[Post-translational Modifications of PML in Regulating the Functions of Nuclear Bodies --Review].

Abstract　　The promyelocytic leukemia (PML) gene encoded PML protein as a tumor suppressor protein, plays important roles in the occurrence and development of various cancers including acute promyelocytic leukemia. Recent studies have indicated that there are a variety of post-translational modifications of the PML protein, such as SUMOylation, ubiquitination, phosphorylation, and acetylation in cells. These modifications of the PML protein can directly affect the formation of PML nuclear bodies (PML-NBs), repair DNA damage, and modulate cell apoptosis. Furthermore, the abnormal modifications of PML not only result in the occurrence of hematopoietic tumors, but also are closely related to the drug-resistance of cancer. Therefore, investigating the post-translational modifications of PML is significant to uncover the mechanism of formation and functions of PML-NBs, thus contributing to the prevention and treatment of related hematopoietic tumors. In this review, the characteristics of the post-translational modifications of PML protein and the relationship between these modifications and functions of PML-NBs are summarized so as to provide the potential targets for the treatment of related cancers.

Hepatitis B virus-related mortality in rheumatoid arthritis patients undergoing long-term low-dose glucocorticoid treatment: A population-based study.

BACKGROUND/PURPOSE: Glucocorticoids (GC) are commonly used in rheumatoid arthritis (RA) patients which bears a risk of hepatitis B virus (HBV) reactivation. The purpose of this study was to investigate the risk of HBV-related mortality under long-term low-dose GCs in Taiwanese RA patients. METHODS: We retrospectively analyzed 45,423 RA patients using National Health Insurance Research Database from January 1999 to December 2011. Of them, 2204 patients had the diagnosis of HBV and were classified into four groups according to GCs regimens. Outcome comparison by Cox model analysis for liver-related mortality was performed. RESULTS: In this cohort, 90.5% were older than 40. One hundred and five patients had been treated with short-term large-dose GCs (Group A); 862 patients received GCs ≥20 mg/day for ≥3 days or a variable dose but did not meet Group C criteria (Group B); 689 patients were continuously treated with low-dose (<20 mg/day) GCs for ≥3 months for at least one session (Group C); and 548 patients had never been exposed to GCs (Group D). Two hundred and sixty-one patients had been exposed to antiviral agents, which was significantly higher in Group C. Fifty-eight patients (2.63%) died of acute hepatic failure, while no statistically significant difference between each groups (p = 0.074). Groups C and D comparison by two-sample test showed that long-term low-dose GC treatment was not associated with liver-related death after adjusting for malignancy. CONCLUSION: Long-term low-dose GC treatment was not associated with liver-related mortality in RA with concomitant HBV patients probably due to commonly applied antiviral therapy by rheumatologists.

Long non-coding RNA RP5-833A20.1 inhibits proliferation, metastasis and cell cycle progression by suppressing the expression of NFIA in U251 cells.

Early reports suggest that nuclear factor IA (NFIA) is important in the pathogenesis of glioma. Our previous study demonstrated that the long non­coding RNA (lncRNA), RP5­833A20.1, suppressed the expression of NFIA in THP­1 macrophage-derived foam cells. However, the effect and possible mechanism of RP5­833A20.1 on glioma remains to be fully elucidated, and whether the NFIA-dependent pathway is involved in its progression has not been investigated. In the present study, the mechanisms by which RP5­833A20.1 regulates the expression of NFIA in glioma were investigated. The expression levels of RP5­833A20.1 and NFIA were determined in U251 cells and clinical samples using reverse transcription­quantitative polymerase chain reaction (PCR) analysis. The effects of RP5­833A20.1 on cell proliferation, invasion, cell cycle and apoptosis were evaluated using in vitro assays. The potential changes in protein expression were investigated using western blot analysis. The methylation status of the CpG island in the NFIA promoter was determined using bisulfite PCR (BSP) sequencing. It was found that the expression of RP5­833A20.1 was downregulated, whereas the expression of NFIA was upregulated in glioma tissues, compared with corresponding adjacent nontumor tissues from 20 patients with glioma. The overexpression of RP5­833A20.1 inhibited proliferation and cell cycle progression, and induced apoptosis in the U251 cells. The mRNA and protein levels of NFIA were markedly inhibited by overexpression of RP5­833A20.1 in the U251 cells. The overexpression of RP5­833A20.1 increased the expression of microRNA­382­5p in the U251 cells. The BSP assay revealed that the overexpression of RP5­833A20.1 enhanced the methylation level of the NFIA promoter. These results demonstrated that RP5­833A20.1 inhibited tumor cell proliferation, induced apoptosis and inhibited cell­cycle progression by suppressing the expression of NFIA in U251 cells. Collectively, these results indicated RP5­833A20.1 as a novel therapeutic target for glioma.

