Jing Yu

Glucocorticoids transcriptionally regulate miR-27b expression promoting body fat accumulation via suppressing the browning of white adipose tissue

Long-term glucocorticoid (GC) treatment induces central fat accumulation and metabolic dysfunction. We demonstrate that microRNA-27b (miR-27b) plays a central role in the pathogenesis of GC-induced central fat accumulation. Overexpression of miR-27b had the same effects as dexamethasone (DEX) treatment on the inhibition of brown adipose differentiation and the energy expenditure of primary adipocytes. Conversely, antagonizing miR-27b function prevented DEX suppression of the expression of brown adipose tissue–specific genes. GCs transcriptionally regulate miR-27b expression through a GC receptor–mediated direct DNA-binding mechanism, and miR-27b suppresses browning of white adipose tissue (WAT) by targeting the three prime untranslated region of Prdm16. In vivo, antagonizing miR-27b function in DEX-treated mice resulted in the efficient induction of brown adipocytes within WAT and improved GC-induced central fat accumulation. Collectively, these results indicate that miR-27b functions as a central target of GC and as an upstream regulator of Prdm16 to control browning of WAT and, consequently, may represent a potential target in preventing obesity.

In Vivo MR Imaging of Intraarterially Delivered Magnetically Labeled Mesenchymal Stem Cells in a Canine Stroke Model

Background This study aimed to evaluate the feasibility of intraarterial (IA) delivery and in vivo MR imaging of superparamagnetic iron oxide (SPIO)-labeled mesenchymal stem cells (MSCs) in a canine stroke model. Methodology MSCs harvested from beagles’ bone marrow were labeled with home-synthesized SPIO. Adult beagle dogs (n = 12) were subjected to left proximal middle cerebral artery (MCA) occlusion by autologous thrombus, followed by two-hour left internal carotid artery (ICA) occlusion with 5 French vertebral catheter. One week later, dogs were classified as three groups before transplantation: group A: complete MCA recanalization, group B: incomplete MCA recanalization, group C: no MCA recanalization. 3×106 labeled-MSCs were delivered through left ICA. Series in vivo MRI images were obtained before cell grafting, one and 24 hours after transplantation and weekly thereafter until four weeks. MRI findings were compared with histological studies at the time point of 24 hours and four weeks. Principal Findings Home-synthesized SPIO was useful to label MSCs without cell viability compromise. MSCs scattered widely in the left cerebral hemisphere in group A, while fewer grafted cells were observed in group B and no cell was detected in group C at one hour after transplantation. A larger infarction on the day of cell transplantation was associated with more grafted cells in the brain. Grafted MSCs could be tracked effectively by MRI within four weeks and were found in peri-infarction area by Prussian blue staining. Conclusion It is feasible of IA MSCs transplantation in a canine stroke model. Both the ipsilateral MCA condition and infarction volume before transplantation may affect the amount of grafted cells in target brain. In vivo MR imaging is useful for tracking IA delivered MSCs after SPIO labeling.

BVT.2733, a selective 11β-hydroxysteroid dehydrogenase type 1 inhibitor, attenuates obesity and inflammation in diet-induced obese mice.

Background Inhibition of 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) is being pursued as a new therapeutic approach for the treatment of obesity and metabolic syndrome. Therefore, there is an urgent need to determine the effect of 11β-HSD1 inhibitor, which suppresses glucocorticoid action, on adipose tissue inflammation. The purpose of the present study was to examine the effect of BVT.2733, a selective 11β-HSD1 inhibitor, on expression of pro-inflammatory mediators and macrophage infiltration in adipose tissue in C57BL/6J mice. Methodology/Principal Findings C57BL/6J mice were fed with a normal chow diet (NC) or high fat diet (HFD). HFD treated mice were then administrated with BVT.2733 (HFD+BVT) or vehicle (HFD) for four weeks. Mice receiving BVT.2733 treatment exhibited decreased body weight and enhanced glucose tolerance and insulin sensitivity compared to control mice. BVT.2733 also down-regulated the expression of inflammation-related genes including monocyte chemoattractant protein 1 (MCP-1), tumor necrosis factor alpha (TNF-α) and the number of infiltrated macrophages within the adipose tissue in vivo. Pharmacological inhibition of 11β-HSD1 and RNA interference against 11β-HSD1 reduced the mRNA levels of MCP-1 and interleukin-6 (IL-6) in cultured J774A.1 macrophages and 3T3-L1 preadipocyte in vitro. Conclusions/Significance These results suggest that BVT.2733 treatment could not only decrease body weight and improve metabolic homeostasis, but also suppress the inflammation of adipose tissue in diet-induced obese mice. 11β-HSD1 may be a very promising therapeutic target for obesity and associated disease.

