Alginate oligosaccharide assimilation by gut microorganisms and the potential role in gut inflammation alleviation.

Dietary fiber metabolism by gut microorganisms plays important roles in host physiology and health. Alginate, the major dietary fiber of daily diet seaweeds, is drawing more attention because of multiple biological activities. To advance the understanding of alginate assimilation mechanism in the gut, we show the presence of unsaturated alginate oligosaccharides (uAOS)-specific alginate utilization loci (AUL) in human gut microbiome. As a representative example, a working model of the AUL from the gut microorganism Bacteroides clarus was reconstructed from biochemistry and transcriptome data. The fermentation of resulting monosaccharides through Entner-Doudoroff pathway tunes the metabolism of short-chain fatty acids and amino acids. Furthermore, we show that uAOS feeding protects the mice against dextran sulfate sodium-induced acute colitis probably by remodeling gut microbiota and metabolome. IMPORTANCE: Alginate has been included in traditional Chinese medicine and daily diet for centuries. Recently discovered biological activities suggested that alginate-derived alginate oligosaccharides (AOS) might be an active ingredient in traditional Chinese medicine, but how these AOS are metabolized in the gut and how it affects health need more information. The study on the working mechanism of alginate utilization loci (AUL) by the gut microorganism uncovers the role of unsaturated alginate oligosaccharides (uAOS) assimilation in tuning short-chain fatty acids and amino acids metabolism and demonstrates that uAOS metabolism by gut microorganisms results in a variation of cell metabolites, which potentially contributes to the physiology and health of gut.

A Novel Ageladine A Derivative Acts as a STAT3 Inhibitor and Exhibits Potential Antitumor Effects.

The Janus kinase/signal transducer and activator of the transcription 3 (JAK/STAT3) signaling pathway controls multiple biological processes, including cell survival, proliferation, and differentiation. Abnormally activated STAT3 signaling promotes tumor cell growth, proliferation, and survival, as well as tumor invasion, angiogenesis, and immunosuppression. Hence, JAK/STAT3 signaling has been considered a promising target for antitumor therapy. In this study, a number of ageladine A derivative compounds were synthesized. The most effective of these was found to be compound 25. Our results indicated that compound 25 had the greatest inhibitory effect on the STAT3 luciferase gene reporter. Molecular docking results showed that compound 25 could dock into the STAT3 SH2 structural domain. Western blot assays demonstrated that compound 25 selectively inhibited the phosphorylation of STAT3 on the Tyr705 residue, thereby reducing STAT3 downstream gene expression without affecting the expression of the upstream proteins, p-STAT1 and p-STAT5. Compound 25 also suppressed the proliferation and migration of A549 and DU145 cells. Finally, in vivo research revealed that 10 mg/kg of compound 25 effectively inhibited the growth of A549 xenograft tumors with persistent STAT3 activation without causing significant weight loss. These results clearly indicate that compound 25 could be a potential antitumor agent by inhibiting STAT3 activation.

Caffeine can alleviate non-alcoholic fatty liver disease by augmenting LDLR expression via targeting EGFR.

Increasing low-density lipoprotein receptor (LDLR) protein levels represents a key strategy for the prevention and treatment. Berberine can reportedly alleviate non-alcoholic fatty liver disease (NAFLD) by increasing the LDLR expression in an ERK1/2 signaling-dependent manner of NAFLD. Studies have shown that caffeine can inhibit fat deposition in the livers of mice; however, caffeine has not been reported to alleviate NAFLD by augmenting the LDLR expression via targeting EGFR. Here, an MTT assay, western blotting, RT-qPCR, immunohistochemistry, and surface plasmon resonance (SPR) analysis were used to investigate the role of caffeine in low-density lipoprotein cholesterol (LDL-C) clearance both in vitro and in vivo. In vitro, we found that caffeine could activate the EGFR-ERK1/2 signaling pathway in HepG2 cells, leading to increased LDLR mRNA and protein expression, and this effect could be inhibited by cetuximab. The SPR assay results have indicated that caffeine may increase the LDLR expression by directly binding to the EGFR extracellular domain and activating the EGFR-ERK1/2 signaling pathway. In vivo, caffeine markedly improved fatty liver and related blood indices in ApoE KO mice with high-fat-diet-induced NAFLD. Consistent with our in vitro results, we found that caffeine could also activate EGFR-ERK1/2 signaling and promote the LDLR expression in ApoE KO mice. In summary, caffeine can enhance the LDLR expression by directly binding to EGFR and activating the EGFR-ERK1/2 signaling pathway. EGFR signaling may represent a novel target for the prevention and treatment of NAFLD.