VNN1 promotes atherosclerosis progression in apoE-/- mice fed a high-fat/high-cholesterol diet.

Accumulated evidence shows that vanin-1 (VNN1) plays a key part in glucose metabolism. We explored the effect of VNN1 on cholesterol metabolism, inflammation, apoptosis in vitro, and progression of atherosclerotic plaques in apoE(-/-) mice. Oxidized LDL (Ox-LDL) significantly induced VNN1 expression through an ERK1/2/cyclooxygenase-2/PPARα signaling pathway. VNN1 significantly increased cellular cholesterol content and decreased apoAI and HDL-cholesterol (HDL-C)-mediated efflux by 25.16% and 23.13%, respectively, in THP-1 macrophage-derived foam cells (P < 0.05). In addition, VNN1 attenuated Ox-LDL-induced apoptosis through upregulation of expression of p53 by 59.15% and downregulation of expression of B-cell lymphoma-2 127.13% in THP-1 macrophage (P < 0.05). In vivo, apoE(-/-) mice were divided randomly into two groups and transduced with lentivirus (LV)-Mock or LV-VNN1 for 12 weeks. VNN1-treated mice showed increased liver lipid content and plasma levels of TG (124.48%), LDL-cholesterol (119.64%), TNF-α (148.74%), interleukin (IL)-1ß (131.81%), and IL-6 (156.51%), whereas plasma levels of HDL-C (25.75%) were decreased significantly (P < 0.05). Consistent with these data, development of atherosclerotic lesions was increased significantly upon infection of apoE(-/-) mice with LV-VNN1. These observations suggest that VNN1 may be a promising therapeutic candidate against atherosclerosis.

Lipoxin A4 promotes ABCA1 expression and cholesterol efflux through the LXRα signaling pathway in THP-1 macrophage-derived foam cells.

Adenosine triphosphate-binding cassette transporter A1 (ABCA1) is a crucial cholesterol transporter and plays a central role in the high density lipoproteins (HDL) cholesterol metabolism and lipid clearance from the foam cell. Lipoxin A4 (LXA4) is an endogenous lipid mediator that requires cell-cell interaction or cell-platelet interaction for its synthesis. The roles of LXA4 on inflammatory responses are well described, while its effects on mediating ABCA1 and underlying mechanisms remain unclear. In this study, we showed that LXA4 significantly increases expression of ABCA1 and LXRα in a dose-dependent manner in THP-1 macrophage-derived foam cells. Cellular cholesterol content was decreased while cholesterol efflux was increased by LXA4 treatment. However, after short interfering RNA of LXRα, the effects of LXA4 on ABCA1 expression and cholesterol metabolism were significantly abolished. These results provide evidence that LXA4 increases ABCA1 expression and promotes cholesterol efflux through LXRα pathway in THP-1 macrophage-derived foam cells.

Upregulation of miR-125b by estrogen protects against non-alcoholic fatty liver in female mice.

