期刊：
JOURNAL OF CARDIOVASCULAR PHARMACOLOGY,2010年56(3):309-319 ISSN：0160-2446
通讯作者：
Tang, Chao-Ke
作者机构：
[Tan, Chun-Zhi; Tang, Chao-Ke; Liu, Xie-Hong; Yin, Kai; Tang, Ya-Ling; Mo, Zhong-Cheng; Jiang, Jin; Xiao, Ji; Cui, Li-Bao] Inst Cardiovasc Res, Key Lab Atherosclerol Hunan Prov, Changsha, Hunan, Peoples R China.;[Liu, Xie-Hong] Changsha Med Univ, Changsha, Hunan, Peoples R China.;[Liao, Duan-Fang] Hunan Univ Chinese Med, Changsha, Hunan, Peoples R China.;[Tang, Chao-Ke] Univ S China, Inst Cardiovasc Res, Key Lab Atherosclerol Hunan Prov, Life Sci Res Ctr, Hengyang 421001, Peoples R China.
通讯机构：
[Tang, Chao-Ke] U;Univ S China, Inst Cardiovasc Res, Key Lab Atherosclerol Hunan Prov, Life Sci Res Ctr, Hengyang 421001, Peoples R China.
关键词：
ABCA1, D4-F, Cdc42/cAMP/PKA, atherosclerosis, reverse cholesterol transport
摘要：
Adenosine triphosphate-binding cassette transporter A1 (ABCA1) plays a crucial role in apolipoprotein A-I (apoA-I) binding activity and promotes cellular cholesterol efflux. ApoA-I mimetic peptide D4-F has reported to have the similar ability as apoA-I. However, the detailed mechanisms of ABCA1 regulation by D4-F are not understood. In the present study, we investigated the effects of D4-F on ABCA1 expression and ABCA1-dependent cholesterol efflux and examined the role of Cdc42/cyclic adenosine monophosphate (cAMP)/protein kinase A (PKA) pathway on the regulation of ABCA1 by D4-F in THP-1 macrophage-derived foam cells. Results showed that D4-F stabilized ABCA1 protein and enhanced ABCA1-dependent cholesterol efflux but had no effect on ABCA1 messenger RNA expression. We also revealed that D4-F enhanced cAMP level and PKA activity and ABCA1 serine phosphorylation. Short interfering RNA of PKA led to reduction of ABCA1 serine phosphorylation and ABCA1-mediated cholesterol efflux compensated by D4-F. PKA-specific activation by PKA agonist enhanced the upregulation of ABCA1 serine phosphorylation and ABCA1-mediated cholesterol efflux by D4-F. However, ABCA1 expression did not change by treatment with PKA agonist or PKA-short interfering RNA. We found that secramine B of Cdc42 inhibitor reduced the cAMP level compensated by D4-F. These results provide evidence that D4-F enhances ABCA1 serine phosphorylation and ABCA1-dependent cholesterol efflux through Cdc42/cAMP/PKA pathway in THP-1 macrophage-derived foam cells.
摘要：
Atherosclerosis is characterized by a chronic inflammatory condition that involves numerous cellular and molecular inflammatory components. A wide array of inflammatory mediators, such as cytokines and proteins produced by macrophages and other cells, play a critical role in the development and progression of the disease. ATP-binding membrane cassette transporter A1 (ABCA1) is crucial for cellular cholesterol efflux and reverse cholesterol transport (RCT) and is also identified as an important target in antiatherosclerosis treatment. Evidence from several recent studies indicates that inflammation, along with other atherogenic-related mediators, plays distinct regulating roles in ABCA1 expression. Proatherogenic cytokines such as interferon (IFN)-γ and interleukin (IL)-1β have been shown to inhibit the expression of ABCA1, while antiatherogenic cytokines, including IL-10 and transforming growth factor (TGF)-β1, have been shown to promote the expression of ABCA1. Moreover, some cytokines such as tumor necrosis factor (TNF)-α seem to regulate ABCA1 expression in species-specific and dose-dependent manners. Inflammatory proteins such as C-reactive protein (CRP) and cyclooxygenase (COX)-2 are likely to inhibit ABCA1 expression during inflammation, and inflammation induced by lipopolysaccharide (LPS) was also found to block the expression of ABCA1. Interestingly, recent experiments revealed ABCA1 can function as an antiinflammatory receptor to suppress the expression of inflammatory factors, suggesting that ABCA1 may be the molecular basis for the interaction between inflammation and RCT. This review aims to summarize recent findings on the role of inflammatory cytokines, inflammatory proteins, inflammatory lipids, and the endotoxin-mediated inflammatory process in expression of ABCA1. Also covered is the current understanding of the function of ABCA1 in modulating the immune response and inflammation through its direct and indirect antiinflammatory mechanisms including lipid transport, high-density lipoprotein (HDL) formation and apoptosis.
