A hypoxia-regulated HO-1 vector modification of MSCs enhances the tolerance of engrafted MSCs to hypoxia-reoxygen injury in vitro and improves their viability in ischemic hearts. This demonstration is the first showing that a physiologically inducible vector expressing of HO-1 genes improves the survival of stem cells in myocardial ischemia.

Fibroplast growth factor (FGF-21) is a recently discovered metabolic regulator. Its pathophysiologic role in humans remains unknown. In this study, we have investigated whether or not plasma FGF-21 level was different in patients with type 2 diabetes mellitus (T2DM) and non-diabetic controls. We also assessed associations between plasma FGF-21 body composition and several metabolic parameters. Fasting FGF-21 levels were significantly increased in patients with T2DM compared with controls (1.82+/-0.65 VS. 1.53+/-0.60 microg/L, P<0.05). In T2DM patients, fasting plasma FGF-21 correlate negatively with fasting blood glucose ( R= -0.31, P<0.05). Multiple regression analysis showed that FBG, plasma insulin and HOMA (IS) were independent influencing plasma FGF-21 levels. The present work suggests a potential role for FGF-21 in the pathogenesis of insulin resistance and T2DM.

These findings reveal a pivotal role for miR-150 as a regulator of cardiomyocyte survival during cardiac injury.

Rationale: The mobilization of bone marrow (BM) progenitor cells (PCs) is largely governed by interactionsbetween stromal cell-derived factor (SDF)-1 and CXC chemokine receptor (CXCR)4. Ischemic injury disrupts the SDF-1-CXCR4 interaction and releases BM PCs into the peripheral circulation, where the mobilized cells are recruited to the injured tissue and contribute to vessel growth. BM PCs can also be mobilized by the pharmacological CXCR4 antagonist AMD3100, but the other components of the SDF-1-CXCR4 signaling pathway are largely unknown. c-kit, a membrane-bound tyrosine kinase and the receptor for stem cell factor, has also been shown to play a critical role in BM PC mobilization and ischemic tissue repair.Objective: To investigate the functional interaction between SDF-1-CXCR4 signaling and c-kit activity in BM PC mobilization. Key Words: CXCR4 Ⅲ c-kit Ⅲ stem cells Ⅲ bone marrow Ⅲ mobilization T he mobilization or release of progenitor cells (PCs) from the bone marrow (BM) to the peripheral blood (PB) is highly regulated and occurs both under normal conditions and in response to stress. 1,2 PB PCs have an essential role in blood cell formation and homeostasis 3 and in the response of various tissues to noxious insults. Thus, therapies that enhance PC mobilization are being investigated as novel strategies for promoting tissue repair. 4,5 Ample evidence suggests that PCs are retained in the BM by interactions between the CXC chemokine stromal cell-derived factor (SDF)-1 and CXC chemokine receptor (CXCR)4. 6 -10 CXCR4 is expressed by BM mononuclear cells (MNCs), and SDF-1 is expressed by osteoblasts, endothelial cells, and a subset of reticular cells scattered throughout the BM. 7 Ischemic injury disrupts the SDF-1-CXCR4 interaction and releases BM PCs into the peripheral circulation; then, the mobilized cells are recruited to Original received March 25, 2010; revision received August 25, 2010; accepted August 27, 2010. In August 2010, the average time from submission to first decision for all original research papers submitted to Circulation Research was 13.2 days. Methods and ResultsFrom the injured tissue and contribute to vessel growth. 11,12 BM PCs can also be mobilized by the pharmacological CXCR4 antagonist AMD3100, 13-15 but the downstream components of the SDF-1-CXCR4 signaling pathway are largely unknown. Like CXCR4, c-kit is expressed predominantly in BM PCs, and the ligand for c-kit, stem cell factor (SCF), is constitutively produced by BM endothelial cells and fibroblasts. 16 c-kit is a class III receptor tyrosine kinase, and administration of a c-kit-neutralizing antibody (ACK2) to wild-type (WT) mice released BM cells to the peripheral circulation and enhanced the engraftment of intravenously injected BM cells. 17 On the other hand, PC mobilization is markedly blunted in c-kit W/W-V mutant mice, which are defective in c-kit kinase activity but have normal levels of c-kit expression and SCF binding at the cell surface. 18 -21 Furthermore, the kinetics of BM PC mobilization induced by the c-kit...

Abstract-Although human heme oxygenase-1 (hHO-1) could provide a useful approach for cellular protection in the ischemic heart, constitutive overexpression of hHO-1 may lead to unwanted side effects. To avoid this, we designed a hypoxia-regulated hHO-1 gene therapy system that can be switched on and off. This vigilant plasmid system is composed of myosin light chain-2v promoter and a gene switch that is based on an oxygen-dependent degradation domain from the hypoxia inducible factor-1-␣. The vector can sense ischemia and switch on the hHO-1 gene system, specifically in the heart. In an in vivo experiment, the vigilant hHO-1 plasmid or saline was injected intramyocardially into myocardial infarction mice or sham operation mice. After gene transfer, expression of hHO-1 was only detected in the ischemic heart treated with vigilant hHO-1 plasmids. Masson trichrome staining showed significantly fewer fibrotic areas in vigilant hHO-1 plasmids-treated mice compared with saline control (43.0%Ϯ4.8% versus 62.5%Ϯ3.3%, PϽ0.01). The reduction of interstitial fibrosis is accompanied by an increase in myocardial hHO-1 expression in peri-infarct border areas, concomitant with higher Bcl-2 levels and lower Bax, Bak, and caspase 3 levels in the ischemic myocardium compared with saline control. By use of a cardiac catheter, heart from vigilant hHO-1 plasmids-treated mice showed improved recovery of contractile and diastolic performance after myocardial infarction compared with saline control. This study documents the beneficial regulation and therapeutic potential of vigilant plasmid-mediated hHO-1 gene transfer. This novel gene transfer strategy can provide cardiac-specific protection from future repeated bouts of ischemic injury.

