摘要：
The role of renal lipoprotein lipase (LPL) per se in kidney diseases is still controversial and obscure. The purpose of this study was to observe the preventive effects of Ibrolipim, a LPL activator, on lipid accumulation and LPL expression in the kidneys of minipigs fed a high-sucrose and high-fat diet (HSFD). Male Chinese Bama minipigs were fed a control diet or HSFD with or without 0.1 g/kg/day Ibrolipim for 5 months. Body weight, plasma glucose, insulin, lipids, LPL activity, and urinary microalbumin were measured. Renal tissue was obtained for detecting LPL activity and contents of triglyceride and cholesterol, observing the renal lipid accumulation by Oil Red O staining, and examining the mRNA and protein expression of LPL by real time PCR, Western Blot and immunohistochemistry. Feeding HSFD to minipigs caused weight gain, hyperglycemia, hyperinsulinemia, hyperlipidemia and microalbuminuria. HSFD increased plasma LPL activity while it decreased the mRNA and protein expression and activity of LPL in the kidney. The increases in renal triglyceride and cholesterol contents were associated with the decrease in renal LPL activity of HSFD-fed minipigs. In contrast, supplementing Ibrolipim into HSFD lowered body weight, plasma glucose, insulin, triglyceride and urinary albumin concentrations while it increased plasma total cholesterol and HDL-C. Ibrolipim suppressed the renal accumulation of triglyceride and cholesterol, and stimulated the diet-induced down-regulation of LPL expression and activity in the kidney. Ibrolipim exerts renoprotective and hypolipidemic effects via the increase in renal LPL activity and expression, and thus the increased expression and activity of renal LPL play a vital role in suppressing renal lipid accumulation and ameliorating proteinuria in diet-induced diabetic minipigs.
作者机构：
[Ouyang, X.; Zhou, S.; Huang, F.; Tian, S.; Gao, J.; Yan, Y.; Deng, H.] Univ S China, Dept Physiol, Coll Med, Hengyang 421001, Hunan, Peoples R China.;[Li, P.] Univ S China, Dept Biol, Coll Life Sci & Technol, Hengyang 421001, Hunan, Peoples R China.
通讯机构：
[Tian, S.] U;Univ S China, Dept Physiol, Coll Med, Hengyang 421001, Hunan, Peoples R China.
关键词：
Fear conditioning;Fear extinction;Learning;Memory;Ventrolateral prefrontal cortex;Ventromedial prefrontal cortex
摘要：
Recent evidence has demonstrated that the ventromedial prefrontal cortex (vmPFC) is a critical site of the neural circuits underlying fear extinction memory. The ventrolateral prefrontal cortex (vlPFC) is not directly involved in extinction processes within the aversive domain. However, most of the current cumulated data on extinction is based on a classical delay fear conditioning paradigm in which the interval between the onset of the conditioned stimulus (CS) and the unconditioned stimulus (US) is consistent in a given protocol. In the present study, we developed a modified delay fear conditioning paradigm in which the temporal distribution of the footshock US during the duration of the tone CS is programmed to be pseudorandom. Here, we examined the effects of electrolytic vmPFC and vlPFC lesions made before training on conditioned fear response in the modified paradigm. The behavioral procedure involved four sessions with a 24-h interval: habituation, fear conditioning, extinction training, and extinction test. Percent freezing to tone was assessed as a measure of conditioned fear response. The results show that neither vmPFC nor vlPFC lesions affect acquisition or extinction of conditioned fear response during the fear conditioning and extinction training sessions, respectively. During the extinction test session, both vmPFC- and vlPFC-lesioned rats showed deficits in the recall of the between-session extinction memory. The deficits could not be attributed to altered nonspecific responses (footshock sensitivity, locomotor activity, and nonspecific freezing response). Furthermore, vlPFC lesions made before training had no effect on conditioned fear response in the classical fear conditioning paradigm. These data suggest a preserved role of the vmPFC in fear extinction and a selective involvement of the vlPFC in extinction process in certain fear conditioning tasks.
