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Macrophage polarization is a dynamic and integral process in tissue inflammation and remodeling. In this study, we describe that lipoprotein-associated phospholipase A2 (Lp-PLA2) plays an important role in controlling inflammatory macrophage (M1) polarization in rodent experimental autoimmune encephalomyelitis (EAE) and in monocytes from multiple sclerosis (MS) patients. Specific inhibition of Lp-PLA2 led to an ameliorated EAE via markedly decreased inflammatory and demyelinating property of M1. The effects of Lp-PLA2 on M1 function were mediated by lysophosphatidylcholine, a bioactive product of oxidized lipids hydrolyzed by Lp-PLA2 through JAK2-independent activation of STAT5 and upregulation of IRF5. This process was directed by the G2A receptor, which was only found in differentiated M1 or monocytes from MS patients. M1 polarization could be inhibited by a G2A neutralizing Ab, which led to an inhibited disease in rat EAE. In addition, G2A-deficient rats showed an ameliorated EAE and an inhibited autoimmune response. This study has revealed a mechanism by which lipid metabolites control macrophage activation and function, modification of which could lead to a new therapeutic approach for MS and other inflammatory disorders.

The B-cell CLL/lymphoma 6 (Bcl6) oncogenic repressor is a master regulator of humoral immunity and B-cell lymphomagenesis. Although much research has focused on its regulation and function of GC B cells and T cells, the role of Bcl6 in regulating the functions of innate immunity is not well defined. Here, we demonstrated that EAE is exacerbated in LysM Cre+/ - Bcl6fl/fl mice. Although other cells such as neutrophils might be involved in this conditional mutant mouse model, we found that the disease pathology is mainly associated with a biased M1 macrophage activity and an enhanced encephalitogenic CD4+ Th17 cell response. In addition, LPS-induced sepsis mice exhibited an enhanced M1 and inhibited M2 response, further confirming that Bcl6 has an important role in regulating macrophage polarization. Mechanistically, Bcl6 interacts with IκBζ and interferes its binding to the interleukin-6 (Il-6) promoter in macrophages, leading to a suppressed transcription of Il-6. These findings have demonstrated that Bcl6 exerts its regulatory function mainly by repressing Il-6 expression in macrophages. Thus, our study presents a novel role for Bcl6 in regulating immune response and inflammation. Interaction between Bcl6 and IκBζ in macrophages may provide a potential therapeutic target for autoimmune inflammatory disease.

Recent research suggests that dihydrolipoamide acetyltransferase (DLAT), which is a copper-induced cell death-related gene, is involved in multiple biological events in tumors. This study sought to investigate the relationship between DLAT and hepatocellular carcinoma (HCC).In the Cancer Genome Atlas (TCGA) database, we first identified the differentially expressed gene (i.e., DLAT), then confirmed DLAT expression, and found a link between it and the prognosis of HCC patients. An internal validation nomogram was built based on a multivariate Cox regression analysis. Data from the Tumor Immune Estimation Resource (TIMER) database was used to examine the association between DLT and immunological cells. A gene set enrichment analysis (GSEA) was conducted to investigate the probable mechanism of action. Finally,The database screenings showed that DLAT was a differentially expressed molecule; that is, DLAT was more highly expressed in the cancer tissues than normal tissues. TCGA results and Kaplan-Meier-plotter data sets showed that HCC patients with reduced DLAT expression had greater disease-specific survival (DSS), overall survival (OS), and progression-free interval (PFI). The prediction model had a concordance index of 0.659 (0.614-0.704), which indicates high accuracy. According to the TIMER database, tumor cells in the HCC microenvironment may be able to bypass the immune system due to the expression of DLAT. TheDecreased DLAT expression significantly prolongs the OS, PFI, and DSS of HCC patients. DLAT may be employed as a new predictive biomarker for HCC, and may be linked to the immune system in HCC patients. The tumor microenvironment (TME) may have a significant effect on the ability of tumor cells to evade the immune system. The PI3K/Akt and Wnt/β-catenin signaling pathways may affect the prognosis of HCC by interfering with DLAT. Given these findings, HCC may be an ideal target for the development of anti-cancer therapies.