通讯机构：
[Zheng, Xing] U;Univ S China, Inst Pharm & Pharmacol, Hengyang 421001, Peoples R China.
摘要：
A series of chrysin derivatives were prepared from 2-hydroxyacetophenone, 2,4-dihydroxyacetophenone, 2,4,6- trihydroxy- acetophenone, using modified Baker-Venkataraman transformation. Their anticancer activities in vitro were evaluated by the standard MTT method. The results of biological test showed that some of chrysin derivatives showed stronger anticancer activity than 5-fluorouracil.
期刊：
Lipids in Health and Disease,2010年9(1):1-10 ISSN：1476-511X
通讯作者：
Qin, Yang
作者机构：
[Qin, Yang; Tian, Li; Liu, Yinghui] Sichuan Univ, Dept Biochem & Mol Biol, W China Sch Preclin & Forens Med, Chengdu 610041, Sichuan, Peoples R China.;[Fu, Mingde] Sichuan Univ, Lab Endocrinol & Metab, W China Hosp, Chengdu 610041, Sichuan, Peoples R China.;[Long, Shiyin] Univ S China, Dept Biochem & Mol Biol, Hengyang 421001, Peoples R China.;[Xu, Yanhua] Chengdu Hoist Biotechnol Co LTD, Chengdu 610075, Peoples R China.
通讯机构：
[Qin, Yang] S;Sichuan Univ, Dept Biochem & Mol Biol, W China Sch Preclin & Forens Med, Chengdu 610041, Sichuan, Peoples R China.
关键词：
Reverse Cholesterol Transport;Cholesterol Ester Transfer Protein;Quebec Cardiovascular Study;West China Medical;Monitor Atherosclerosis Regression Study
摘要：
To evaluate the relationship between the low-density lipoprotein cholesterol (LDL-C)/high-density lipoprotein cholesterol (HDL-C) ratio and HDL subclass distribution and to further examine and discuss the potential impact of LDL-C and HDL-C together with TG on HDL subclass metabolism. Small-sized preβ1-HDL, HDL3b and HDL3a increased significantly while large-sized HDL2a and HDL2b decreased significantly as the LDL-C/HDL-C ratio increased. The subjects in low HDL-C level (< 1.03 mmol/L) who had an elevation of the LDL-C/HDL-C ratio and a reduction of HDL2b/preβ1-HDL regardless of an undesirable or high LDL-C level. At desirable LDL-C levels (< 3.34 mmol/L), the HDL2b/preβ1-HDL ratio was 5.4 for the subjects with a high HDL-C concentration (≥ 1.55 mmol/L); however, at high LDL-C levels (≥ 3.36 mmol/L), the ratio of LDL-C/HDL-C was 2.8 in subjects, and an extremely low HDL2b/preβ1-HDL value although with high HDL-C concentration. With increase of the LDL-C/HDL-C ratio, there was a general shift toward smaller-sized HDL particles, which implied that the maturation process of HDL was blocked. High HDL-C concentrations can regulate the HDL subclass distribution at desirable and borderline LDL-C levels but cannot counteract the influence of high LDL-C levels on HDL subclass distribution.
摘要：
Cholesterol efflux from lipid-loaded cells is a key athero-protective event that counteracts cholesterol uptake. The imbalance between cholesterol efflux and uptake determines the prevention or development of atherosclerosis. Many proteins and factors participate in the cholesterol efflux event. However, there are currently no systematic models of reverse cholesterol transport (RCT) that include most RCT-related factors and events. On the basis of recent research findings from other and our laboratories, we propose a novel model of one center and four systems with coupling transportation and networking regulation. This model represents a common way of cholesterol efflux; however, the systems in the model consist of different proteins/factors in different cells. In this review, we evaluate the novel model in vascular smooth muscle cells (VSMCs) and macrophages, which are the most important original cells of foam cells. This novel model consists of 1) a caveolae transport center, 2) an intracellular trafficking system of the caveolin-1 complex, 3) a transmembrane transport system of the ABC-A1 complex, 4) a transmembrane transport system of the SR-B1 complex, and 5) an extracelluar trafficking system of HDL/Apo-A1. In brief, the caveolin-1 system transports cholesterol from intracellular compartments to caveolae. Subsequently, both ABC-A1 and SR-B1 complex systems transfer cholesterol from caveolae to extracellular HDL/Apo-A1. The four systems are linked by a regulatory network. This model provides a simple and concise way to understand the dynamic process of atherosclerosis.