摘要：
Objective: Volume-regulated Cl(-) channel (VRCC) plays a critical role in regulation of a variety of physiological functions. However, little is known whether VRCC is involved in atherosclerosis. In this study, we investigated the functions of VRCC during foam cell formation in macrophages. Methods and results: Treatment of RAW264.7 cells with ox-LDL increased intracellular cholesterol content as well as cell volume. After ox-LDL treatment, the resting [Cl(-)](i) in isotonic solution was decreased. Hypotonic solution reduced [Cl(-)](i) and evoked volume-regulated Cl(-) current in all the cells, however, the swelling-induced reduction of [Cl(-)](i) and increase of Cl(-) current were more prominent in ox-LDL treated cells than that in control. The increases of volume-regulated Cl(-) movement positively correlated with the intracellular cholesterol content. Moreover, in peritoneal macrophages isolated from high-fat diet ApoE(-/-) mice, the swelling-induced Cl(-) movement and current were enhanced compared with those in control group, and their increments positively correlated with atherosclerotic plaque area. Finally, activation of VRCC by hypotonic medium significantly accelerated, whereas, inhibition of VRCC with Cl(-) channel blockers remarkably attenuated, ox-LDL-induced macrophage-derived foam cell formation. Conclusion: The activity of VRCC is augmented during macrophage-derived foam cell formation. Activation of VRCC accelerated, whereas, inhibition of VRCC attenuated, ox-LDL-induced lipid accumulation in macrophages, suggesting VRCC is involved in the regulation of foam cell formation. (C) 2011 Elsevier Ireland Ltd. All rights reserved.
作者：
Hou, Qi;Jin, Junfei;Zhou, Hui;Novgorodov, Sergei A.;Bielawska, Alicja;...
期刊：
Journal of Lipid Research,2011年52(2):278-288 ISSN：0022-2275
通讯作者：
Hsu, Yi-Te
作者机构：
[Jin, Junfei; Hsu, Yi-Te; Hou, Qi; Bielawska, Alicja; Zhou, Hui; Szulc, Zdzislaw M.; Hannun, Yusuf A.] Med Univ S Carolina, Dept Biochem & Mol Biol, Charleston, SC 29425 USA.;[Obeid, Lina M.; Novgorodov, Sergei A.] Med Univ S Carolina, Dept Med, Charleston, SC 29425 USA.;[Hou, Qi] Peking Union Med Coll, Inst Mat Med, Dept Pharmacol, Beijing 100050, Peoples R China.;Chinese Acad Med Sci, Beijing 100050, Peoples R China.;[Jin, Junfei] Univ S China, Res Ctr Life Sci, Hengyang 421001, Hunan, Peoples R China.
通讯机构：
[Hsu, Yi-Te] M;Med Univ S Carolina, Dept Biochem & Mol Biol, Charleston, SC 29425 USA.
关键词：
ceramide;Bax;mitochondria
摘要：
C6-pyridinium (d-erythro-2-N-[6′-(1′′-pyridinium)-hexanoyl]sphingosine bromide [LCL29]) is a cationic mitochondrion-targeting ceramide analog that promotes mitochondrial permeabilization and cancer cell death. In this study, we compared the biological effects of that compound with those of d-erythro-C6-ceramide, its non-mitochondrion-targeting analog. In MCF7 cells it was found that C6-pyridinium ceramide preferentially promoted autophagosome formation and retarded cell growth more extensively than its uncharged analog. This preferential inhibition of cell growth was also observed in breast epithelial cells and other breast cancer cells. In addition, this compound could promote Bax translocation to mitochondria. This redistribution of Bax in MCF7 cells could be blocked by the pan-caspase inhibitor zVAD-fmk but via a Bid-independent signaling pathway. Moreover, C6-pyridinium ceramide-induced translocation of Bax to mitochondria led to mitochondrial permeabilization and cell death. Overall, we show that mitochondrial targeting of C6-pyridinium ceramide significantly enhances cellular response to this compound.