BACKGROUND & AIMS: Due to the protective effect of estrogen against hepatic fat accumulation, the prevalence of non-alcoholic fatty liver disease (NAFLD) in premenopausal women is lower than that in men at the same age and in postmenopausal women. Our study was to further elucidate an underlying mechanism by which estrogen prevents NAFLD from miRNA perspective in female mice. METHODS: miRNA expression was evaluated by TaqMan miRNA assay. Luciferase and ChIP assay were done to validate regulation of miR-125b by estrogen via estrogen receptor alpha (ERα). Nile red and Oil red O staining were used to check lipid content. Overexpressing or inhibiting the physiological role of miR-125b in the liver of mice through injecting adenovirus were used to identify the function of miR-125b in vivo. RESULTS: miR-125b expression was activated by estrogen via ERα in vitro and in vivo. miR-125b inhibited lipid accumulation both in HepG2 cells and primary mouse hepatocytes. Consistently, ovariectomized or liver-specific ERα knockdown mice treated with miR-125b overexpressing adenoviruses were resistant to hepatic steatosis induced by high-fat diet, due to decreased fatty acid uptake and synthesis and decreased triglyceride synthesis. Conversely, inhibiting the physiological role of miR-125b with a sponge decoy slightly promoted liver steatosis with a high-fat diet. Notably, we provided evidence showing that fatty acid synthase was a functional target of miR-125b. CONCLUSION: Our findings identify a novel mechanism by which estrogen protects against hepatic steatosis in female mice via upregulating miR-125b expression.

The miR-573/apoM/Bcl2A1-dependent signal transduction pathway is essential for hepatocyte apoptosis and hepatocarcinogenesis.

Hepatocellular carcinoma (HCC) is one of the most common malignant tumors with an increasing incidence worldwide. Apolipoprotein M (apoM) is a novel apolipoprotein that is mainly expressed in liver and kidney tissues. However, the anti-tumor properties of apoM remain largely unknown. We evaluated the anti-tumor activities and mechanisms of apoM in HCC both in vivo and in vitro. Bioinformatic analysis and luciferase reporter assay results showed that apoM was a potential target of hsa-miR-573 and was downregulated after transfection with hsa-miR-573 mimics. Overexpression of apoM suppressed migration, invasion, and proliferation of hepatoma cells in vitro. Overexpression of hsa-miR-573 in hepatoma cells reduced apoM expression, leading to promotion of the invasion, migration, and proliferation of hepatoma cells in vitro. In addition, hsa-miR-573 markedly promoted growth of xenograft tumors in nude mice with an accompanying reduction in cell apoptosis. ApoM markedly inhibited growth of xenograft tumors in nude mice and promoted cell apoptosis. Moreover, Bcl2A1 mRNA and protein levels were inhibited by apoM overexpression and an increase in apoptosis rate by apoM was markedly compensated by Bcl2A1 overexpression in HepG2 cells. These results provide evidence that hsa-miR-573 promoted tumor growth by inhibition of hepatocyte apoptosis and this pro-tumor effect might be mediated through Bcl2A1 in an apoM-dependent manner. Therefore, our findings may be useful to improve understanding of the critical effects of hsa-miR-573 and apoM in HCC pathogenesis.

Ox-LDL Upregulates IL-6 Expression by Enhancing NF-κB in an IGF2-Dependent Manner in THP-1 Macrophages.

Interleukin 6 (IL-6) is a pro-inflammatory cytokine that is well established as a vital factor in determining the risk of coronary heart disease and pathogenesis of atherosclerosis. Moreover, accumulating evidences have shown that oxidized low-density lipoprotein (ox-LDL) can promote IL-6 expression in macrophages. Nevertheless, the underlying mechanism of how ox-LDL upregulates IL-6 expression remains largely unexplained. We found that the expression of insulin-like growth factor 2 (IGF2), nuclear factor kappa B (NF-κB), and IL-6 was upregulated at both the messenger RNA (mRNA) and protein levels in a dose-dependent manner when treated with 0, 25, 50, or 100 µg/mL of ox-LDL for 48 h in THP-1 macrophages. Moreover, overexpression of IGF2 significantly upregulated NF-κB and IL-6 expressions in THP-1 macrophages. However, the upregulation of NF-κB and IL-6 expressions induced by ox-LDL were significantly abolished by IGF2 small interfering RNA (siRNA) in THP-1 macrophages. Further studies indicated the upregulation of IL-6 induced by ox-LDL could be abolished when treated with NF-κB siRNA in THP-1 macrophages. Ox-LDL might upregulate IL-6 in the cell and its secretion via enhancing NF-κB in an IGF2-dependent manner in THP-1 macrophages.

ApoM Suppresses TNF-α-Induced Expression of ICAM-1 and VCAM-1 Through Inhibiting the Activity of NF-κB.