Melatonin is an amine hormone produced by mammals and the human pineal gland. Modern biomedical research has shown that melatonin has antitumor effects. However, the underlying mechanisms of these effects remain unclear. In this study, we explore the effect of melatonin on TE-1 esophageal cancer cells metastasis and study the roles of the NF-κB signaling pathway and MMP9 in this process. We found that melatonin significantly suppressed the migration and invasion of TE-1 esophageal cancer cells, inhibited the activation NF-κB signaling pathway, and decreased the expression of MMP9. When adding NF-κB inhibitor, the results show that the expression of MMP9 decreased while E-cadherin increased. Taken together, the results indicate that melatonin inhibits esophageal cancer cell metastasis by down-regulating the NF-κB signaling pathway and MMP9. Therefore, melatonin may be a new drug for the effective treatment of esophageal cancer.

Macrophage polarization is a dynamic and integral process of tissue inflammation and remodeling. Here we demonstrate an important role of Aurora kinase A in the regulation of inflammatory M1 macrophage polarization. We found that there was an elevated expression of Aurora-A in M1 macrophages and inhibition of Aurora-A by small molecules or specific siRNA selectively led to the suppression of M1 polarization, sparing over the M2 macrophage differentiation. At the molecular level, we found that the effects of Aurora-A in M1 macrophages were mediated through the down-regulation of NF-κB pathway and subsequent IRF5 expression. In an autoimmune disease model, experimental autoimmune encephalitis (EAE), treatment with Aurora kinase inhibitor blocked the disease development and shifted the macrophage phenotype from inflammatory M1 to anti-inflammatory M2. Thus, this study reveals a novel function of Aurora-A in controlling the polarization of macrophages, and modification of Aurora-A activity may lead to a new therapeutic approach for chronic inflammatory diseases.

Inducible regulatory T-cells (iT Reg ) can be generated from CD4 + Foxp3 − naive conventional T-cells by a combination of TGF-β and T-cell receptor (TCR) signaling. It is of enormous clinical importance to identify agents that can promote the generation and differentiation of functional iTreg cells. We have established a phenotypic screening platform to identify new compounds that can promote the TGFβ-mediated iTreg differentiation. We have found Kenpaullone, a potent CDK1, CDK2 and CDK5 inhibitor, as new enhancer for iTreg cell differentiation. Kenpaullone promotes iTreg cell differentiation through increased and prolonged transcription of foxp3 gene by enhancing TGFβ-Smad3 signaling pathway. Thus, we have demonstrated that CDK2 is the biological target of Kenpaullone and proven that CDK2 is a novel negative regulator of iTreg cell differentiation.

Purpose Some studies were undertaken to evaluate the association between cigarette smoking and age-related macular degeneration (AMD). This meta-analysis summarized the risk estimate of smoking and AMD and provided robust evidence for the association. Methods Relevant studies were identified by searching PubMed and MEDLINE (from 1966 to June 2007) and reviewing the reference lists of key articles. The summary relative risk ratio (RR) or odds ratio (OR) and 95% confidence interval (CI) were calculated. Study-specific risk estimates were pooled using a random-effects model. Results Five prospective cohort and eight case-control studies met our inclusion criteria. Ever smoking was statistically significant associated with increased risk of AMD among cohort studies (RR, 1.61; 95% CI, 1.01–2.57) or case-control studies (RR, 1.76; 95% CI, 1.56–1.99). Current smokers were at higher risk of AMD than past smokers. Both geographic atrophy (GA) and neovascular AMD (NV) are subtypes of AMD. A significant relationship was found between smoking and GA risk. Smoking increased the risk of NV, with marginal nonsignificance (RR, 1.47; 95% CI, 0.92–2.37) in cohort studies and significance in case-control studies (RR, 1.96; 95% CI, 1.69–2.27). Conclusions This meta-analysis indicated smoking, especially current smoking, was significantly associated with increased risks of AMD and its subtypes.