期刊：
Journal of Histochemistry & Cytochemistry,2010年58(6):517-527 ISSN：0022-1554
通讯作者：
Chen, Zhuchu
作者机构：
[Li, Maoyu; Xiao, Zhiqiang; Li, Cui; Li, Feng; Peng, Fang; Xiao, Zhefeng; Chen, Zhuchu; Li, Guoqing] Cent S Univ, Xiangya Hosp, Key Lab Canc Prote, Chinese Minist Hlth, Changsha 410008, Hunan, Peoples R China.;[Yu, Yanhui; Li, Feng; Ouyang, Yongmei; Xiao, Zhefeng] Cent S Univ, Canc Res Inst, Xiangya Sch Med, Changsha 410008, Hunan, Peoples R China.;[Li, Guoqing] Univ S China, Sch Pharm & Life Sci, Dept Biol, Hengyang, Hunan, Peoples R China.;[Chen, Yongheng] Univ So Calif, Los Angeles, CA USA.;[Chen, Zhuchu] Cent S Univ, Xiangya Hosp, Key Lab Canc Prote, Chinese Minist Hlth, 87 Xiangya Rd, Changsha 410008, Hunan, Peoples R China.
通讯机构：
[Chen, Zhuchu] C;Cent S Univ, Xiangya Hosp, Key Lab Canc Prote, Chinese Minist Hlth, 87 Xiangya Rd, Changsha 410008, Hunan, Peoples R China.
关键词：
NPC;FFPE;iTRAQ;2D LC-MS/MS
摘要：
Formalin-fixed, paraffin-embedded (FFPE) tissue specimens represent a potentially valuable resource for protein biomarker investigations. In this study, proteins were extracted by a heat-induced antigen retrieval technique combined with a retrieval solution containing 2% SDS from FFPE tissues of normal nasopharyngeal epithelial tissues (NNET) and three histological types of nasopharyngeal carcinoma (NPC) with diverse differentiation degrees. Then two-dimensional liquid chromatography-tandem mass spectrometry coupled with isobaric tags for relative and absolute quantification (iTRAQ) labeling was employed to quantitatively identify the differentially expressed proteins among the types of NPC FFPE tissues. Our study resulted in the identification of 730 unique proteins, the distributions of subcellular localizations and molecular functions of which were similar to those of the proteomic database of human NPC and NNET that we had set up based on the frozen tissues. Additionally, the relative expression levels of cathepsin D, keratin8, SFN, and stathmin1 identified and quantified in this report were consistent with the immunohistochemistry results acquired in our previous study. In conclusion, we have developed an effective approach to identifying protein changes in FFPE NPC tissues utilizing iTRAQ technology in conjunction with an economical and easily accessible sample preparation method. (J Histochem Cytochem 58:517-527, 2010)
摘要：
AIM: To investigate whether the apoptotic activities of 8-bromo-7-methoxychrysin (BrMC) involve reactive oxygen species (ROS) generation and c-Jun N-terminal kinase (JNK) activation in human hepatocellular carcinoma cells (HCC). METHODS: HepG2, Bel-7402 and L-02 cell lines were cultured in vitro and the apoptotic effects of BrMC were evaluated by flow cytometry (FCM) after propidium iodide (PI) staining, caspase-3 activity using enzyme-linked immunosorbent assay (ELISA), and DNA agarose gel electrophoresis. ROS production was evaluated by FCM after dichlorodihydrofluorescein diacetate (DCHFDA) probe labeling. The phosphorylation level of JNK and c-Jun protein was analyzed by Western blotting. RESULTS: FCM after PI staining showed a dose-dependent increase in the percentage of the sub-G1 cell population (P < 0.05), reaching 39.0% +/- 2.8% of HepG2 cells after 48 h of treatment with BrMC at 10 mu mol/L. The potency of BrMC to HepG2 and Bel-7402 (32.1% +/- 2.6%) cells was found to be more effective than the lead compound, chrysin (16.2% +/- 1.6% for HepG2 cells and 11.0% +/- 1.3% for Bel-7402 cell) at 40 mu mol/L and similar to 5-flurouracil (33.0% +/- 2.1% for HepG2 cells and 29.3% +/- 2.3% for Bel-7402 cells) at 10 mu mol/L. BrMC had little effect on human embryo liver L-02 cells, with the percentage of sub-G1 cell population 5.4% +/- 1.8%. Treatment of HepG2 cells with BrMC for 48 h also increased the levels of active caspase-3, in a concentration-dependent manner. z-DEVD-fmk, a caspase-3-specific