20(S)-Protopanaxadiol decreases atherosclerosis in ApoE KO mice by increasing the levels of LDLR and inhibiting its binding with PCSK9.

Chinese medicinal and edible plants such as Panax notoginseng and ginseng are widely used for the treatment of atherosclerosis (AS). AS is the main pathological basis of cardiac-cerebral vascular disease, which seriously threatens human health and quality of life. Low-density lipoprotein (LDL) is the main pathogenic factor of AS. The LDL receptor (LDLR) is an important protein that functions to mediate the uptake and degradation of plasma LDL. Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) can mediate the internalization and degradation of LDLR. So, increasing the LDLR level by inhibiting PCSK9 is an important means of prevention and treatment of AS. In this study, by combining interaction technology (surface plasmon resonance, SPR) of small molecule compounds with membrane receptor proteins, cell experiments, and in vivo experiments, it is proved for the first time that 20(S)-protopanaxadiol (PPD), as a hydrolytic product of Panax notoginseng saponins in the intestinal tract, can bind to the extracellular domain of LDLR and inhibit the role of Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) in mediating LDLR degradation. The results showed that PPD significantly reduced aortic plaques and hepatic steatosis in HFD-fed ApoE KO mice. LDLR protein levels were elevated in the liver tissues isolated from PPD-treated HFD-fed ApoE KO mice and PPD-treated HepG2 cells. Our findings demonstrated that PPD significantly increased LDLR levels and reduced AS in the HFD-fed ApoE KO mice on account of LDLR degradation being inhibited by PPD inhibiting the interaction between PCSK9 and LDLR.

A retrospective study of endodontic microsurgery about 302 patients.

OBJECTIVES: To investigate the outcome of endodontic microsurgery and analyze the potential prognostic factors, and to evaluate the value of surgical classification by Kim and Kratchman. METHODS: Collecting clinical examination and radiographical examination of endodontic microsurgery cases (which were followed up at least 1 year), which were classified according to Kim and Kratchman, and we analyzed the outcome of endodontic microsurgery and its potential prognostic factors. RESULTS: 302 patients (400 teeth) who received endodontic microsurgery were included. The one year success rate of endodontic microsurgery was 94.25%. Different classification had significant influences on the outcome of endodontic microsurgery (P<0.05), and the success rate of class B and C were better than those of class D, E, and F. The position of teeth had significant influences on the outcome of endodontic microsurgery (P<0.05). The success rate of maxillary teeth was higher than that of mandibular teeth. The success rate of anterior teeth was higher than that of posterior teeth (P<0.05). The quality of root end filling and first or second surgery had no effect on the outcome (P>0.05). CONCLUSIONS: Endodontic microsurgery is an effective treatment method for saving affected teeth, and it can get a good result. Tooth position and classification are the potential prognostic factors. The surgical classification of Kim and Kratchman can help to predict the outcome of endodontic microsurgery.

Exploration of suitable pharmacodynamic parameters for acarbose bioequivalence evaluation: A series of clinical trials with branded acarbose.

AIMS: To determine deficiencies in the Food and Drug Administration (FDA)'s guidance for assessing acarbose bioequivalence (BE) and to explore optimal pharmacodynamic (PD) metrics for better evaluation of acarbose BE. METHODS: Three clinical trials with branded acarbose were conducted in healthy subjects, including a pilot study (Study I, n = 11, 50 and 100 mg), a 2×2 crossover BE study (Study II, n = 36, 100 mg) and a 4×4 Williams study (Study III, n = 16, 50/100/150 mg). Serum glucose concentrations were measured by the glucose oxidase method. RESULTS: In Study I, compared with 50 mg acarbose, only 100 mg acarbose had a significantly lower Cmax0-4h than that of sucrose administration alone (7.96 ± 0.83 mmol/L vs 6.78 ± 1.02 mmol/L, P < .05). In Study II, the geometric mean ratios of the test formulation to the reference formulation (both formulations were the branded drug) for FDA PD metrics, ΔCmax0-4h and ΔAUC0-4h , were 0.903 and 0.776, respectively, and the 90% confidence intervals were 67.44-120.90 and 53.65-112.13, respectively. The geometric mean ratios (confidence interval) for possible optimal evaluation PD metrics (Cmax0-2h and AUC0-2h ) were 1.035 (94.23-112.68) and 0.982 (89.28-107.17), respectively. Further, Cmax0-2h and AUC0-2h also met the sensitivity requirements for BE evaluation in Study III. CONCLUSION: Considering the mechanisms of action of acarbose, the PD effect was shown to be dose independent during the 2-4 hours postadministration of acarbose. Hence PD metrics based on the serum glucose concentration from 0 to 2 hours (Cmax0-2h and AUC0-2h ) are more sensitive than the FDA-recommended PD metrics for acarbose BE evaluation from 0-4 hours (ΔCmax0-4h and ΔAUC0-4h ). The trial has been registered at the Chinese Clinical Trial Registry (http://www.chictr.org.cn, ChiCTR1800015795, ChiCTR-IIR-17013918, ChiCTR-IIR-17011903). All subjects provided written informed consent before screening.