To examine the effect of the TIMP-2 G-418C polymorphism on gastric cancer risk.We conducted a hospital-based, case-control study using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method in 412 individuals (206 gastric cancer patients and 206 age, sex matched cancer-free controls).The genotype and allele frequencies were significantly different (P = 0.007 and 0.005, respectively) between cases and controls. Further analysis showed that the variant TIMP-2 genotypes (CC+GC) had a 51% increased risk of gastric cancer compared with GG [adjusted odds ratio (OR) 1.51, 95% confidence interval (CI) 1.00-2.26, P = 0.049]. The elevated gastric cancer risk was especially evident in younger individuals (age58 years old) (adjusted OR 2.21, 95% CI 1.18-4.16) and smokers (adjusted OR 2.61, 95% CI 1.01-6.72). However, no significant association was observed between the variant genotypes and clinicopathological features of gastric cancer.These findings suggest that the TIMP-2 G-418C polymorphism is a genetic predisposing factor for gastric cancer.

The aim of the present study was to assess the influence of the endothelial lipase (EL) gene 584C/T variant, which results in a change at codon 111 of the EL gene from threonine to isoleucine, on the risk of coronary artery disease (CAD) in a Chinese population. The study population consisted of 265 CAD patients and 265 age- and sex-matched control subjects. The T allele frequency was significantly lower among CAD patients than among control subjects (18.3% vs. 29.8%; P < 0.001). In both the CAD and control groups, the T allele carriers had higher high density lipoprotein cholesterol (HDL-C) levels than homozygote C allele carriers. In a multiple logistic regression model adjusted for age, sex, body mass index, smoking, hypertension, diabetes, hyperlipidemia, and low density lipoprotein cholesterol, a significantly decreased risk of developing CAD was found in subjects carrying a variant CT or TT genotype (odds ratio = 0.496, 95% confidence interval = 0.341–0.723; P < 0.001), and the significance persisted after further adjustment for HDL-C. In conclusion, our observation that the EL 584T allele was associated with protection from CAD in this Chinese population replicates the findings in a Japanese study, which found a similar association of this allele with acute myocardial infarction, independent of HDL-C levels.

Background Ghrelin, a novel endogenous ligand for the growth hormone secretagogue receptor, is considered to exert a protective effect against atherosclerosis. The Leu72Met (+ 408C > A) polymorphic variant of the preproghrelin, the gene for the ghrelin precursor, has been linked to obesity, diabetes and metabolic syndrome. However, it is unclear whether this polymorphism is associated with coronary artery disease (CAD). Methods We conducted a case-control study with 317 CAD patients and 323 controls to investigate the potential association of the Leu72Met polymorphism with the occurrence of CAD and CAD-related phenotypes in Chinese population. Results No significant difference in the Leu72Met genotype frequency was observed between CAD patients and controls (P = NS). The Leu72Met polymorphism was not associated with hypertension, diabetes, dyslipidemia, the number of diseased vessels, plasma total cholesterol, triglyceride, high density lipoprotein cholesterol, low density lipoprotein cholesterol or fasting glucose levels in CAD patients. However, among CAD patients, those with variant genotypes (Leu72Met and Met72Met) had lower BMI (24.4 ± 0.3 kg/m2) than Leu72Leu carriers (25.4 ± 0.2 kg/m2, adjusted P = 0.033). Conclusion Our data indicate that the preproghrelin Leu72Met polymorphism is not associated with CAD in Chinese population. However, the Leu72Met variant is associated with BMI among CAD patients.

Monocyte chemoattractant protein-1 (MCP-1, CCL2) has been suggested to be associated with gastric cancer. We investigated whether the functional single nucleotide polymorphism A-2518G in CCL2 gene influenced susceptibility to gastric cancer. The CCL2 genotypes were determined using polymerase chain reaction–restriction fragment length polymorphism in 1,216 individuals (608 gastric cancer patients and 608 age- and sex-matched controls). The gastric cancer patients showed a significant higher frequency of the variant G allele compared to the controls (P = 0.01). Compared with the wild-type AA carriers, the variant genotypes (GA + GG) of A-2518G polymorphism were associated with a higher risk of gastric cancer (adjusted odds ratio = 1.55, 95% confidence interval = 1.03–2.35). Moreover, the elevated risk of gastric cancer associated with the variant genotypes was especially noteworthy in rural subjects (adjusted odds ratio = 1.92, 95% confidence interval = 1.01–3.65). In addition, stratification of gastric cancer cases according to clinicopathological characters showed that the polymorphism was associated significantly with the depth of tumor infiltration. Our data suggest that the genetic polymorphism CCL2 A-2518G may not only be associated with an increased risk of gastric cancer, but also with advanced stage of gastric cancer in the Chinese population.

