at pH 6.8 destroys the original aggregates of HTCC-CA and produces smaller SOD/HTCC-CA complex nanoparticles via electrostatic and hydrophobic interactions. The SOD loading efficiency and loading capacity of HTCC-CA can reach to more than 90% and 45%, respectively. Confocal laser scanning microscopy observation and flow cytometry analysis reveal that SOD/HTCC-CA complex nanoparticles greatly enhance the cellular internalization of the loaded SOD. The SOD activities and malonaldehyde concentrations in the serum and organs of the rats, administrated intravenously with free SOD, free HTCC-CA, and SOD/HTCC-CA nanoparticles, were assayed to evaluate the antioxidant efficiency in vivo. The results demonstrate that free HTCC-CA is effective to scavenge superoxide radicals in the blood circulation and SOD/HTCC-CA nanoparticles have better antioxidant efficiency than free SOD as well as free HTCC-CA.
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An antigenic recombinant serine protease from Trichinella spiralis induces protective immunity in BALB/c mice.
Parasitol. Res.
PUBLISHED: 04-02-2013
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In this study, we report the cloning and characterization of a cDNA encoding a Trichinella serine protease gene (TspSP-1.3) from GenBank. The recombinant TspSP-1.3 protein (rTspSP-1.3) was expressed in an Escherichia coli expression system and purified with Ni-affinity chromatography. Real-time quantitative PCR analysis revealed that TspSP-1.3 was expressed at significantly higher levels in muscle larvae and adult worms than in newborn larvae. TspSP-1.3 was detected in excretory-secretory proteins of Trichinella spiralis with western blotting. Immunization with the rTspSP-1.3 antigen induced humoral immune responses, which manifested as elevated specific anti-rTspSP-1.3 IgG and IgE antibodies and a mixed Th1/Th2 response. To determine whether purified rTspSP-1.3 had good antigenicity and could be a vaccine candidate for the control of T. spiralis infection, we immunized BALB/c mice with rTspSP-1.3 and subsequently challenged the mice with T. spiralis larvae. The results showed that mice vaccinated with rTspSP-1.3 exhibited an average reduction in the muscle larvae burden of 39 % relative to the control group. These results suggest that TspSP-1.3 could be a novel vaccine candidate for controlling Trichinella infection.
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The altered expression profile of microRNAs in cardiopulmonary bypass canine models and the effects of mir-499 on myocardial ischemic reperfusion injury.
J Transl Med
PUBLISHED: 03-31-2013
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MicroRNAs were enrolled in various cardiovascular disease especially ischemic heart diseases, but the microRNA changes during myocardial ischemia reperfusion injury underwent cardiopulmonary bypass are still unknown. This study screens the microRNA differences in CPB canines and evaluates the relationship of microRNAs with myocardial ischemia reperfusion injury.
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Pathogenesis of RON receptor tyrosine kinase in cancer cells: activation mechanism, functional crosstalk, and signaling addiction.
J Biomed Res
PUBLISHED: 03-28-2013
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The RON receptor tyrosine kinase, a member of the MET proto-oncogene family, is a pathogenic factor implicated in tumor malignancy. Specifically, aberrations in RON signaling result in increased cancer cell growth, survival, invasion, angiogenesis, and drug resistance. Biochemical events such as ligand binding, receptor overexpression, generation of structure-defected variants, and point mutations in the kinase domain contribute to RON signaling activation. Recently, functional crosstalk between RON and signaling proteins such as MET and EFGR has emerged as an additional mechanism for RON activation, which is critical for tumorigenic development. The RON signaling crosstalk acts either as a regulatory feedback loop that strengthens or enhances tumorigenic phenotype of cancer cells or serves as a signaling compensatory pathway providing a growth/survival advantage for cancer cells to escape targeted therapy. Moreover, viral oncoproteins derived from Friend leukemia or Epstein-Barr viruses interact with RON to drive viral oncogenesis. In cancer cells, RON signaling is integrated into cellular signaling network essential for cancer cell growth and survival. These activities provide the molecular basis of targeting RON for cancer treatment. In this review, we will discuss recent data that uncover the mechanisms of RON activation in cancer cells, review evidence of RON signaling crosstalk relevant to cancer malignancy, and emphasize the significance of the RON signaling addiction by cancer cells for tumor therapy. Understanding aberrant RON signaling will not only provide insight into the mechanisms of tumor pathogenesis, but also lead to the development of novel strategies for molecularly targeted cancer treatment.