Virtual Screening Based on Ensemble Docking Targeting Wild-Type p53 for Anticancer Drug Discovery.

The tumor-suppressor function of p53 makes it an attractive drug target. Efforts were mostly put on stabilization of the functional p53 or reactivation of mutated p53. Previous studies have shown that small molecules targeting Loop1/Sheet3 (L1/S3) can reactivate the R175H-p53 and stabilize p53 in vitro. Since the L1/S3 pocket is shared by the mutate and the wild type (WT) p53, virtual screening is introduced to identify natural products targeting the L1/S3 of WT p53. Considering the high flexibility of Loop1, ensemble docking method is utilized for different clusters of the L1/S3. Seven conformations were chosen for docking. As one of the 181 selected candidates, torilin not only improved p53 activity, but also increased p21 protein expression level, which lies downstream of p53, therefore suppressing HCT116 cancer cell growth. Torilin may covalently bind to Cys124 of p53 by 2-methyl-2-butenal (2M2B) group, as torilin derivatives, which do not contain the 2M2B group, were not able to increase the p53 transcription activity. In conclusion, this study demonstrated that L1/S3 of WT-p53 is a druggable pocket, and torilin has a potential cytotoxicity through activating the p53 pathway.

Photoelectrical properties of insulating LaAlO3-SrTiO3 interfaces.

We report photoconductivity of an insulating LaAlO3-SrTiO3 (LAO-STO) heterointerface. Persistent photocurrent induced by a 514 nm laser at room temperature is significant, which is attributed to carriers trapped by a built-in potential well at the interface. Further studies of photoconductivity of the insulating LAO-STO interface performed with a monochrometer demonstrate the photoelectrical response not only in the ultraviolet region but also in the visible and infrared regions. The extrinsic photoconductivity indicates several midgap states located in the insulating LAO-STO interface. Our results provide a deep understanding of the band structure of the insulating LAO-STO heterointerface and promising applications as optoelectronic devices.

[Micro-CT evaluation of root canal deviation after preparation].

OBJECTIVE: To establish a new evaluation system of curved root canal deviation by the technique of micro-CT. METHODS: Curved simulated root canals were prepared with ProTaper NiTi-hand files by crown-down technique. After root canals were scanned by micro-CT and analyzed by image processing software, the planar area and centers' transportation of each cross-section were compared to evaluate the prepare effect of ProTaper, and a three-dimensional model about it were established. RESULTS: The same cross-section's area of the root canals which was prepared with ProTaper NiTi-hand files were essentially consistent. With the data analysis of micro-CT, a system of combining planar and three-dimensional index to evaluate the root canal deviation were established. The shapes of root canal before and after prepared with ProTaper showed less deviation, which proved the shaping ability of ProTaper could meet the requirements for clinical use. CONCLUSION: A three-dimensional root canal central axis model is established using micro-CT. It provides a new method to analyze the shaping ability of the instrumentation after root canal preparation. It will give us a more direct view to analyze the situation of the root canal deviation combining the two-dimensional image and the three-dimensional model.

TNF-alpha stimulates the ACAT1 expression in differentiating monocytes to promote the CE-laden cell formation.

