璧勮涓績 > 浜у搧鏂囩尞闆?> Pharmacology (7)

  鉁旀湰綃囪鏂囦嬌鐢ㄥ崕鑱斾駭鍝侊細Human OneArray  
 Mol Nutr Food Res. 2012, 56(6):878-88. doi: 10.1002/mnfr.201100798.
 The natural carotenoid astaxanthin, a PPAR-偽 agonist and PPAR-緯 antagonist, reduces hepatic lipid accumulation by rewiring the transcriptome in lipid-loaded hepatocytes 
 Yaoyao Jia, Jin-young Kim, Hee-jin Jun, Sun-joong Kim, Ji-hae Lee, Minh Hien Hoang, Kwang-yeon Hwang, Soo-jong Um, Hyo Ihl Chang, Sung-joon Lee
  Abstract
A natural carotenoid abundant in seafood, astaxanthin (AX), has hypolipidemic activity, but its underlying mechanisms of action and protein targets are unknown. We investigated the molecular mechanism of action of AX in hepatic hyperlipidemia by measuring peroxisome proliferator-activated receptors (PPAR) activity. We examined the binding of AX to PPAR subtypes and its effects on hepatic lipid metabolism. AX binding activated PPAR-偽, but inhibited PPAR-緯 transactivation activity in reporter gene assay and time-resolved fluorescence energy transfer analyses. AX had no effect on PPAR未/尾 transactivation. AX bound directly to PPAR-偽 and PPAR-緯 with moderate affinity, as assessed by surface plasmon resonance experiments. The differential effects of AX on PPARs were confirmed by measuring the expression of unique responsive genes for each PPAR subtype. AX significantly reduced cellular lipid accumulation in lipid-loaded hepatocytes. Transcriptome analysis revealed that the net effects of stimulation with AX (100 渭M) on lipid metabolic pathways were similar to those elicited by fenofibrate and lovastatin (10 渭M each), with AX rewiring the expression of genes involved in lipid metabolic pathways. AX is a PPAR-偽 agonist and PPAR-緯 antagonist, reduces hepatic lipid accumulation by rewiring the transcriptome in lipid-loaded hepatocytes.
   

Topic Related Articles

  鉁旀湰綃囪鏂囦嬌鐢ㄥ崕鑱斾駭鍝侊細Human OneArray  
 Plos One. 2014 December 1. doi: 10.1371/journal.pone.0113649.
 Nifedipine Promotes the Proliferation and Migration of Breast Cancer Cells
 
 
 Dong-qing Guo, Hao Zhang, Sheng-jiang Tan, Yu-chun Gu
  Abstract
Nifedipine is widely used as a calcium channel blocker (CCB) to treat angina and hypertension,but it is controversial with respect the risk of stimulation of cancers. In this study, we demonstrated that nifedipine promoted the proliferation and migration of breast cancer cells both invivo and invitro. However, verapamil, another calcium channel blocker, didn鈥檛 exert the similar effects. Nifedipine and high concentration KCl failed to alter the [Ca2+]i in MDA-MB-231 cells, suggesting that such nifedipine effect was not related with calcium channel. Moreover, nifedipine decreased miRNA-524-5p, resulting in the up-regulation of brain protein I3 (BRI3). Erk pathway was consequently activated and led to the proliferation and migration of breast cancer cells. Silencing BRI3 reversed the promoting effect of nifedipine on the breast cancer. In a summary, nifedipine stimulated the proliferation and migration of breast cancer cells via the axis of miRNA-524-5p-BRI3鈥揈rk pathway independently of its calcium channel-blocking activity. Our findings highlight that nifedipine but not verapamil is conducive for breast cancer growth and metastasis, urging that the caution should be taken in clinic to prescribe nifedipine to women who suffering both hypertension and breast cancer, and hypertension with a tendency in breast cancers.
   

  鉁旀湰綃囪鏂囦嬌鐢ㄥ崕鑱斾駭鍝侊細Mouse OneArray  
 Food Chemistry. 2013, 136(2):426-34. doi: 10.1016/j.foodchem.2012.08.009.
 Toona sinensis and its major bioactive compound gallic acid inhibit LPS-induced inflammation in nuclear factor-魏B transgenic mice as evaluated by in vivo bioluminescence imaging
 
 
 Chien-yun Hsiang, You-cheng Hseu, Yi-chih Chang, K.j. Senthil Kumar, Tin-yun Ho, Hsin-ling Yang
  Abstract
In the present study, we investigated the anti-inflammatory effects of a nutritious vegetable Toona sinensis (leaf extracts, TS) and its major bioactive compound gallic acid (GA) by analysing LPS-induced NF-魏B activation in transgenic mice, using bioluminescence imaging. Mice were challenged intraperitoneally with LPS (1 mg/kg) and treated orally with TS or GA (100 or 5 mg/kg, respectively). In vivo and ex vivo imaging showed that LPS increased NF-魏B luminescence in the abdominal region, which was significantly inhibited by TS or GA. Immunohistochemical and ELISA analyses confirmed that TS and GA inhibited LPS-induced NF-魏B, interleukin-1尾, and tumour necrosis factor-偽 expression. Microarray analysis revealed that biological pathways associated with metabolism and the immune responses were affected by TS or GA. Particularly, LPS-induced thioredoxin-like 4B (TXNL4B) 2 expression in the small intestine, and TXNL4B, iNOS, and COX-2 expression in RAW 264.7 cells were significantly inhibited by TS or GA. Thus, the anti-inflammatory potential of TS was mediated by the downregulation of NF-魏B pathway.
   