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A General Strategy for Biocompatible, High-Effective Upconversion Nanocapsules Based on Triplet-Triplet Annihilation.
J. Am. Chem. Soc.
PUBLISHED: 03-19-2013
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A general strategy for constructing high-effective upconversion nanocapsules based on triplet-triplet annihilation (TTA) was developed by loading both sensitizer and annihilator into BSA-dextran stabilized oil droplets. This strategy can maintain high translational mobility of the chromophores, avoid luminescence quenching of chromophore by aggregation, and decrease the O2-induced quenching of TTA-based upconversion emission. Pt(II)-tetraphenyl-tetrabenzoporphyrin (PtTPBP) and BODIPY dyes (BDP-G and BDP-Y with the maximal fluorescence emission at 528 and 546 nm, respectively) were chosen as sensitizer/annihilator couples to fabricate green and yellow upconversion luminescent emissive nanocapsules, named UCNC-G and UCNC-Y, respectively. In water under the atmospheric environment, interestingly, UCNC-G and UCNC-Y exhibit intense upconversion luminescence (UCL) emission (?ex = 635 nm) with the quantum efficiencies (?UCL) of 1.7% and 4.8%, respectively, whereas very weak UCL emission (?UCL < 0.1%) was observed for the corresponding previous reported SiO2-coating nanosystems because of aggregation-induced fluorescence quenching of annihilators. Furthermore, application of theses upconversion nanocapsules for high-contrast UCL bioimaging in vivo of living mice without removing the skin was demonstrated under 635-nm excitation with low power density of 12.5 mW cm(-2).
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Evaluation of reproductive and developmental toxicities of Pu-erh black tea (Camellia sinensis var. assamica) extract in Sprague Dawley rats.
J Ethnopharmacol
PUBLISHED: 03-18-2013
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Pu-erh black tea, which is obtained by first parching crude green tea leaves and followed by secondary fermentation with microorganisms, has been believed to be beneficial beverages for health in PR China. But its potential toxicity when administered at a high dose as concentrated extract has not been completely investigated.
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Small-molecule inhibitor BMS-777607 induces breast cancer cell polyploidy with increased resistance to cytotoxic chemotherapy agents.
Mol. Cancer Ther.
PUBLISHED: 03-06-2013
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The RON receptor tyrosine kinase is a therapeutic target for cancer treatment. Here, we report therapeutic effect and phenotypic change of breast cancer cells in response to BMS-777607, a RON tyrosine kinase inhibitor. Treatment of breast cancer cells with BMS-777607 at therapeutic doses inhibited cancerous clonogenic growth but had only minimal effect on cell apoptosis. Significantly, BMS-777607 induced extensive polyploidy with multiple sets of chromosomes in cancer cells. This effect is independent of RON expression. Knockdown of RON in T-47D and ZR-75-1 cells by specific siRNA did not prevent polyploid formation. Immunofluorescent analysis of ?-tubulin and ?-tubulin expression in polyploid cells revealed that BMS-777607 disrupts bipolar spindle formation and causes multipolar-like microtubule assembly. Also, both metaphase equatorial alignment and chromosomal segregation were absent in polyploid cells. These results suggest that cellular mitosis arrests at prophase/pro-metaphase and fails to undergo cytokinesis. By analyzing kinase-inhibitory profiles, aurora kinase B was identified as the target molecule inhibited by BMS-777607. In BMS-777607-treated cells, aurora kinase B was inhibited followed by protein degradation. Moreover, BMS-777607 inhibited Ser10 phosphorylation of histone H3, a substrate of aurora kinase B. Chemosensitivity analysis indicated the resistance of polyploid cells toward chemotherapeutics. Treatment with doxorubicin, bleomycin, methotrexate, and paclitaxel significantly increased cellular IC50 values. These findings highlight the theory that BMS-777607 acts as a multikinase inhibitor at therapeutic doses and is capable of inducing polyploidy by inhibiting aurora kinase B. Increased resistance of polyploid cells to cytotoxic chemotherapeutics could have a negative impact on targeted cancer therapy using BMS-777607.
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Quercetin suppressed CYP2E1-dependent ethanol hepatotoxicity via depleting heme pool and releasing CO.