High levels of the inflammatory cytokine tumor necrosis factor-alpha (TNF-alpha) are present in atherosclerotic lesions. TNF-alpha regulates expression of multiple genes involved in various stages of atherosclerosis, and it exhibits proatherosclerotic and antiatherosclerotic properties. ACAT catalyzes the formation of cholesteryl esters (CE) in monocytes/macrophages, and it promotes the foam cell formation at the early stage of atherosclerosis. We hypothesize that TNF-alpha may be involved in regulating the ACAT gene expression in monocytes/macrophages. In this article, we show that in cultured, differentiating human monocytes, TNF-alpha enhances the expression of the ACAT1 but not ACAT2 gene, increases the cholesteryl ester accumulation, and promotes the lipid-laden cell formation. Several other proinflammatory cytokines tested do not affect the ACAT1 gene expression. The stimulation effect is consistent with a receptor-dependent process, and is blocked by using nuclear factor-kappa B (NF-kappa B) inhibitors. A functional and unique NF-kappa B element located within the human ACAT1 gene proximal promoter is required to mediate the action of TNF-alpha. Our data demonstrate that TNF-alpha, through the NF-kappa B pathway, specifically enhances the expression of human ACAT1 gene to promote the CE-laden cell formation from the differentiating monocytes, and our data support the hypothesis that TNF-alpha is proatherosclerotic during early phase of lesion development.

[Three-dimensional finite analysis of the stress in first mandibular molar with composite class I restoration when various mixing ratios of bases were used].

OBJECTIVE: To analyze the possible damage to the remaining tooth and composite restorations when various mixing ratios of bases were used. METHODS: Testing elastic modulus and poission's ratio of glass-ionomer Vitrebond and self-cured calcium hydroxide Dycal with mixing ratios of 1:1, 3:4, 4:3. Micro-CT was used to scan the first mandibular molar, and the three-dimensional finite element model of the first permanent mandibular molar with class I cavity was established. Analyzing the stress of tooth structure, composite and base cement under physical load when different mixing ratios of base cement were used. RESULTS: The elastic modulus of base cement in various mixing ratios was different, which had the statistic significance. The magnitude and location of stress in restored tooth made no differences when the mixing ratios of Vitrebond and Dycal were changed. The peak stress and spreading area in the model with Dycal was more than that with Vitrebond. CONCLUSION: Changing the best mixing ratio of base cement can partially influence the mechanistic character, but make no differences on the magnitude and location of stress in restored tooth. During the treatment of deep caries, the base cement of the elastic modulus which is proximal to the dentin and restoration should be chosen to avoid the fracture of tooth or restoration.

[Influence of hand-mixed methods on compressive strength of zinc phosphate dental cement].

OBJECTIVE: To study the influence of hand-mixed methods on the compressive strength of the zinc phosphate dental cement. METHODS: Three skilled nurses used three kinds of common clinical hand-mixed methods (included the unidirectional rotation method, the alternate pro and con bidirectional rotation method and the pulling and pushing with folding method) to mix the zinc phosphate dental cement on the same condition (i.e. same indoor temperature and humidity, the same mixing ratio, mixing time, mixing frequency and the same mixing instruments and so on). The mixed zinc phosphate cement was packed into the plastic cylinders with 10 mm-high and 5 mm-bore. After the mixed zinc phosphate cement coagulated, compressive strength was tested separately. RESULTS: The compressive strength of the zinc phosphate dental cement mixed with the alternate pro and con bidirectional rotation method was the best, and the value was (106.11+/- 4.82) MPa. The compressive strength of the zinc phosphate dental cement mixed with the pulling and pushing with folding method was lower, and the value was (77.57 +/- 6.26) MPa. The compressive strength of the zinc phosphate dental cement mixed with the unidirectional rotation method was the lowest, and the value was (54.41 +/- 5.08) MPa. The compressive strength of the zinc phosphate dental cement mixed with the unidirectional rotation method and the pulling and pushing with folding method could not achieve the clinical required compressive strength (about 100 MPa), while the compressive strength mixed with the alternate pro and con bidirectional rotation method was above 100 MPa. CONCLUSION: The alternate pro and con bidirectional rotation method to mix the zinc phosphate dental cement is recommended in clinic.

[Differential analyses of mRNA expression of gtfs from Streptococcus mutans in different pH condition].

OBJECTIVE: To determine the expression level of each gtf under different pH cultural conditions and to find the relationship between gtf expression levels with environmental pH in different strains of Streptococcus mutans (S.mutans). METHODS: S. mutans form clinical isolation with different extracellular polysaccharides (EPS) producibility and UA159 were selected. Their ability to produce EPS under pH5.5 and pH7 were tested. Then in two strains, the relative quantity of gtfA, gtfB, gtfC, gtfD's mRNA which were related to S. mutan's ability to produce EPC, were examined by real-time reverse transcription-polymerase chain reaction (real-time RT-PCR) methods under different pH culture condition. RESULTS: At pH5.5, expression levels of gtfA, gtfB, gtfD were increased while that of gtfC were decreased in both strains, and that of gtfB, gtfC were higher in strain which produces more ECP. CONCLUSION: The expression levels of gtfs related closely to the cariogenicity of S. mutan.