作者机构：
[Yin, Jie; Yang, Xiao Yang; Lei, Xiao Yong; Xiang, Qiong; Hu, Nan; Yu, Jia] Univ S China, Inst Pharm & Pharmacol, Hengyang, Hunan, Peoples R China.;[Tang, Hui Fang] Univ S China, Affiliated Hosp 1, Hengyang, Hunan, Peoples R China.;[Lei, Xiao Yong] Univ S China, Inst Pharm & Pharmacol, 28 Changsheng Rd, Hengyang, Hunan, Peoples R China.
通讯机构：
[Lei, Xiao Yong] U;Univ S China, Inst Pharm & Pharmacol, 28 Changsheng Rd, Hengyang, Hunan, Peoples R China.
摘要：
To investigate the changes in drug sensitivity of miR-122 transfected BEL-7402/5-FU cells. MiR-122 and negative miRNA expression vectors were constructed and stably transfected into BEL-7402/5-FU cells. Real-time RT-PCR was used to detect the level of miR-122, Bcl-XL, Bcl-2 and P53 mRNA. Western Blotting was used to detect Bcl-2, Bcl-XL and P53 protein expression. Drug sensitivity of the cells to 5-fluorouracil (5- FU) was analyzed with MTT and flow cytometry. Compared with negative miRNA transfectants or untreated cells, mRNA and protein expression level of Bcl-2, Bcl-XL in stable miR-122 transfectants were decreased. Accordingly, P53 protein expression showed a significant up-regulation; MTT results showed that after incubation with 5-FU, miR-122 transfectants had higher cell inhibitory rates than negative miRNA or untreated cells; flow cytometry results demonstrated that apoptosis rate increased in miR-122 transfected cells, compared with negative miRNA or untreated cells. After addition of 5-FU (10 and 100 μmol/l), miR-122 transfected cells showed higher apoptosis rate than negative miRNA or untreated cells. MiR-122 can specifically down-regulate the expression of Bcl-2 and Bcl-XL, and increase P53 activity in BEL-7402/5-FU cells, which increased cells spontaneous apoptosis and sensitize cells to 5-FU. Therefore, MiR-122 can be used as a potential therapy agent against human hepatoblastoma.
期刊：
Lipids in Health and Disease,2011年10(1):1-9 ISSN：1476-511X
通讯作者：
Fu, Mingde
作者机构：
[Tian, Li; Fu, Mingde; Jia, Lianqun] Sichuan Univ, W China Hosp, Lab Endocrinol & Metab, Chengdu 610041, Sichuan, Peoples R China.;[Long, Shiyin; Liu, Yinghui] Univ S China, Dept Biochem & Mol Biol, Hengyang, Hunan, Peoples R China.;[Xu, Yanhua] Chengdu Hoist Biotechnol Co LTD, Chengdu, Sichuan, Peoples R China.
通讯机构：
[Fu, Mingde] S;Sichuan Univ, W China Hosp, Lab Endocrinol & Metab, Chengdu 610041, Sichuan, Peoples R China.
关键词：
Total Cholesterol;Total Cholesterol Level;High Density Lipoprotein;Total Cholesterol Concentration;High Total Cholesterol
摘要：
To investigate alteration of high density lipoproteins (HDL) subclasses distribution in different total cholesterol (TC) levels, mainly the characteristics of HDL subclasses distribution in desirable TC levels and analyze the related mechanisms. ApoA-I contents of plasma HDL subclasses were determined by 2-dimensional gel electrophoresis coupled with immunodetection. 486 Chinese Adults subjects were assigned to different TC groups according to the third Report of NCEP (ATP- III) guidelines. The increase in contents of small preβ1-HDL, HDL3c, HDL3b, and HDL3a particles clustered and reduce in HDL2b with increased of TC. The distribution of HDL subclasses have shown abnormality characterized by the lower HDL2b (324.2 mg/L) contents and the higher preβ1-HDL (90.4 mg/L) contents for desirable TC Chinese subjects. Among 176 desirable TC subjects, 58.6% subjects with triglyceride (TG) < 2.26 mmol/L, 61.2% subjects with HDL-C ≥1.03 mmol/L and 88.6% subjects with low density lipoprotein cholesterol(LDL-C) < 3.34 mmol/L, and the profile of HDL subclasses distribution for above these subjects was reasonable. The particles size of HDL subclasses shifted towards smaller with increased TC levels. The TC was liner with HDL2b contents and those can be reduced 17 mg/L for 0.5 mmol/L increment in TC levels. The HDL subclasses distribution phenotype was not expectation for Chinese Population with desirable TC levels. Thus, from the HDL subclasses distribution point, when assessing the coronary heart disease(CHD) risk not only rely on the TC levels, but also the concentrations of TG, HDL-C and LDL-C must considered in case the potential risk for desirable TC subjects with other plasma lipids metabolism disorders.