inhibitor, prevented the activation of caspase-3. Treatment with BrMC at 10 mu mol/L for 48 h resulted in the formation of a DNA ladder. Treatment of cells with BrMC (10 mu mol/L) increased mean fluorescence intensity of DCHF-DA in HepG2 cells from 7.2 +/- 1.12 at 0 h to 79.8 +/- 3.9 at 3 h and 89.7 +/- 4.7 at 6 h. BrMC did not affect ROS generation in L-02 cells. BrMC treatment failed to induce cell death and caspase-3 activation in HepG2 cells pretreated with N-acetylcysteine (10 mmol/L). In addition, in HepG2 cells treated with BrMC (2.5, 5.0, 10.0 mu mol/L) for 12 h, JNK activation was observed. Peak JNK activation occurred at 12 h post-treatment and this activation persisted for up to 24 h. The expression of phosphorylated JNK and c-Jun protein after 12 h with BrMC-treated cells was inhibited by N-acetylcysteine and SP600125 pre-treatment, but GW9662 had no effect. SP600125 substantially reduced BrMC-induced cell death and caspase-3 activation of HepG2 cells. N-acetylcysteine and GW9662 also attenuated induction of cell death and caspase-3 activation in HepG2 cells treated with BrMC. CONCLUSION: BrMC induces apoptosis of HCC cells by ROS generation and sustained JNK activation. (C) 2010 Baishideng. All rights reserved.
期刊：
Frontiers in Bioscience - Scholar,2010年2(2):515-526 ISSN：1945-0516
通讯作者：
Cao, D.
作者机构：
School of Pharmaceutical Sciences, Central South University, Changsha, 410083, China;Institute of Pharmacy and Pharmacology, College of Science and Technology, University of South China, Hengyang, 421001, China;[Cao, Deliang; Rajput, Sandeep; Watabe, Kounosuke] Department of Medical Microbiology, Immunology, and Cell Biology, Simmons Cooper Cancer Institute, Southern Illinois University School of Medicine, 913 N. Rutledge Street, Springfield, IL 62794, United States;[Wang, Chun] School of Pharmaceutical Sciences, Central South University, Changsha, 410083, China, Institute of Pharmacy and Pharmacology, College of Science and Technology, University of South China, Hengyang, 421001, China, Department of Medical Microbiology, Immunology, and Cell Biology, Simmons Cooper Cancer Institute, Southern Illinois University School of Medicine, 913 N. Rutledge Street, Springfield, IL 62794, United States;[Liao, Duan-Fang] School of Pharmaceutical Sciences, Central South University, Changsha, 410083, China, Institute of Pharmacy and Pharmacology, College of Science and Technology, University of South China, Hengyang, 421001, China
通讯机构：
[Cao, D.] D;Department of Medical Microbiology, Immunology, and Cell Biology, Simmons Cooper Cancer Institute, Southern Illinois University School of Medicine, 913 N. Rutledge Street, United States
摘要：
Acetyl-CoA carboxylases (ACC) are rate-limiting enzymes in de novo fatty acid synthesis, catalyzing ATP-dependent carboxylation of acetyl-CoA to form malonyl-CoA. Malonyl-CoA is a critical bi-functional molecule, i.e., a substrate of fatty acid synthase (FAS) for acyl chain elongation (fatty acid synthesis) and an inhibitor of carnitine palmitoyltransferase I (CPT-I) for fatty acid beta-oxidation. Two ACC isoforms have been identified in mammals, i.e. ACC-alpha (ACCA, also termed ACC1) and ACC-beta (ACCB, also designated ACC2). ACC has long been used as a target for the management of metabolic diseases, such as obesity and metabolic syndrome, and various inhibitors have been developed in clinical trials. Recently, ACCA up-regulation has been recognized in multiple human cancers, promoting lipogenesis to meet the need of cancer cells for rapid growth and proliferation. Therefore, ACCA might be effective as a potent target for cancer intervention, and the inhibitors developed for the treatment of metabolic diseases would be potential therapeutic agents for cancer therapy. This review summarizes our recent findings and updates the current understanding of the ACCA with focus on cancer research.