Human acyl-CoA:cholesterol acyltransferase 2 gene expression in intestinal Caco-2 cells and in hepatocellular carcinoma.

Humans express two ACAT (acyl-CoA:cholesterol acyltransferase) genes, ACAT1 and ACAT2. ACAT1 is ubiquitously expressed, whereas ACAT2 is primarily expressed in intestinal mucosa and plays an important role in intestinal cholesterol absorption. To investigate the molecular mechanism(s) responsible for the tissue-specific expression of ACAT2, we identified five cis-elements within the human ACAT2 promoter, four for the intestinal-specific transcription factor CDX2 (caudal type homeobox transcription factor 2), and one for the transcription factor HNF1alpha (hepatocyte nuclear factor 1alpha). Results of luciferase reporter and electrophoretic mobility shift assays show that CDX2 and HNF1alpha exert a synergistic effect, enhancing the ACAT2 promoter activity through binding to these cis-elements. In undifferentiated Caco-2 cells, the ACAT2 expression is increased when exogenous CDX2 and/or HNF1alpha are expressed by co-transfection. In differentiated Caco-2 cells, the ACAT2 expression significantly decreases when the endogenous CDX2 or HNF1alpha expression is suppressed by using RNAi (RNA interference) technology. The expression levels of CDX2, HNF1alpha, and ACAT2 are all greatly increased when the Caco-2 cells differentiate to become intestinal-like cells. These results provide a molecular mechanism for the tissue-specific expression of ACAT2 in intestine. In normal adult human liver, CDX2 expression is not detectable and the ACAT2 expression is very low. In the hepatoma cell line HepG2 the CDX2 expression is elevated, accounting for its elevated ACAT2 expression. A high percentage (seven of fourteen) of liver samples from patients affected with hepatocellular carcinoma exhibited elevated ACAT2 expression. Thus, the elevated ACAT2 expression may serve as a new biomarker for certain form(s) of hepatocellular carcinoma.

[Study on the effect of concentrations of glucose on initial adherence of Streptococcus mutans].

OBJECTIVE: To study the effect of concentrations of glucose on the initial adherence of Streptococcus mutans (S. mutans) to saliva-coated hydroxyapatite (SHA), and to compare the initial adherence of S. mutans from caries-active group with that of S. mutans from caries-free group. METHODS: Each 10 clinical isolates of S. mutans from caries-active and caries-free subjects were used in this study. And S. mutans UA159 was also included in this experiment. SHA was used to simulate tooth surface in oral cavity. S. mutans clinical isolates and strain UA159 were cultured in TPY liquid medium containing 3H-TdR in the same radioactive concentration and glucose in 0.2%, 1.0%, 5.0% concentration. Then grown cells were harvested to produce a suspension. SHA and radiolabelled bacterial suspension (A550(nm) = 0.52) were mixed for 90 minutes, samples were assayed by using liquid scintillation counter, and binding abilities of strains were evaluated by the count per minute (CPM). RESULTS: The initial adherence ability of S. mutans from caries-active group was higher than that of S. mutans from caries-free group (P < 0.05). And the initial adherence ability of S. mutans cultured in different concentration of glucose was also significantly different (P < 0.05), 5.0% glucose group had the highest adherence ability, and 0.2% glucose group had the lowest adherenceability. CONCLUSION: (1)Difference of the initial adherence of S. mutans might relate to difference of carious experiences; (2) Glucose may play an important role in S. mutans initial adherence, to some extent, S. mutans cultured in the higher concentration of glucose has the higher initial adherence property.

[Histological evaluation of direct pulp capping with a self-etching adhesive and calcium hydroxide].

OBJECTIVE: To evaluate the beagles' pulp response following direct pulp capping with Clearfil SE BOND (SB). METHODS: 130 sound teeth were used. 120 had their pulps mechanically exposed and were divided in two groups. In group A, teeth were capped with SB. In group B, teeth were capped with calcium hydroxide (CH). The left 10 teeth were used as control. After 7, 30 and 90 days, the teeth were extracted and processed for light microscopical examination. RESULTS: In 7 day observation period, inflammatory reaction in SB group was slighter than that of CH group, but the difference was statistical insignificant. In the 30 day and 90 day observation period, inflammatory reaction was slight in both groups, but specimens with dentin bridge formation was significantly less in SB group than in CH group (P < 0.05). CONCLUSION: SB showed acceptable biocompatibility with pulp, but its ability to induce hard tissue barrier on pulp exposure is weaker than CH.

