Lifeng Zhang

BACKGROUND: Inflammatory mediators that originate in vascular and extravascular tissues promote coronary lesion formation. Adipose tissue may function as an endocrine organ that contributes to an inflammatory burden in patients at risk of cardiovascular complications. In this study, we sought to compare expression of inflammatory mediators in epicardial and subcutaneous adipose stores in patients with critical CAD. METHODS AND RESULTS: Paired samples of epicardial and subcutaneous adipose tissues were harvested at the outset of elective CABG surgery (n=42; age 65+/-10 years). Local expression of chemokine (monocyte chemotactic protein [MCP]-1) and inflammatory cytokines (interleukin [IL]-1beta, IL-6, and tumor necrosis factor [TNF]-alpha) was analyzed by TaqMan real-time reverse transcription-polymerase chain reaction (mRNA) and by ELISA (protein release over 3 hours). Significantly higher levels of IL-1beta, IL-6, MCP-1, and TNF-alpha mRNA and protein were observed in epicardial adipose stores. Proinflammatory properties of epicardial adipose tissue were noted irrespective of clinical variables (diabetes, body mass index, and chronic use of statins or ACE inhibitors/angiotensin II receptor blockers) or plasma concentrations of circulating biomarkers. In a subset of samples (n=11), global gene expression was explored by DNA microarray hybridization and confirmed the presence of a broad inflammatory reaction in epicardial adipose tissue in patients with coronary artery disease. The above findings were paralleled by the presence of inflammatory cell infiltrates in epicardial adipose stores. CONCLUSIONS: Epicardial adipose tissue is a source of several inflammatory mediators in high-risk cardiac patients. Plasma inflammatory biomarkers may not adequately reflect local tissue inflammation. Current therapies do not appear to eliminate local inflammatory signals in epicardial adipose tissue.

The obesity epidemic has expanded globally, due in large part to the increased consumption of high-fat diets (HFD), and has increased the risk of major chronic diseases, including type 2 diabetes. Diet manipulation is the foundation of prevention and treatment of obesity and diabetes. The molecular mechanisms that mediate the diet-based prevention of insulin resistance, however, remain to be identified. Here, we report that treatment with orally administered ginger-derived nanoparticles (GDNP) prevents insulin resistance by restoring homeostasis in gut epithelial Foxa2 mediated signaling in mice fed a high-fat diet (HFD). Methods: Ginger-derived nanoparticles (GDNP) were added into drinking water to treat high-fat diet fed mice for at least one year or throughout their life span. A micro array profile of intestinal, liver and fat tissue of GDNP treated mice was used to analyze their gene expression profile. Genes associated with metabolism or insulin signaling were further quantified using the real time polymerase chain reaction (RT-PCR). Surface plasmon resonance (SPR) was used for determining the interaction between Foxa2 protein and phosphatic acid lipid nanoparticles. Results: HFD-feeding inhibited the expression of Foxa2; the GDNPs increased the expression of Foxa2 and protected Foxa2 against Akt-1 mediated phosphorylation and subsequent inactivation of Foxa2. Increasing expression of Foxa2 leads to altering the composition of intestinal epithelial cell (IEC) exosomes of mice fed a HFD and prevents IEC exosome mediated insulin resistance. Collectively, oral administration of GDNP prevents insulin resistance in HFD mice. Interestingly, oral administration of GDNP also extended the life span of the mice and inhibited skin inflammation. Conclusion: Our findings showed that GDNP treatment can prevent HFD-induced obesity and insulin resistance via protecting the Foxa2 from Akt-1 mediated phosphorylation. GDNP treatment provides an alternative approach based on diet manipulation for the development of therapeutic interventions for obesity.

AIM: We investigated the expression of the inhibitory costimulatory molecules B7-H1, B7-H3, and B7-H4 in human pancreatic cancer to define their clinical significance and mechanism in a tumor microenvironment. PATIENTS AND METHODS: Sixty-three pancreatic cancer tissues and 12 normal pancreatic tissues were examined in our research. Patients were enrolled in the study between December 2000 and August 2010. Expression levels of the B7 family of molecules and densities of tumor-infiltrating lymphocytes in the tissues were characterized with immunohistochemical assays. RESULTS: More than 50% of the patients expressed B7-H1 and B7-H4, and nearly 100% of the patients expressed B7-H3. B7-H1 expression was correlated with tumor size, B7-H3 expression was correlated with lymph-node metastasis and differentiation grade, and B7-H4 expression was correlated with tumor size, lymph-node metastasis, and invasion depth. High B7-H4 expression was also correlated with poor survival in pancreatic cancer. We determined the value of these three B7 family molecules in the postoperative survival prognosis for patients with pancreatic cancer, and pancreatic cancer patients with less coexpression of the B7 family of molecules had a significantly higher survival rate. B7-H1 expression was found to be negatively related to the intensity of both CD3(+) T cells and CD8(+) T cells, and B7-H4 expression was negatively related to CD3(+) T-cell infiltration intensity, but not to CD8(+) T cells. CONCLUSION: B7-H1, B7-H3, and B7-H4 are involved in pancreatic cancer progression, and their coexpression could be a valuable prognostic indicator. Negative regulation of T-cell infiltration might be the main mechanism of action of the B7 family of molecules in pancreatic cancer.

Collectively our findings reveal that oral administration of GDNP to HFD mice improves host glucose tolerance and insulin response via regulating AhR expression by GDNP induced miR-375 and VAMP7.