Phytomedicine
PUBLISHED: 03-05-2013
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Naturally occuring quercetin protects hepatocytes from ethanol-induced oxidative stress, and heme oxygenase-1 (HO-1) induction and carbon monoxide (CO) metabolite may be implicated in the beneficial effect. However, the precise mechanism by which quercetin counteracts CYP2E1-mediated ethanol hepatotoxicity through HO-1 system is still remained unclear. To explore the potential mechanism, herein, ethanol (4.0 g/kg.bw.) was administrated to rats for 90 days. Our data showed that chronic ethanol over-activated CYP2E1 but suppressed HO-1 with concurrent hepatic oxidative damage, which was partially normalized by quercetin (100mg/kg.bw.). Quercetin (100 ?M) induced HO-1 and depleted heme pool when incubated to human hepatocytes. Ethanol-stimulated (100mM) CYP2E1 upregulation was suppressed by quercetin but further enhanced by HO-1 inhibition with resultant heme accumulation. CO scavenging blocked the suppression of quercetin only on CYP2E1 activity. CO donor dose-dependently inactivated CYP2E1 of ethanol-incubated microsome, which was mimicked by HO-1 substrate but abolished by CO scavenger. Thus, CYP2E1-mediated ethanol hepatotoxicity was alleviated by quercetin through HO-1 induction. Depleted heme pool and CO releasing limited protein synthesis and inhibited enzymatic activity of CYP2E1, respectively.
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Inhibition of UVB-induced nonmelanoma skin cancer: a path from tea to caffeine to exercise to decreased tissue fat.
Top Curr Chem
PUBLISHED: 03-05-2013
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Oral administration of green tea, black tea, or caffeine (but not the decaffeinated teas) inhibited ultraviolet B radiation (UVB)-induced skin carcinogenesis in SKH-1 mice. Studies with caffeine indicated that its inhibitory effect on the ATR/Chk1 pathway is an important mechanism for caffeines inhibition of UVB-induced carcinogenesis. The regular teas or caffeine increased locomotor activity and decreased tissue fat. In these studies, decreased dermal fat thickness was associated with a decrease in the number of tumors per mouse. Administration of caffeine, voluntary exercise, and removal of the parametrial fat pads all stimulated UVB-induced apoptosis, inhibited UVB-induced carcinogenesis, and stimulated apoptosis in UVB-induced tumors. These results suggest that caffeine administration, voluntary exercise, and removal of the parametrial fat pads inhibit UVB-induced carcinogenesis by stimulating UVB-induced apoptosis and by enhancing apoptosis in DNA-damaged precancer cells and in cancer cells. We hypothesize that tissue fat secretes antiapoptotic adipokines that have a tumor promoting effect.
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In situ preparation of gold nanoparticle-loaded lysozyme-dextran nanogels and applications for cell imaging and drug delivery.
Nanoscale
PUBLISHED: 03-01-2013
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An effective, green, and facile approach to synthesize gold nanoparticle-loaded protein-polysaccharide nanogels was developed in this study. Biocompatible gold nanoparticle-loaded lysozyme-dextran (Au@Lys-Dex) nanogels were produced using lysozyme-dextran nanogels as reducing and stabilizing agents. Lysozyme-dextran nanogels have a size of about 200 nm and a structure of lysozyme core and dextran shell. At pH around 4, AuCl4(-) ions are attracted and locally enriched by lysozyme due to the electrostatic and coordination interactions. When the solution is under UV irradiation, the AuCl4(-) ions are reduced to gold nanoparticles in situ by solvated electrons and reactive radicals produced from aromatic amino acid residues in the lysozyme. The produced gold nanoparticles with a size of about 8 nm are trapped inside the nanogels and the Au@Lys-Dex nanogels are well dispersible by virtue of the dextran shell. Antitumor drug, doxorubicin, can be loaded effectively inside Au@Lys-Dex nanogels via diffusion. In vitro study demonstrates the doxorubicin loaded Au@Lys-Dex nanogels have the same antitumor activity as free doxorubicin. The nanogels can be used as a contrasting agent in optical cell imaging, in which direct visual images of the subcellular distributions of the gold nanoparticles and the released doxorubicin are presented synchronously. The dual functional drug loaded Au@Lys-Dex nanogels are a promising system for simultaneous drug delivery and biomedical imaging.