To explore the anti-inflammatory effect of apolipoprotein M (apoM) on regulation of tumor necrosis factor-α (TNF-α)-induced expression of intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) and further investigate the molecular mechanism of apoM in this process. We found that TNF-α could decrease expression of apoM and inhibitor of NF-κB-α (IκBα) in HepG2 cells. Overexpression of apoM caused a significant decrease of ICAM-1 and VCAM-1 expression, while it caused a significant increase of IκBα expression in HepG2 cells. Furthermore, the treatment with TNF-α could increase ICAM-1 and VCAM-1 expression, decrease IκBα protein expression, and increase nuclear factor-κB (NF-κB) activity, and these effects were markedly enhanced by small interfering RNA (siRNA)-mediated silencing of apoM in HepG2 cells. Our findings demonstrated that apoM suppressed TNF-α-induced expression of ICAM-1 and VCAM-1 through inhibiting the activity of NF-κB.

MicroRNA-195-5p acts as an anti-oncogene by targeting PHF19 in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is the fifth most common malignancy worldwide. PHD finger protein 19 (PHF19) encodes a member of the polycomb group (PcG) of proteins that functions by maintaining the repressive transcriptional states of many developmental regulatory genes. In addition, it has been shown that miR-195 plays an important role in the molecular etiology of HCC; however, the effect and possible mechanism of PHF19 on HCC is unclear, and the association between PHF19 and miR-195 has seldom been addressed. In the present study, we investigated the carcinogenic activity and mechanism of PHF19 on HCC in vivo and in vitro. Our results showed that PHF19 is a potential target of hsa-miR-195-5p based on a bioinformatic analysis and results of a luciferase reporter assay. PHF19 was downregulated after transfection with hsa-miR-195-5p mimics. Moreover, we demonstrated that overexpression of PHF19 promoted hepatoma cell migration, invasion and proliferation in vitro. In contrast, overexpression of hsa-miR-195-5p in hepatoma cells reduced PHF19 expression, leading to suppression of hepatoma cell invasion, migration and proliferation in vitro. In addition, PHF19 markedly promoted the growth of xenograft tumors, while hsa-miR-195-5p markedly suppressed the growth of xenograft tumors in nude mice. These results provide evidence that PHF19 promotes HCC and is regulated by the tumor-suppressor, miR-195-5p.

Hospitalization for cancer among radiologists in Taiwan.

BACKGROUND: Population aging and the incremental use of high-tech instruments increase the demand for radiological examinations and treatments in medical services. The exposure of radiologists and other medical workers to medical treatment radiation may thus be increased. OBJECTIVES: The aim of the study was to explore the average number of cancer hospitalizations and use of hospitalization as cancer treatment for radiologists compared with that for family medicine physicians, as well as the trends in the annual average number of cancer hospitalizations among radiologists. METHODS: Research data were obtained from the 2000-2010 Taiwan National Health Insurance Research Database. These samples collected for this study were unbalanced panel data. RESULTS: The average number of cancer hospitalizations for radiologists from 2000 to 2010 ranged between 3.67 and 28.26‰. After controlling the effects of gender, age, hospital accreditation level and year using generalized estimating equations with a binomial distribution and logit link function, our study found that radiologists had non significant higher risk of cancer hospitalizations compared with family medicine physicians. However, the average number of cancer hospitalizations for radiologists showed an annual decline from 2000 to 2010. CONCLUSIONS: Compared with family medicine physicians, radiologists had non significant higher risk of cancer hospitalizations. The data period examined in this study was only 11 years. Considering the numerous new radiological procedures currently in use in modern medical treatments, the health status of medical radiation workers should be continuously monitored in the future.

Propofol Attenuates Lipopolysaccharide-Induced Monocyte Chemoattractant Protein-1 Production Through Enhancing apoM and foxa2 Expression in HepG2 Cells.