作者机构：
[Ren, Yan-Kai; Chen, Rong-Qian; Tang, Xiao-Qing; Hu, Bi; He, Jian-Qin; Shen, Xin-Tian; Yin, Wei-Lan] Univ S China, Dept Physiol, Coll Med, Hengyang 421001, Hunan, Peoples R China.;[Jiang, Zhi-Sheng] Univ S China, Dept Pathophysiol, Coll Med, Hengyang 421001, Hunan, Peoples R China.;[Shen, Xin-Tian; Huang, Yi-E] Huaihua Med Coll, Dept Physiol, Huaihua 418000, Hunan, Peoples R China.;[Xu, Jin-Hua] Univ S China, Lab Ctr Biochem & Mol Biol, Hengyang 421001, Hunan, Peoples R China.;[Tang, Xiao-Qing] Univ S China, Dept Physiol, Coll Med, 28 W Changsheng Rd, Hengyang 421001, Hunan, Peoples R China.
通讯机构：
[Tang, Xiao-Qing] U;Univ S China, Dept Physiol, Coll Med, 28 W Changsheng Rd, Hengyang 421001, Hunan, Peoples R China.
关键词：
Bcl-2;Homocysteine;Hydrogen sulfide;Mitochondrial membrane potential;Neuroprotection;Reactive oxygen species
摘要：
Hydrogen sulfide (H(2)S) has been shown to protect neurons against oxidative stress. Lower levels of H(2)S as well as accumulation of homocysteine (Hcy), a strong risk of Alzheimer's disease (AD), are reported in the brains of AD patients. The aim of present study is to explore the protection of H(2)S against Hcy-induced cytotoxicity and apoptosis and the molecular mechanisms underlying in PC12 cells. We show that sodium hydrosulfide (NaHS), a H(2)S donor, protects PC12 cells against Hcy-mediated cytotoxicity and apoptosis by preventing both the loss of mitochondrial membrane potential (MMP) and the increase in intracellular reactive oxygen species (ROS) induced by Hcy. NaHS not only promotes the expression of bc1-2, but also blocks the down-regulation of bc1-2 by Hcy. These results indicate that H(2)S protects neuronal cells against neurotoxicity of Hcy by preserving MMP and attenuating ROS accumulation through up-regulation of bcl-2 level. Our study suggests a promising future of H(2)S-based therapies for neurodegenerative diseases such as AD. (C) 2010 Elsevier Ireland Ltd and the Japan Neuroscience Society. All rights reserved.
摘要：
Genistein has been shown to increase nitric oxide (NO) production derived from endothelial nitric oxide synthase (eNOS). This study was to investigate whether genistein could prevent myocardial hypertrophy in the 2-kidney 1-clip (2K1C) renohypertensive rat through the NO pathway and to clarify the underlying mechanisms. After the 2K1C operation, plasma angiotensin II increased, and the rats developed significant left ventricular hypertrophy (LVH) and increased collagen I expression. Phosphorylated eNOS, NOS activity, NO production and cGMP contents were markedly decreased in ventricular tissues of 2K1C rats. Chronic administration of genistein to 2K1C rats restored NO, NOS activity, phosphorylated eNOS expression, cGMP in ventricular tissues, and the restoration was parallel with the improvement of LVH and attenuated the excessive ventricular collagen I expression. Genistein also elevated angiotensin II type 2 receptor (AT2) expression, and the effects of genistein on LVH could be completely abolished by an AT2 antagonist, PD123319. The antagonist also reversed the increase in eNOS activity, NO and cGMP restored by genistein in hypertensive rats. We further explored the mechanisms by which genistein restored NO in hypertension and found that genistein significantly enhanced phosphorylated eNOS but left relatively unchanged total eNOS and the eNOS dimer/monomer ratio. In addition, genistein decreased the binding of eNOS with caveolin 3 and simultaneously promoted its binding with calmodulin and heat shock protein 90. We conclude that the preventive effects of genistein on cardiac remodeling induced by 2K1C hypertension are mediated by AT2-dependent NO production.
摘要：
Aim: High density lipoprotein (HDL) and its apolipoproteins can promote cholesterol efflux from macrophage foam cells via the ATP-binding cassette transporter A1 (ABCA1), ABCG1, and scavenger receptor class B type. (SR-BI). Liver X receptors (LXRs) operate as cholesterol sensors which may protect from cholesterol overload by stimulating cholesterol efflux from cells to HDL through ABCA1, ABCG1 and SR-BI. The regulation of ABCA1, ABCG1 and SR-BI expression by cytokines present within the microenvironment of the atheroma may play an important role in determining the impact of reverse cholesterol transport on the atherosclerotic lesion. In the current study, we examined the effect of transforming growth factor-alpha 1 (TGF-alpha 1) on expressions of ABCA1, ABCG1 and SR-BI and explored the role of LXR alpha in the regulation of ABCA1, ABCG1 and SR-BI in THP-1 macrophage-derived foam cells. Methods and Results: TGF-alpha 1 significantly increased expressions of ABCA1, ABCG1 and SR-BI at both transcriptional and translational levels in a dose-dependent and time-dependent manner. Cellular cholesterol content was decreased while cholesterol efflux was increased by TGF-alpha 1 treatment. Moreover, LXR alpha was up-regulated by TGF-alpha 1 treatment. In addition, LXR alpha small interfering RNA completely abolished the promotion effect induced by TGF-alpha 1. Conclusion: These results provide evidence that TGF-alpha 1 up-regulates expressions of ABCA1, ABCG1 and SR-BI through the LXR alpha pathway in THP-1 macrophage-derived foam cells.