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Inactivation of Wnt/?-catenin signaling in human adipose-derived stem cells is necessary for chondrogenic differentiation and maintenance.
Biomed. Pharmacother.
PUBLISHED: 02-15-2013
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The Wnt/?-catenin signaling pathway plays critical roles in self-renewal and differentiation of mesenchymal stem cells. However, very little is known about its role in the chondrogenesis of human adipose-derived stem cells (hADSCs). In this study, we analyzed protein expression of several key components of the Wnt/?-catenin signaling pathway using a 21-day in vitro model of hADSC chondrogenesis. Wnt1, ?-catenin, and GSK3? levels increased sharply at day 12, peaked at day 18, and then declined. Expression of TCF1, a target gene of Wnt/?-catenin signaling, closely followed that of Wnt1. These results were consistent with changes in endonuclear ?-catenin levels. Gene expression of the chondrocyte-specific markers, collagen type II (COL II), SOX9, and aggrecan, increased during hADSC chondrogenesis, peaked at day 12, and then declined. Adding a Wnt inhibitor (days 0-21) resulted in consistently elevated levels of COL II, SOX9, and aggrecan mRNA. In contrast, adding Wnt1 (days 0-21) to cultures led to sustained Wnt/?-catenin signaling over the 21 days and suppressed expression of chondrocyte-specific markers. Moreover, adding Wnt1 at late stages of differentiation (day 18) further diminished chondrocyte-specific marker expression. Together, these results showed that inactivation of Wnt/?-catenin signaling is needed for the progression of chondrogenesis and the maturation and phenotype maintenance of chondroid cells.
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The roles of integrin ?1 in phenotypic maintenance and dedifferentiation in chondroid cells differentiated from human adipose-derived stem cells.
Nanoscale Res Lett
PUBLISHED: 02-15-2013
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The aim of this study is to probe the intrinsic mechanism of chondroid cell dedifferentiation in order to provide a feasible solution for this in cell culture.
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Chronic leucine supplementation increases body weight and insulin sensitivity in rats on high-fat diet likely by promoting insulin signaling in insulin-target tissues.
Mol Nutr Food Res
PUBLISHED: 02-13-2013
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This study investigated the effect of chronic leucine supplementation on insulin sensitivity and the associated mechanisms in rats on high-fat diet (HFD).
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Leucine facilitates insulin signaling through a G?i protein-dependent signaling pathway in hepatocytes.
J. Biol. Chem.
PUBLISHED: 02-12-2013
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In this study, we addressed the direct effect of leucine on insulin signaling. In investigating the associated mechanisms, we found that leucine itself does not activate the classical Akt- or ERK1/2 MAP kinase-dependent signaling pathways but can facilitate the insulin-induced phosphorylations of Akt(473) and ERK1/2 in a time- and dose-dependent manner in cultured hepatocytes. The leucine-facilitated insulin-induced phosphorylation of Akt at residue 473 was not affected by knocking down the key component of mTORC1 or -2 complexes but was blocked by inhibition of c-Src (PP2), PI3K (LY294002), G?i protein (pertussis toxin or siRNA against G?i1 gene, or ?-arrestin 2 (siRNA)). Similarly, the leucine-facilitated insulin activation of ERK1/2 was also blunted by pertussis toxin. We further show that leucine facilitated the insulin-mediated suppression of glucose production and expression of key gluconeogenic genes in a G?i1 protein-dependent manner in cultured primary hepatocytes. Together, these results show that leucine can directly facilitate insulin signaling through a G?i protein-dependent intracellular signaling pathway. This is the first evidence showing that macronutrients like amino acid leucine can facilitate insulin signaling through G proteins directly.
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Compounds from the Fruits of the Popular European Medicinal Plant Vitex agnus-castus in Chemoprevention via NADP(H):Quinone Oxidoreductase Type 1 Induction.