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  鉁旀湰綃囪鏂囦嬌鐢ㄥ崕鑱斾駭鍝侊細Human OneArray  
 Bmc Cancer. DOI 10.1186/s12885-015-1671-5.
 Upregulation of MicroRNA-19b predicts good prognosis in patients with hepatocellular carcinoma presenting with vascular invasion or multifocal disease
 
 
 
  Abstract
Background After surgical resection of hepatocellular carcinoma (HCC), recurrence is common, especially in patients presenting with vascular invasion or multifocal disease after curative surgery. Consequently, we examined the expression pattern and prognostic value of miR-19b in samples from these patients. Methods We performed a miRNA microarray to detect differential expression of microRNAs (miRNAs) in 5 paired samples of HCC and non-tumoral adjacent liver tissue and a quantitative real-time polymerase chain reaction (PCR) analysis to validate the results in 81 paired samples of HCC and adjacent non-tumoral liver tissues. We examined the associations of miR-19b expression with clinicopathological parameters and survival. MiR-19b was knocked down in Hep3B and an mRNA microarray was performed to detect the affected genes. Results In both the miRNA microarray and real-time PCR, miR-19b was significantly overexpressed in the HCC tumor compared with adjacent non-tumor liver tissues (P < 0.001). The expression of miR-19b was significantly higher in patients who were disease-free 2 years after surgery (P < 0.001). High miR-19b expression levels were associated with higher 偽-fetoprotein levels (P = 0.017). In the log-rank test, high miR-19b was associated with better disease-free survival (median survival 37.107 vs. 11.357; P = 0.022). In Cox multivariate analysis, high miR-19b predicted better disease-free survival and overall survival (hazards ratio [HR] = 0.453, 95 % confidence interval [CI] = 0.245鈥?.845, P = 0.013; HR = 0.318, CI = 0.120鈥?.846, P = 0.022, respectively). N-myc downstream regulated 1 (NDRG1) was downregulated, while epithelial cell adhesion molecule (EPCAM), hypoxia-inducible factor 1-alpha (HIF1A), high-mobility group protein B2 (HMGB2), and mitogen activated protein kinase 14 (MAPK14) were upregulated when miR-19b was knocked down in Hep3B. Conclusions The overexpression of miR-19b was significantly correlated with better disease-free and overall survival in patients with HCC presenting with vascular invasion or multifocal disease after curative surgery. MiR-19b may influence the expression of NDRG1, EPCAM, HMGB2, HIF1A, and MAPK14.
   

  鉁旀湰綃囪鏂囦嬌鐢ㄥ崕鑱斾駭鍝侊細Human OneArray  
 Amino Acids. doi: 10.1007/s00726-015-1956-7. Epub 2015 Mar 24..
 Homocysteine thiolactone and N-homocysteinylated protein induce pro-atherogenic changes in gene expression in human vascular endothelial cells
 
 
 
  Abstract
Genetic or nutritional deficiencies in homocysteine (Hcy) metabolism lead to hyperhomocysteinemia (HHcy) and cause endothelial dysfunction, a hallmark of atherosclerosis. In addition to Hcy, related metabolites accumulate in HHcy but their role in endothelial dysfunction is unknown. Here, we examine how Hcy-thiolactone, N-Hcy-protein, and Hcy affect gene expression and molecular pathways in human umbilical vein endothelial cells. We used microarray technology, real-time quantitative polymerase chain reaction, and bioinformatic analysis with PANTHER, DAVID, and Ingenuity Pathway Analysis (IPA) resources. We identified 47, 113, and 30 mRNAs regulated by N-Hcy-protein, Hcy-thiolactone, and Hcy, respectively, and found that each metabolite induced a unique pattern of gene expression. Top molecular pathways affected by Hcy-thiolactone were chromatin organization, one-carbon metabolism, and lipid-related processes [−log(P value) = 20鈥?1]. Top pathways affected by N-Hcy-protein and Hcy were blood coagulation, sulfur amino acid metabolism, and lipid metabolism [−log(P value)] = 4鈥?1; also affected by Hcy-thiolactone, [−log(P value) = 8鈥?4]. Top disease related to Hcy-thiolactone, N-Hcy-protein, and Hcy was 鈥榓therosclerosis, coronary heart disease鈥?[−log(P value) = 9鈥?6]. Top-scored biological networks affected by Hcy-thiolactone (score = 34鈥?0) were cardiovascular disease and function; those affected by N-Hcy-protein (score = 24鈥?5) were 鈥榮mall molecule biochemistry, neurological disease,鈥?and 鈥榗ardiovascular system development and function鈥? and those affected by Hcy (score = 25鈥?7) were 鈥榓mino acid metabolism, lipid metabolism,鈥?鈥榗ellular movement, and cardiovascular and nervous system development and function.鈥?These results indicate that each Hcy metabolite uniquely modulates gene expression in pathways important for vascular homeostasis and identify new genes and pathways that are linked to HHcy-induced endothelial dysfunction and vascular disease.
   

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