Monocyte chemoattractant protein-1 (MCP-1) is a cytokine that mediates the influx of cells to sites of inflammation. Our group recently reported that propofol exerted an anti-inflammatory effect and could inhibit lipopolysaccharide (LPS)-induced production of pro-inflammatory cytokines. However, the effect and possible mechanisms of propofol on MCP-1 expression remain unclear. LPS-stimulated HepG2 cells were treated with 50 µM propofol for 0, 6, 12, and 24 h, respectively. The transcript and protein levels were measured by real-time quantitative PCR and Western blot analyses, respectively. We found that propofol markedly decreased both MCP-1 messenger RNA (mRNA) and protein levels in LPS-stimulated HepG2 cells in a time-dependent manner. Expression of apolipoprotein M (apoM) and forkhead box protein A2 (foxa2) was increased by propofol treatment in HepG2 cells. In addition, the inhibitory effect of propofol on MCP-1 expression was significantly abolished by small interfering RNA against apoM and foxa2 in LPS-stimulated HepG2 cells. Propofol attenuates LPS-induced MCP-1 production through enhancing apoM and foxa2 expression in HepG2 cells.

RP5-833A20.1/miR-382-5p/NFIA-dependent signal transduction pathway contributes to the regulation of cholesterol homeostasis and inflammatory reaction.

OBJECTIVE: Cardiovascular disease caused by atherosclerosis is the number one cause of death in Western countries and threatens to become the major cause of morbidity and mortality worldwide. Long noncoding RNAs are emerging as new players in gene regulation, but how long noncoding RNAs operate in the development of atherosclerosis remains unclear. APPROACH AND RESULTS: Using microarray analysis, we found that long noncoding RNA RP5-833A20.1 expression was upregulated, whereas nuclear factor IA (NFIA) expression was downregulated in human acute monocytic leukemia macrophage-derived foam cells. Moreover, we showed that long noncoding RNA RP5-833A20.1 may decreases NFIA expression by inducing hsa-miR-382-5p expression in vitro. We found that the RP5-833A20.1/hsa-miR-382-5p/NFIA pathway is essential to the regulation of cholesterol homeostasis and inflammatory responses in human acute monocytic leukemia macrophages. Lentivirus-mediated NFIA overexpression increased high-density lipoprotein cholesterol circulation, reduced low-density lipoprotein cholesterol, and very-low-density lipoprotein cholesterol circulation, decreased circulation of inflammatory cytokines, including interleukin-1ß, interleukin-6, tumor necrosis factor-α, and C-reactive protein, enhanced reverse cholesterol transport, and promoted regression of atherosclerosis in apolipoprotein E-deficient mice. CONCLUSIONS: Our findings indicated that the RP5-833A20.1/miR-382-5p/NFIA pathway was essential to the regulation of cholesterol homeostasis and inflammatory reactions and suggested that NFIA may represent a therapeutic target to ameliorate cardiovascular disease.

Risk of nonpsychotic mental disorders development in antiviral-treated mentally healthy chronic hepatitis C patients: A population-based study.

BACKGROUND/PURPOSE: Interferon (IFN) is able to induce significant psychiatric side effects in chronic hepatitis C (CHC) patients, whereas the risk of nonpsychotic mental disorder (NPMD) development in antiviral-treated mentally healthy CHC patients remains obscure. We used a population-based study to assess the risk of NPMD development in patients who had undergone antiviral treatment compared with untreated chronic hepatitis C virus (HCV)-infected and nonalcoholic fatty liver disease (NAFLD) patients. METHODS: Data were retrieved from Taiwan's National Health Insurance Research Database cohort consisting of 1 million individuals for a longitudinal analysis. A total of 313 mentally healthy CHC patients who received IFN-based antiviral therapy were recruited and compared with those without antiviral therapy and NAFLD patients. The Chi-square test was used to obtain the hazard ratio and 95% confidence interval. RESULTS: Among the 313 CHC patients receiving pegylated interferon/ribavirin therapy, 62 patients (19.8%) were associated with NPMD. In the comparison cohort, composed of 313 age- and sex-matched CHC patients not receiving antiviral therapy, 70 patients (22.4%) were associated with NPMD. The Chi-square analysis revealed that antiviral therapy was not significantly associated with NPMD. The diagnosis of HCV-infected hepatitis was independently associated with NPMD when compared with NAFLD. The hazard ratio was 1.67 (95% confidence interval, 1.11-2.52; p = 0.018). Furthermore, generalized anxiety disorder was specifically higher in HCV-infected patients than those with NAFLD. CONCLUSION: Patients with HCV infection are at high risk of developing NPMD with or without IFN-based therapy.