摘要：
The aryl hydrocarbon receptor (AhR) is a period-aryl hydrocarbon receptor nuclear transporter-simple minded domain transcription factor that shares structural similarity with circadian clock genes and readily interacts with components of the molecular clock. Activation of AhR by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) alters behavioral circadian rhythms and represses the Period1 (Per1) gene in murine hematopoietic stem and progenitor cells. Per1 expression is driven by circadian locomotor activity cycles kaput-brain muscle ARNT-like (CLOCK-BMAL1)–dependent activation of Eboxes in the Per1 promoter. We hypothesized that the effects of AhR activation on the circadian clock are mediated by disruption of CLOCK-BMAL1 function and subsequent Per1 gene suppression. Effects of AhR activation on rhythmic Per1 transcripts were examined in livers of mice after treatment with the AhR agonist, TCDD; the molecular mechanisms of Per1 repression by AhR were determined in hepatoma cells using TCDD and β-napthoflavone as AhR activators. This study reports, for the first time, that AhR activation by TCDD alters the Per1 rhythm in the mouse liver and that Per1 gene suppression depends upon the presence of AhR. Furthermore, AhR interaction with BMAL1 attenuates CLOCK-BMAL1 activity and decreases CLOCK binding at Ebox1 and Ebox3 in the Per1 promoter. Taken together, these data suggest that AhR activation represses Per1 through disrupting CLOCK-BMAL1 activity, producing dysregulation of rhythmic Per1 gene expression. These data define alteration of the Per1 rhythm as novel signaling events downstream of AhR activation. Downregulation of Per1 could contribute to metabolic disease, cancer, and other detrimental effects resulting from exposure to certain environmental pollutants.
摘要：
Transcription factors (TFs) are modulators of gene expression that are critically important in the establishment and progression of human cancers. In the current study, the activity profiles of TFs in a normal nasopharyngeal epithelial cell line and in nasopharyngeal carcinoma (NPC) cell lines were studied using oligonucleotide array-based TF assays. Compared to the normal epithelial cell line NP69, nine TFs in the non-meta static NPC cell line (6-10B) and eight TFs in a metastatic NPC cell line (5-8F) were upregulated. Among upregulated TFs, Sp1, AP2, and ATF/CREB families exhibited relatively high activities in NPC cell lines. Transcription levels of Sp1, ATF-1, ATF-2, AP2 alpha, AP2 gamma, and CREB I were higher in 5-8F cells than in 6-10B cells. In addition, higher expression of the Sp1 target genes MMP-9 and VEGF was observed in 5-8F cells. Sp1 silencing reduced VEGF and MMP-9 expression. Inhibition of Sp1 expression and activity in 5-8F cells by mithramycin resulted in downregulated expression and secretion of MMP-9 and VEGF, concomitant with inhibition of cell migration and invasion. These results suggest that dynamic changes in TF activities Occur in NPC cells and that these changes may play important roles in regulating the expression of-genes associated with the development and progression of NPC. J. Cell. Biochem. 109: 173-183, 2010. (C) 2009 Wiley-Liss, Inc.