摘要：
Background: The efflux of cellular cholesterol mediated by apolipoprotein (apo)A-I and ATP-binding cassette transporter A1 (ABCA1) is a major pathway of reverse cholesterol transport. We investigated the effect of aspirin on this process. Methods: The expression levels of ABCA1 in RAW264.7 cells were determined using reverse transcription polymerase chain reaction and Western blot analysis. H-3-cholesterol efflux was measured by scintillation counting. Results: 0.5 mmol/laspirin increased apoA-I-mediated cholesterol efflux and increased the expression of ABCA1. By increasing the dose of aspirin higher than 0.5 mmol/1, ABCA1 expression and function were significantly decreased. In cells transfected with a specific peroxisome proliferator-activated receptor (PPAR)-alpha small interfering RNA, the induction of ABCA1 expression and apoA-I-mediated H-3-cholesterol efflux by aspirin were substantially suppressed. Conclusions: The data demonstrate that low-dose aspirin increases ABCA1 expression via a PPAR-alpha-dependent mechanism and increases apoA-I-mediated cholesterol efflux. Copyright (C) 2010 S. Karger AG, Basel
作者机构：
[Wang, Yuequn; Wan, Yongqi; Ye, Xiangli; Yuan, Wuzhou; Deng, Yun; Wang, Zequn; Zhou, Junmei; Mo, Xiaoyan; Li, Yongqing; Fan, Xiongwei; Yan, Yan; Luo, Na; Wu, Xiushan] Hunan Normal Univ, Coll Life Sci, Ctr Heart Dev, Changsha 410081, Hunan, Peoples R China.;[Zhou, Junmei] Univ S China, Coll Life Sci, Hengyang 421001, Peoples R China.
通讯机构：
[Deng, Yun] H;Hunan Normal Univ, Coll Life Sci, Ctr Heart Dev, Changsha 410081, Hunan, Peoples R China.
关键词：
NFAT;p21;Zinc finger protein;ZNF424
摘要：
Zinc finger-containing transcription factors are the largest single family of transcriptional regulators in mammals, which play an essential role in cell differentiation, cell proliferation, apoptosis, and neoplastic transformation. Here we have cloned a novel KRAB-related zinc finger gene, ZNF424, encoding a protein of 555aa. ZNF424 gene consisted of 4 exons and 3 in-trons, and mapped to chromosome 19p13.3. ZNF424 gene was ubiquitously expressed in human embryo tissues by Northern blot analysis. ZNF424 is conserved across species in evolution. Using a GFP-labeled ZNF424 protein, we demonstrate that ZNF424 localizes mostly in the nucleus. Transcriptional activity assays shows ZNF424 suppresses transcriptional activity of L8G5-luciferase. Overexpression of ZNF424 in HEK-293 cells inhibited the transcriptional activity of NFAT and p21, which may be silenced by siRNA. The results suggest that ZNF424 protein may act as a transcriptional repressor that suppresses NFAT and p21 pathway to mediate cellular functions.
通讯机构：
[Yin, Weidong] U;Univ S China, Life Sci Res Ctr, Inst Cardiovasc Res, Key Lab Atherosclerol Hunan Prov, Hengyang 421001, Hunan, Peoples R China.