miRNAs play critical role in the development and progression of prostate cancer. Here we studied the role of miR-618 in prostate cancer migration and invasion. miR-618 was downregulated in metastatic androgen-independent prostate cancer (AIPC), patients with low miR-618 had poor outcome. Overexpression of miR-618 inhibited migration and invasion and induced mesenchymal to epithelial transition (MET). Conversely, knockdown of miR-618 promoted migration and invasion and induced epithelial to mesenchymal transition (EMT). FOXP2 was the direct target of miR-618, and promoted TGF-β expression, inhibition of TGF-β reversed the effect of miR-618 knockdown. We further analyzed the correlation between miR-618 expression and FOXP2 in human prostate cancer tissues, and found there was a negative correlation between miR-618 expression and FOXP2 levels. In conclusion, we found miR-618 inhibited prostate cancer migration and invasion by targeting FOXP2 and inhibiting TGF-β.

Background: Nonalcoholic fatty liver disease (NAFLD) has become prevalent in recent decades, especially in developed countries, and approaches for the prevention and treatment of NAFLD are not clear. The aim of this research was to analyze and summarize randomized controlled trials that investigated the effects of probiotics on NAFLD. Methods: Seven databases (PubMed, Embase, the Web of Science, the Cochrane Library, China National Knowledge Infrastructure, Wan Fang Data, and VIP Database) were searched. Then, eligible studies were identified. Finally, proper data extraction, synthesis and analysis were performed by trained researchers. Results: Anthropometric parameters: with use of probiotics weight was reduced by 2.31 kg, and body mass index (BMI) was reduced by 1.08 kg/m2. Liver function: probiotic treatment reduced the alanine aminotransferase level by 7.22 U/l, the aspartate aminotransferase level by 7.22 U/l, the alkaline phosphatase level by 25.87 U/l, and the glutamyl transpeptidase level by −5.76 U/l. Lipid profiles: total cholesterol, low-density lipoprotein cholesterol, and triglycerides were significantly decreased after probiotic treatment. Their overall effects (shown as standard mean difference) were −0.73, −0.54, and −0.36, respectively. Plasma glucose: probiotics reduced the plasma glucose level by 4.45 mg/dl and the insulin level by 0.63. Cytokines: probiotic treatment decreased tumor necrosis factor alpha by 0.62 and leptin by 1.14. Degree of liver fat infiltration (DFI): the related risk of probiotics for restoring DFI was 2.47 (95% confidence interval, 1.61–3.81, p < 0.001). Conclusion: Probiotic treatment or supplementation is a promising therapeutic method for NAFLD.

Preeclampsia leads to adverse outcomes for pregnant women. Bisphenol A (BPA) is an environmental endocrine disruptor and has been shown to be positively associated with increased risk of preeclampsia in human studies. We investigated whether BPA exposure causes preeclampsia‐like features in pregnant mice and the associated underlying mechanisms. Experiments were performed in animal models and cell cultures. In pregnant mice, BPA‐exposed mice exhibited preeclampsia‐like features including hypertension, disruption of the circulation, and the placental angiogenesis biomarkers fms‐related tyrosine kinase 1 and placenta growth factor, and glomerular atrophy; urinary protein was not affected. These preeclampsia‐like features correlated with increased retention of smooth muscle cells and reduced vessel areas at the junctional zone of the placenta. In addition, there were disrupted expression of invasion‐related genes including increased tissue inhibitors of metalloproteinases, decreased metalloproteinases, and Wnt family member WJVT2/β‐catenin, which correlated with increased DNA methylation in its promoter region and upregulation of DNA methyltransferase (Dnmt)l. BPA exposure impeded the interaction between the human cytotrophoblast cell line, HTR‐8/SVneo, and endothelium cells. BPA exposure down‐regulated WNT2 expression, and elevated the DNA methylation of WNT2; these results were consistent with in vivo observations. Inhibition of DNMT in HTR‐8/SVneo cells resulted in reduced DNA methylation and increased expression of WNT2. Taken together, these data demonstrate that BPA exposure alters trophoblast cell invasion and causes abnormal placental vessel remodeling, both of which lead to the development of preeclampsia‐like features in pregnant mice. Our results suggest that this phenomenon involves the epigenetic reprogramming and down‐regulation of WNT2 mediated by DNMT1.—Ye, Y., Tang, Y., Xiong, Y., Feng, L., Li, X. Bisphenol A exposure alters placentation and causes preeclampsia‐like features in pregnant mice involved in reprogramming of DNA methylation of WNT2. FASEB J. 33,2732–2742 (2019). http://www.fasebj.org