Evid Based Complement Alternat Med
PUBLISHED: 01-30-2013
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As part of our continuing efforts in the search for potential biologically active compounds from medicinal plants, we have isolated 18 compounds including two novel nitrogen containing diterpenes from extracts of the fruits of Vitex agnus-castus. These isolates, along with our previously obtained novel compound vitexlactam A (1), were evaluated for potential biological effects, including cancer chemoprevention. Chemically, the nitrogenous isolates were found to be two labdane diterpene alkaloids, each containing an ? , ? -unsaturated ? -lactam moiety. Structurally, they were elucidated to be 9 ? -hydroxy-13(14)-labden-16,15-amide (2) and 6 ? -acetoxy-9 ? -hydroxy-13(14)-labden-15,16-amide (3), which were named vitexlactams B and C, respectively. The 15 known isolates were identified as vitexilactone (4), rotundifuran (5), 8-epi-manoyl oxide (6), vitetrifolin D (7), spathulenol (8), cis-dihydro-dehydro-diconiferylalcohol-9-O- ? -D-glucoside (9), luteolin-7-O-glucoside (10), 5-hydroxy-3,6,7,4-tetramethoxyflavone (11), casticin (12), artemetin (13), aucubin (14), agnuside (15), ? -sitosterol (16), p-hydroxybenzoic acid (17), and p-hydroxybenzoic acid glucose ester (18). All compound structures were determined/identified on the basis of 1D and/or 2D NMR and mass spectrometry techniques. Compounds 6, 8, 9, and 18 were reported from a Vitex spieces for the first time. The cancer chemopreventive potentials of these isolates were evaluated for NADP(H):quinone oxidoreductase type 1 (QR1) induction activity. Compound 7 demonstrated promising QR1 induction effect, while the new compound vitexlactam (3) was only slightly active.
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Can Hedysari Radix replace Astragali Radix in Danggui Buxue Tang, a Chinese herbal decoction for woman aliment?
Phytomedicine
PUBLISHED: 01-25-2013
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Astragali Radix (AR) has been used for over 2000 years in China for the enrichment of "Qi". Hedysari Radix (HR), a herb having similar chemical composition with AR, has been commonly used as a substitute of AR in herbal decoction. In order to evaluate the possible replacement of HR for AR in Chinese herbal decoction, systematic comparison of AR and HR was done by chemical and biological assessments. The water extract of AR contained higher levels of calycosin, calycosin-glucoside, ononin, astragaloside III and astragaloside IV, while higher amount of formononetin was found in the HR extract. The estrogenic, erythropoetic and osteogenic effects were compared between the water extracts of AR and HR, and in all cases AR extract showed higher biological activities. Danggui Buxue Tang (DBT) is a very common herbal decoction for woman aliment, and which contains AR and Angelica Sinensis Radix. Here, we generated two forms of DBT having either AR or HR as the major herbs. Chemically, AR-contained DBT showed higher amounts of various active chemicals, except formononetin that was higher in HR-contained DBT. In parallel, the estrogenic, osteogenic and erythropoetic effects of DBT containing AR showed better activities than that of DBT having HR. Thus, AR and HR showed distinct differences in terms of chemical and biological properties. In order to achieve the best therapeutical effect, as well as to guarantee the safety, AR is recommended here to be used for making DBT.
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Aldosterone and mortality in hemodialysis patients: role of volume overload.
PLoS ONE
PUBLISHED: 01-22-2013
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Elevated aldosterone is associated with increased mortality in the general population. In patients on dialysis, however, the association is reversed. This paradox may be explained by volume overload, which is associated with lower aldosterone and higher mortality.
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Preparation, characterization, and in vivo evaluation of doxorubicin loaded BSA nanoparticles with folic acid modified dextran surface.
Int J Pharm
PUBLISHED: 01-20-2013
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Biocompatible and biodegradable doxorubicin loaded nanoparticles with targeting ability were prepared from BSA-dextran-folic acid conjugate via a pH adjustment and heating process. The BSA-dextran-folic acid conjugate was produced by an esterification reaction between folic acid and dextran and then the Maillard reaction between the modified dextran and BSA. The nanoparticles have a size about 90nm and excellent dispersibility at pH 7.4 aqueous solution. The doxorubicin loading efficiency and loading amount of the nanoparticles are larger than 90% and 14%, respectively. The antitumor activity and toxicity of the nanoparticles were evaluated through murine ascites hepatoma H22 tumor-bearing mice. The nanoparticles allow the administration of the doxorubicin with higher dose. At doxorubicin dose of 10mg/kg, the nanoparticles can achieve 88.9% of the tumor inhibition rate that is the same as the free doxorubicin at the dose of 5mg/kg. Importantly, the nanoparticles can decrease the toxicity of doxorubicin that results in a significant increase of the average life time in comparison with the free doxorubicin as well as the nanoparticles without folic acid.
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