[Clinical analysis of 1 423 cases of root canal therapy].

OBJECTIVE: To evaluate the clinical quality of root canal therapy (RCT) in West China Dental Hospital of Sichuan University. METHODS: 1 423 RCT teeth were finished from Mar. 2001 to Feb. 2002 in West China Dental Hospital. Root canal filling quality and treatment period of these teeth were evaluated. 695 teeth of the total were revisited 2 years later and 2-year success rate were evaluated. RESULTS: The ratios of adequate filling, underfilling, and overfilling were 79.97%, 14.62% and 5.41%, receptively. Full canal RCT ratio of molar was 89.44%. Average RCT treatment period was 2.8 weeks. 2-year success rate of RCT was 94.39%. CONCLUSION: Clinical RCT level of West China Dental Hospital was satisfactory from 2001 to 2002.

[Expression of the heat-shock protein 70 family polymorphism in A549 cell line exposed to benzo(a)pyrene].

OBJECTIVE: To study the pattern of polymorphism expression of heat-shock protein 70 (HSP70) family in A549 cell line treated with different concentrations of benzo(a)pyrene (BaP) and its probable biological effect. METHOD: Two-dimensional polyacrylamide gel electrophoresis (2D-PAGE) was used for the HSP70 expression analysis. RESULTS: 2D-PAGE showed that when A549 cells were exposed to different concentrations of BaP (0.1, 1.0, 5.0, 10.0 micromol/L) for 24, 48 h respectively, the HSP72 in A549 gradually declined as BaP concentrations increased [the integral OD (IOD)] for 24 h were: 150.36 +/- 26.03, 98.57 +/- 13.34, 64.92 +/- 15.03, 34.65 +/- 19.10, 32.92 +/- 18.71 respectively, for 48 h: 126.85 +/- 17.41, 106.19 +/- 15.32, 73.64 +/- 21.02, 35.18 +/- 11.95, 16.27 +/- 9.35 respectively), while the IOD of HSP73 did not show any remarkable change (24 h: 102.29 +/- 21.24, 87.71 +/- 18.70, 71.19 +/- 14.08, 71.87 +/- 15.16, 72.78 +/- 17.31 respectively; 48 h: 86.66 +/- 16.86, 75.67 +/- 10.61, 66.83 +/- 12.63, 67.29 +/- 10.26, 91.37 +/- 13.68 respectively). CONCLUSION: BaP can inhibit HSP72 expression and with certain dose-effect relationship, but cannot affect HSP73 expression.

Enhancement of human ACAT1 gene expression to promote the macrophage-derived foam cell formation by dexamethasone.

In macrophages, the accumulation of cholesteryl esters synthesized by the activated acyl-coenzyme A:cholesterol acyltransferase-1 (ACAT1) results in the foam cell formation, a hallmark of early atherosclerotic lesions. In this study, with the treatment of a glucocorticoid hormone dexamethasone (Dex), lipid staining results clearly showed the large accumulation of lipid droplets containing cholesteryl esters in THP-1-derived macrophages exposed to lower concentration of the oxidized low-density lipoprotein (ox-LDL). More notably, when treated together with specific anti-ACAT inhibitors, the abundant cholesteryl ester accumulation was markedly diminished in THP-1-derived macrophages, confirming that ACAT is the key enzyme responsible for intracellular cholesteryl ester synthesis. RT-PCR and Western blot results indicated that Dex caused up-regulation of human ACAT1 expression at both the mRNA and protein levels in THP-1 and THP-1-derived macrophages. The luciferase activity assay demonstrated that Dex could enhance the activity of human ACAT1 gene P1 promoter, a major factor leading to the ACAT1 activation, in a cell-specific manner. Further experimental evidences showed that a glucocorticoid response element (GRE) located within human ACAT1 gene P1 promoter to response to the elevation of human ACAT1 gene expression by Dex could be functionally bound with glucocorticoid receptor (GR) proteins. These data supported the hypothesis that the clinical treatment with Dex, which increased the incidence of atherosclerosis, may in part due to enhancing the ACAT1 expression to promote the accumulation of cholesteryl esters during the macrophage-derived foam cell formation, an early stage of atherosclerosis.