Ox-LDL upregulates CRP expression through the IGF2 pathway in THP-1 macrophages.

C-reactive protein (CRP) is an acute-phase reactant protein that not only plays a predictive role in determining atherogenesis risk but also represents an active participant in atherogenesis onset and progression. Moreover, an increasing number of studies have reported that oxidized low-density lipoprotein (Ox-LDL) plays a significant role in the initiation and progression of atherosclerosis. However, the effect and underlying mechanism of Ox-LDL on CRP expression remains unclear. THP-1 macrophages were treated with 0, 25, 50, or 100 µg/mL of Ox-LDL for 48 h, or 50 µg/mL of Ox-LDL for 0, 12, 24, and 48 h, respectively. Messenger RNA (mRNA) and protein levels were measured by real-time quantitative PCR and Western blot analysis, respectively. We found that Ox-LDL markedly increased insulin-like growth factor 2 (IGF2) and CRP mRNA and protein levels in a dose- and time-dependent manner in THP-1 macrophages. Treatment with Ox-LDL increased CRP protein expression, and this effect was completely abolished by siRNA-mediated silencing of IGF2 in THP-1 macrophages. Moreover, treatment with pcDNA3.1-IGF2 significantly enhanced CRP protein expression in Ox-LDL-stimulated THP-1 macrophages. CRP expression is upregulated by Ox-LDL through the IGF2 pathway in THP-1 macrophages.

The impact of global budgeting on treatment intensity and outcomes.

This paper investigates the effects of global budgets on the amount of resources devoted to cardio-cerebrovascular disease patients by hospitals of different ownership types and these patients' outcomes. Theoretical models predict that hospitals have financial incentives to increase the quantity of treatments applied to patients. This is especially true for for-profit hospitals. If that's the case, it is important to examine whether the increase in treatment quantity is translated into better treatment outcomes. Our analyses take advantage of the National Health Insurance of Taiwan's implementation of global budgets for hospitals in 2002. Our data come from the National Health Insurance's claim records, covering the universe of hospitalized patients suffering acute myocardial infarction, ischemic heart disease, hemorrhagic stroke, and ischemic stroke. Regression analyses are carried out separately for government, private not-for-profit and for-profit hospitals. We find that for-profit hospitals and private not-for-profit hospitals did increase their treatment intensity for cardio-cerebrovascular disease patients after the 2002 implementation of global budgets. However, this was not accompanied by an improvement in these patients' mortality rates. This reveals a waste of medical resources and implies that aggregate expenditure caps should be supplemented by other designs to prevent resources misallocation.

An agomir of miR-144-3p accelerates plaque formation through impairing reverse cholesterol transport and promoting pro-inflammatory cytokine production.

AIMS: ATP-binding cassette transporter A1 (ABCA1) mediates the efflux of cholesterol and phospholipids to lipid-poor apolipoproteins, which then form nascent HDL, a key step in the mechanism of reverse cholesterol transport (RCT). While a series of microRNAs (miRNAs) have been identified as potent post-transcriptional regulators of lipid metabolism, their effects on ABCA1 function and associated mechanisms remain unclear. METHODS AND RESULTS: ABCA1 was identified as a potential target of miR-144-3p, based on the results of bioinformatic analysis and the luciferase reporter assay, and downregulated after transfection of cells with miR-144-3p mimics, as observed with real-time PCR and western blot. Moreover, miR-144-3p mimics (agomir) enhanced the expression of inflammatory factors, including IL-1ß, IL-6 and TNF-α, in vivo and in vitro, inhibited cholesterol efflux in THP-1 macrophage-derived foam cells, decreased HDL-C circulation and impaired RCT in vivo, resulting in accelerated pathological progression of atherosclerosis in apoE-/- mice. Clinical studies additionally revealed a positive correlation of circulating miR-144-3p with serum CK, CK-MB, LDH and AST in subjects with AMI. CONCLUSIONS: Our findings clearly indicate that miR-144-3p is essential for the regulation of cholesterol homeostasis and inflammatory reactions, supporting its utility as a potential therapeutic target of atherosclerosis and a promising diagnostic biomarker of AMI.