Aberrant microRNA (miRNA) expression is presently proposed to correlate with various human cancers and common single-nucleotide polymorphisms (SNP) at miRNA genes can influence the maturation of miRNAs or miRNA-mediated transcriptional regulation. However, whether miRNAs SNP alter gastric cancer susceptibility is still unclear. Here we investigated the possible role of a common A/G polymorphism (rs895819) within hsa-mir-27a in the development or progression of gastric cancer, and assessed the effect of rs895819 on the expression of miR-27a and its target gene Zinc finger and BTB domain containing 10 (ZBTB10). In the present case-control study, we found that subjects with the variant genotypes (AG + GG) showed a significantly increased risk of gastric cancer relative to AA carriers (adjusted odds ratio = 1.48, 95% confidence interval 1.06-2.05; P = 0.019). The elevated risk was especially evident in older subjects (age >58 years), men, nonsmokers and rural subjects. A significant association of hsa-mir-27a variant genotypes with lymph node metastasis was also observed. Further functional analyses indicated that variant genotypes might be responsible for elevated miR-27a levels and reduced ZBTB10 mRNA. Moreover, an inverse correlation was found between ZBTB10 and miR-27a levels. In conclusion, we were the first to show that a common polymorphism (rs895819) in hsa-mir-27a, by modulating miR-27a and ZBTB10 levels, acted as an important factor of the gastric cancer susceptibility.

Genistein, an isoflavone isolated from soybean, has been found to be a potent antitumor agent. However, both the effect of genistein on human uveal melanoma cells and the precise mechanism by which genistein suppresses tumorigenesis remain unclear. In the present study, we explored the possible activity of genistein to inhibit human uveal melanoma cell growth and investigated the possible role of genistein on microRNA-27a (miR-27a) as well as its target gene zinc finger and BTB domain containing 10 (ZBTB10) expression levels. The results suggested a significant inhibition of uveal melanoma cell growth in a time- and dose-related manner. In vivo study also indicated treatment groups with genistein could significantly inhibit the growth of xenografts. Further functional assays revealed that the levels of miR-27a and its target gene ZBTB10 were significantly different based on the dose of genistein. In conclusion, the present study demonstrates that genistein exerts growth inhibitory activities in human uveal melanoma cells. Moreover, we for the first time report a correlation between antitumor activity of genistein and miR-27a mediated regulatory mechanism.

A social health insurance (SHI) program has been established in China to ensure that people can obtain health care economically and equitably. Our analysis indicates that in 2005–06, 66.5 percent of Chinese citizens were non-SHI inpatients. We also found that drug spending for SHI inpatients was significantly higher than that for non-SHI inpatients. After adjusting for other variables, we found that the SHI coverage was also associated positively with higher drug costs. We present evidence to show that drug spending differences are attributable at least in part to differences in insurance courage.

Purpose: It has been shown that the expression of the receptor for advanced glycation end products (RAGE) is closely associated with invasion and metastasis in gastric cancer. A Gly82Ser polymorphism in exon 3 of RAGE gene was identified and thought to have an effect on the functions of its protein. Therefore, the goal of the present study was to investigate whether the polymorphism is involved in the development or progression of gastric cancer. Experimental Design: In the hospital-based case-control study, the RAGE genotypes were determined using PCR-RFLP in 566 individuals (283 gastric cancer patients and 283 age- and sex-matched controls). Results: The distribution of genotype was significantly different between cases and controls (P = 0.038). Compared with the wild-type 82Gly/Gly carriers, subjects with the variant genotypes (82Gly/Ser and 82Ser/Ser) had a significantly higher risk of gastric cancer (adjusted odds ratio, 1.47; 95% confidence interval, 1.05-2.06). Moreover, the elevated gastric cancer risk was especially evident in younger individuals (ages ≤58 years), nonsmokers, and rural subjects. Further analyses revealed that the variant genotypes were associated with adjacent organ invasion in the subanalysis of gastric cancer patients. Conclusions: Our findings indicate that the RAGE Gly82Ser polymorphism may confer not only an increased risk of gastric cancer but also with invasion of gastric cancer in the Chinese population.