摘要：
Insulin resistance and dyslipidemia are both considered to be risk factors for metabolic syndrome. Low levels of IGF1 are associated with insulin resistance. Elevation of low-density lipoprotein cholesterol (LDL-C) concomitant with depression of high-density lipoprotein cholesterol (HDL-C) increase the risk of obesity and type 2 diabetes mellitus (T2DM). Liver secretes IGF1 and catabolizes cholesterol regulated by the rate-limiting enzyme of bile acid synthesis from cholesterol 7α-hydroxylase (CYP7A1). NO-1886, a chemically synthesized lipoprotein lipase activator, suppresses diet-induced insulin resistance with the improvement of HDL-C. The goal of the present study is to evaluate whether NO-1886 upregulates IGF1 and CYP7A1 to benefit glucose and cholesterol metabolism. By using human hepatoma cell lines (HepG2 cells) as an in vitro model, we found that NO-1886 promoted IGF1 secretion and CYP7A1 expression through the activation of signal transducer and activator of transcription 5 (STAT5). Pretreatment of cells with AG 490, the inhibitor of STAT pathway, completely abolished NO-1886-induced IGF1 secretion and CYP7A1 expression. Studies performed in Chinese Bama minipigs pointed out an augmentation of plasma IGF1 elicited by a single dose administration of NO-1886. Long-term supplementation with NO-1886 recovered hyperinsulinemia and low plasma levels of IGF1 suppressed LDL-C and facilitated reverse cholesterol transport by decreasing hepatic cholesterol accumulation through increasing CYP7A1 expression in high-fat/high-sucrose/high-cholesterol diet minipigs. These findings indicate that NO-1886 upregulates IGF1 secretion and CYP7A1 expression to improve insulin resistance and hepatic cholesterol accumulation, which may represent an alternative therapeutic avenue of NO-1886 for T2DM and metabolic syndrome. Abstract Insulin resistance and dyslipidemia are both considered to be risk factors for metabolic syndrome. Low levels of IGF1 are associated with insulin resistance. Elevation of low-density lipoprotein cholesterol (LDL-C) concomitant with depression of high-density lipoprotein cholesterol (HDL-C) increase the risk of obesity and type 2 diabetes mellitus (T2DM). Liver secretes IGF1 and catabolizes cholesterol regulated by the rate-limiting enzyme of bile acid synthesis from cholesterol 7α-hydroxylase (CYP7A1). NO-1886, a chemically synthesized lipoprotein lipase activator, suppresses diet-induced insulin resistance with the improvement of HDL-C. The goal of the present study is to evaluate whether NO-1886 upregulates IGF1 and CYP7A1 to benefit glucose and cholesterol metabolism. By using human hepatoma cell lines (HepG2 cells) as an in vitro model, we found that NO-1886 promoted IGF1 secretion and CYP7A1 expression through the activation of signal transducer and activator of transcription 5 (STAT5). Pretreatment of cells with AG 490, the inhibitor of STAT pathway, completely abolished NO-1886-induced IGF1 secretion and CYP7A1 expression. Studies performed in Chinese Bama minipigs pointed out an augmentation of plasma IGF1 elicited by a single dose administration of NO-1886. Long-term supplementation with NO-1886 recovered hyperinsulinemia and low plasma levels of IGF1 suppressed LDL-C and facilitated reverse cholesterol transport by decreasing hepatic cholesterol accumulation through increasing CYP7A1 expression in high-fat/high-sucrose/high-cholesterol diet minipigs. These findings indicate that NO-1886 upregulates IGF1 secretion and CYP7A1 expression to improve insulin resistance and hepatic cholesterol accumulation, which may represent an alternative therapeutic avenue of NO-1886 for T2DM and metabolic syndrome.
摘要：
To investigate whether apelin-13 induced THP-1 monocytes (MCs) adhesion to ECV304 human umbilical vein endothelial cells (HUVECs) via 14-3-3 signaling transduction pathway and the potential novel physiological function and signaling transduction pathway of apelin-APJ, HUVECs ECV304 were cultured in DMEM and MCs THP-1 were cultured in RPMI 1640 medium. Monocyte adhesion and the expression of vascular cell adhesion molecule-1 (VCAM-1) and 14-3-3 were measured with monocyte adhesion assay and western blot analysis. Data showed that apelin-13 increased adhesion of MCs to HUVECs in a concentration- and time-dependent manner, which reached their peaks at 1 µM and 12 h, respectively. Similarly, apelin-13 induced the expression of HUVECs adhesion molecule, VCAM-1, in a concentration- and time-dependent manner, reached their peaks at 1 µM and 12 h, respectively. Apelin-13 induced the expression of 14-3-3 in a concentration- and time-dependent manner, which reached their peaks at 1 µM and 5 min, respectively. Furthermore, the potent 14-3-3 inhibitor difopein significantly reduced the expression of 14-3-3 and VCAM-1 in apelin-13 stimulated HUVECs, and difopein significantly inhibited the effect of apelin-13 on induction of MCs adhesion to HUVECs. These data suggested that 14-3-3 mediated the induction of adhesion of MCs to HUVECs by Apelin-13.