Dihydrocapsaicin down-regulates apoM expression through inhibiting Foxa2 expression and enhancing LXRα expression in HepG2 cells.

BACKGROUND: Apolipoprotein M (apoM), as a novel apolipoprotein which is mainly expressed in liver and kidney tissues, is associated with development and progression of atherosclerosis and diabetes. Our group have recently shown that Dihydrocapsaicin(DHC)can significantly decrease atherosclerotic plaque formation in apoE-/- mice. However, the effect and possible mechanism of DHC on apoM expression remain unclear. METHODS: HepG2 cells were treated with 0 µM, 25 µM, 50 µM and 100 µM DHC for 24 h or were treated with 100 µM DHC for 0, 6, 12, and 24 h, respectively. The mRNA levels and protein levels were measured by real-time quantitative PCR and western blot analysis, respectively. RESULTS: We found that DHC markedly decreased expression of apoM at both mRNA and protein level in HepG2 cells in a dose-dependent and time-dependent manner. Expression of Foxa2 was decreased while expression of LXRα was increased by DHC treatment in HepG2 cells. In addittion, overexpression of Foxa2 markedly compensated the inhibition effect induced by DHC on apoM expression. LXRα small interfering RNA significantly abolished the inhibition effect which induced by DHC on apoM expression. The liver of C57BL/6 mice treated with DHC had significantly lower expression of apoM. Furthermore, the liver had lower expression of Foxa2 while had higher expression of LXRα. CONCLUSIONS: DHC could down-regulate apoM expression through inhibiting Foxa2 expression and enhancing LXRα expression in HepG2 cells.

Nur77 decreases atherosclerosis progression in apoE(-/-) mice fed a high-fat/high-cholesterol diet.

RATIONALE: It is clear that lipid disorder and inflammation are associated with cardiovascular diseases and underlying atherosclerosis. Nur77 has been shown to be involved in inflammatory response and lipid metabolism. OBJECTIVE: Here, we explored the role of Nur77 in atherosclerotic plaque progression in apoE(-/-) mice fed a high-fat/high cholesterol diet. METHODS AND RESULTS: The Nur77 gene, a nuclear hormone receptor, was highly induced by treatment with Cytosporone B (Csn-B, specific Nur77 agonist), recombinant plasmid over-expressing Nur77 (pcDNA-Nur77), while inhibited by treatment with siRNAs against Nur77 (si-Nur77) in THP-1 macrophage-derived foam cells, HepG2 cells and Caco-2 cells, respectively. In addition, the expression of Nur77 was highly induced by Nur77 agonist Csn-B, lentivirus encoding Nur77 (LV-Nur77), while silenced by lentivirus encoding siRNA against Nur77 (si-Nur77) in apoE(-/-) mice fed a high-fat/high cholesterol diet, respectively. We found that increased expression of Nur77 reduced macrophage-derived foam cells formation and hepatic lipid deposition, downregulated gene levels of inflammatory molecules, adhesion molecules and intestinal lipid absorption, and decreases atherosclerotic plaque formation. CONCLUSION: These observations provide direct evidence that Nur77 is an important nuclear hormone receptor in regulation of atherosclerotic plaque formation and thus represents a promising target for the treatment of atherosclerosis.

CHL1 is involved in human breast tumorigenesis and progression.

Neural cell adhesion molecules (CAM) play important roles in the development and regeneration of the nervous system. The L1 family of CAMs is comprised of L1, Close Homolog of L1 (CHL1, L1CAM2), NrCAM, and Neurofascin, which are structurally related trans-membrane proteins in vertebrates. Although the L1CAM has been demonstrated play important role in carcinogenesis and progression, the function of CHL1 in human breast cancer is limited. Here, we found that CHL1 is down-regulated in human breast cancer and related to lower grade. Furthermore, overexpression of CHL1 suppresses proliferation and invasion in MDA-MB-231 cells and knockdown of CHL1 expression results in increased proliferation and invasion in MCF7 cells in vitro. Finally, CHL1 deficiency promotes tumor formation in vivo. Our results may provide a strategy for blocking breast carcinogenesis and progression.