Glutathione peroxidase 1 (GPX1), the key antioxidant enzyme in vascular endothelial cells, has been shown to exert a protective effect against the presence of coronary artery disease (CAD). The 198Pro/leu variant, located at codon 198 of GPX1 gene, has recently been linked to cardiovascular disease, but data were inconsistent. We investigated the association between the occurrence of CAD and the 198Pro/leu variant in a Chinese population.A total of 265 unrelated CAD patients and 265 age- and sex-matched control subjects were recruited in this study. The GPX1 198Pro/leu genotype was determined using polymerase chain reaction-restriction fragment length polymorphism.Compared to the 198Pro/Pro carriers, subjects with the variant genotypes (198Pro/leu and 198Leu/leu) had a significantly higher risk of CAD (adjusted OR=2.02, 95%CI=1.27-3.22). In stratified analyses, the variant genotypes were significantly associated with increased CAD risk in subjects64 y (adjusted OR=2.41, 95%CI=1.16-4.98), males (adjusted OR=1.86, 95%CI=1.09-3.18) and non-smokers (adjusted OR=2.40, 95%CI=1.15-5.01). However, no significant association was observed between this variant and the severity of CAD.These data provide evidence that GPX1 198Pro/leu variant genotypes are significantly associated with CAD risk in this Chinese population.

Objective Epidemiologic findings are inconsistent concerning the association of endometrial cancer risk with cigarette smoking. We conducted a meta-analysis of epidemiologic studies to examine this relation. Methods A systematic literature search up to June of 2007 was performed in MEDLINE and EMBASE. Study-specific risk estimates were pooled using a random-effects model. Results Ten prospective and 24 case-control studies were included in the analysis of the effect of ever smoking. Ever smoking was statistically significantly associated with a reduced risk of endometrial cancer among prospective studies (relative risk 0.81; 95% confidence interval [CI], 0.74-0.88) and case-control studies (odds ratio 0.72; 95% CI, 0.66-0.79). The inverse association was significant among current and former smokers. Six prospective and 6 case-control studies were included in the quantitative analysis. We noted that an increase in smoking of 20 cigarettes per day was statistically significantly associated with 16% and 27% reduced risks of endometrial cancer in prospective and case-control studies, respectively. We also found that cigarette smoking was significantly associated with a decreased risk of endometrial cancer among postmenopausal women (relative risk 0.71; 95% CI, 0.65-0.78) but not among premenopausal women. In addition, the risk reduction seemed to be stronger among hormone replacement therapy users than nonusers. Conclusion Cigarette smoking was found to be significantly associated with a reduced risk of endometrial cancer, especially among postmenopausal women.

Resistin, a novel adipocyte-derived peptide, has been linked to inflammatory process and coronary artery disease (CAD). The -420CG polymorphism located in the resistin gene (RETN) promoter has recently been suggested to play a potential role in proinflammatory conditions (e.g., atherogenesis). However, whether this polymorphism has any effect on the inflammatory process in patients with stable CAD is unclear.The RETN -420CG polymorphism was determined by using PCR-restriction fragment length polymorphism. Plasma lipid profiles, glucose and high-sensitivity C-reactive protein (hs-CRP) were measured in fasting state.Patients with variant genotypes (CG+GG) had significantly higher levels of hs-CRP than CC carriers (adjusted p0.001). In addition, the variant genotypes were observed to be independently associated with higher hs-CRP levels (3 mg/L, p=0.004). However, no association was found between this polymorphism and plasma lipids or glucose levels.Our data suggest that the RETN -420C-to-G variant is associated with increased CRP levels in patients with stable CAD, suggesting that the RETN -420CG polymorphism may be potentially involved in the inflammatory component of atherogenesis through an enhanced production of CRP.