期刊：
Biochemical and Biophysical Research Communications,2010年391(4):1693-1697 ISSN：0006-291X
通讯作者：
Luo, Di-xian
作者机构：
[Liao, Duan-fang; Xia, Chenglai; Luo, Di-xian; Li, Junmo; Wang, Chun; Xu, Canxin; Zhu, Bingyang] Univ S China, Res Ctr Life Sci, Inst Pharm & Pharmacol, Div Pharmacoproteom, Hengyang 421001, Hunan, Peoples R China.;[Hu, Zhuowei] Peking Union Med Coll, Beijing 100730, Peoples R China.;[Hu, Zhuowei] Chinese Acad Med Sci, Inst Mat Med, Beijing 100730, Peoples R China.;[Luo, Di-xian] First Peoples Hosp Chenzhou City, Chenzhou 421001, Hunan, Peoples R China.;[Xiong, Yan; Luo, Di-xian] Cent S Univ, Sch Pharmaceut, Dept Pharmacol, Changsha 410083, Hunan, Peoples R China.
通讯机构：
[Luo, Di-xian] U;Univ S China, Res Ctr Life Sci, Inst Pharm & Pharmacol, Div Pharmacoproteom, Hengyang 421001, Hunan, Peoples R China.
摘要：
Forkhead box protein A1 (FoxA1) is an evolutionarily conserved winged helix transcription factor with diverse regulatory functions. However, little is known about the role of FoxA1 in acute lung injury (ALI) and pulmonary cell injury. In this study, an in vivo model was employed whereby rats were administered an intravenous injection of oleic acid (OA, 0.1 ml/kg), and alveolar type II epithelial cells (AT-2 cells) injury was induced by hydrogen peroxide (H2O2) in vitro. OA injection resulted in lung injury and AT-2 cells apoptosis in vivo. OA injection and H2O2 upregulated FoxA1 mRNA and protein in lung tissue of the in vivo ALI model and in H2O2 challenged AT-2 cells. Overexpression of FoxA1 promoted apoptosis, whereas FoxA1 deficiency, induced by antisense oligonucleotides, decreased AT-2 cells apoptosis induced by H2O2, as shown by flow cytometry. These results suggest that FoxA1 may play an important role in ALI by promoting apoptosis of pulmonary epithelial cells.
作者机构：
[Hu, Yan-Wei] Institute of Cardiovascular Research, Key Laboratory for Atherosclerology of Hunan Province, Life Science Research Center, University of South China, Hengyang, Hunan 421001 China;Department of Anesthesiology, The First Affiliated Hospital of University of South China, Hengyang, Hunan 421001, China;Research Unit, Health Research Division, Saskatchewan Cancer Agency, Department of Oncology, University of Saskatchewan, Saskatoon, Saskatchewan S7N 4H4, Canada;Institute of Pharmacy and Pharmacology, Life Science Research Center, University of South China, Hengyang, Hunan 421001, China
通讯机构：
Institute of Cardiovascular Research, Key Laboratory for Atherosclerology of Hunan Province, Life Science Research Center, China
摘要：
ABCA1 is a key mediator of cholesterol efflux to apoA-I in cholesterol loaded macrophages, a first step of RCT in vivo. Unsaturated fatty acids can inhibit cholesterol efflux from macrophages by increasing degradation of ABCA1. However, the detailed mechanisms of ABCA1 regulation by unsaturated fatty acids are not fully understood. In the present study, we investigated the effects of EPA on ABCA1 expression and ABCA1-dependent cholesterol efflux and examined the role of cAMP/PKA pathway on the regulation of ABCA1 by EPA in THP-1 macrophage-derived foam cells. Results showed that EPA significantly destabilized ABCA1 protein and reduced ABCA1-dependent cholesterol efflux but had no effect on ABCA1 mRNA expression. We also revealed that EPA markedly reduced cAMP level and PKA activity and ABCA1 serine phosphorylation. PKA-specific activation by PKA agonist markedly compensated the down-regulation of ABCA1 serine phosphorylation and ABCA1-mediated cholesterol efflux by EPA, while, siRNA of PKA leaded to reduce of ABCA1 serine phosphorylation and ABCA1-mediated cholesterol efflux more significantly than EPA. However, EPA-Induced enhancement of degradation rate of ABCA1 protein did not change by treatment with PKA agonist or PKA-siRNA. These results provide evidence that EPA may have dual negative effects on ABCA1 activity by decreasing ABCA1 protein level and by reducing PKA-mediated ABCA1 serine phosphorylation in THP-1 macrophage-derived foam cells.