Summary Objective Resistin, a novel adipocyte-derived peptide, has been linked to the pathogenesis of atherosclerosis. Recently, –420C>G, a variant located in the promoter region of the resistin gene (RETN) was identified. The aim of this study was to investigate the association between this RETN–420C>G polymorphism and the risk of coronary artery disease (CAD). Design A hospital-based case–control study. Patients A total of 225 CAD patients and 225 age- and sex-matched control subjects. Measurements Genotyping was performed by polymerase chain reaction (PCR) and restriction enzyme analysis to detect the presence of the RETN–420C>G polymorphism. Results The frequencies of RETN–420C>G genotypes in the CAD group were significantly different from those in the control group (P = 0·024). Subjects with the variant genotypes (CG and GG) had a 62% increased risk of CAD compared to CC carriers [adjusted odds ratio (OR) = 1·62, 95% confidence interval (CI) = 1·09–2·41, P = 0·016]. However, there were no significant differences between the genotypes with respect to weight, body mass index (BMI) and lipid profiles in CAD patients, and no significant association was found between the RETN–420C>G polymorphism and the severity of CAD. Conclusions Our data suggest that the RETN–420C>G polymorphism might be associated with an increased risk of CAD in a Chinese population.

Objectives Epidemiologic findings are inconsistent concerning the risk for ovarian cancer associated with hormone replacement therapy (HRT). We conducted a meta-analysis to summarize the available evidence from observational studies to examine this relation. Methods We searched PUBMED and MEDLINE for relevant studies that were published from January 1, 1966, through May 1, 2007. Study-specific risk estimates were pooled by the use of a random-effects model. Results Eight cohort (including 4715 cases and 1,555,374 participants) and 19 case–control studies (involving 8240 cases and 20,996 controls) were included. We found a summary relative risk (RR) of 1.24 (95% confidence interval [CI] 1.15–1.34) from cohort studies and a summary odds ratio [OR] of 1.19 (95%CI 1.02–1.40) from case–control studies for ever HRT use. However, the risk estimates of case–control studies might be upwardly biased. Summary risk estimates of four cohort and six case–control studies that distinguished estrogen replacement treatment (ERT) and estrogen–progestin replacement treatment (EPRT) from HRT both indicated that association was stronger among ERT user than EPRT user. Based on data abstracted from six case–control studies, duration of HRT use was not significant. The summary risk estimates for less than 5 years, 6–10, and more than 10 years use were 1.02, 1.13, and 1.21, respectively and 95%CI for each estimate crossed 1.0. Conclusion HRT use was associated with increased risk of ovarian cancer. These findings may expand the range of possible risks associated with HRT use. However, this positive association should also be considered in the context of HRT's other favorable effects on health.

Background Vasculogenic mimicry (VM) was increasingly recognized as a form of aggressive melanoma acquiring blood supply. Genistein had attracted much attention as a potential anticancer agent. Therefore, we examined the effect of Genistein on VM in human uveal melanoma cells. Methods VM structure was detected by periodic acid-Schiff (PAS) staining for uveal melanoma C918 cells cultured on the three-dimensional type I collagen gels after exposed to Genistein. We used reverse transcription polymerase chain reaction (RT-PCR) and Western Blot analysis to examine the effect of Genistein on vascular endothelial cadherin (VE-cadherin) mRNA and protein expression. The nude mice models of human uveal melanoma C918 cells were established to assess the number of VM using immunohistochemical and PAS double-staining. Results Genistein inhibited the survival of C918 cells in vitro. The ectopic model study showed that VM in tumor tissue sections were significantly reduced by Genistein in vivo. In vitro, the VM structure was found in control, 25 and 50 μM Genistein-treatment groups but not in 100 and 200 μM. RT-PCR and Western Blot showed that 100 and 200 μM concentration of Genistein could significantly decrease VE-cadherin mRNA and protein expression of C918 cells compared with control (P < 0.05). However, the 25 and 50 μM Genistein slightly decreased the VE-cadherin level in vitro (P > 0.05). Conclusion Genistein inhibits VM formation of uveal melanoma cells in vivo and in vitro. One possible underlying molecular mechanism by which Genistein could inhibit VM formation of uveal melanoma is related to down-regulation of VE-cadherin.