Identification of differentially expressed microRNAs in Culex pipiens and their potential roles in pyrethroid resistance

Pyrethroids are the major class of insecticides used for mosquito control. Excessive and improper use of insecticides, however, has resulted in pyrethroid resistance, which has become a major obstacle for mosquito control. The development of pyrethroid resistance is a complex process involving many genes, and information on post-transcription regulation of pyrethroid resistance is lacking. In this study, we extracted RNA from mosquitoes in various life stages (fourth-instar larvae, pupae, male and female adult mosquitoes) from deltamethrin-sensitive (DS) and resistant (DR) strains. Using illumina sequencing, we obtained 13760296 and 12355472 reads for DS-strains and DR-strains, respectively. We identified 100 conserved miRNAs and 42 novel miRNAs derived from 21 miRNA precursors in Culex pipiens. After normalization, we identified 28 differentially expressed miRNAs between the two strains. Additionally, we found that cpp-miR-71 was significant down regulated in female adults from the DR-strain. Based on microinjection and CDC Bottle Bioassay data, we found that cpp-miR-71 may play a contributing role in deltamethrin resistance. The present study provides the firstly large-scale characterization of miRNAs in Cu. pipiens and provides evidence of post-transcription regulation. The differentially expressed miRNAs between the two strains are expected to contribute to the development of pyrethroid resistance.

Expression Profiling of PPARγ-Regulated MicroRNAs in Human Subcutaneous and Visceral Adipogenesis in both Genders

Clinical evidence shows that visceral fat accumulation decreases whereas sc fat increases in patients treated with thiazolidinediones (TZDs), a type of peroxisome proliferator-activated receptor (PPAR)γ agonist. To clarify the molecular mechanism of the differential effects of PPARγ agonists on sc and visceral adipose, we investigated expression profiling of PPARγ-regulated micro-RNAs (miRNAs) using miRNA microarray. The level of 182 miRNAs changed in human sc adipose treated with pioglitazone, whereas only 46 miRNAs changed in visceral adipose. Among these miRNAs, 27 miRNAs changed in both human sc and visceral adipocytes. Specifically, 7 miRNAs changed at the same direction in sc and visceral adipocytes, whereas 20 miRNAs changed at opposite directions in these two fat depots. Bioinformatics analysis showed that these miRNAs and the predicted target genes were involved in TGF-β-, Wnt/β-catenin-, and insulin-signaling pathways and related to metabolic regulation or cell cycle. Among the miRNAs changed at the same direction in sc and visceral adipocytes, miR-378, located in the first intron of PPARγ coactivator 1β (PGC1β), was coordinately expressed with PGC1β during adipogenesis. Moreover, miR-378 and PGC1β were both up-regulated by PPARγ agonist. We also provided evidence that miR-378 promoted adipogenesis in sc fat, but not in visceral fat. These results display miRNAs expression profiling altered in sc and visceral adipogenesis regulated by PPARγ and suggest a potential mechanism underlying the differential effects of TZDs on the 2 fat depot accumulations.

Utility of dynamic contrast-enhanced magnetic resonance imaging for differentiating glioblastoma, primary central nervous system lymphoma and brain metastatic tumor.

PURPOSE The study aimed to investigate the use of dynamic contrast-enhanced magnetic resonance imaging (MRI)-derived permeability parameters for the differentiation of glioblastoma multiformes (GBMs), primary central nervous system lymphomas (PCNSLs), and brain metastatic tumors (MTs). MATERIALS AND METHODS Seventy-five patients with histopathologically confirmed GBMs (n=38), PCNSLs (n=16) and MTs (n=21) underwent dynamic contrast-enhanced MRIs before surgery. The volume transfer constant K(trans), the flux rate constant between extravascular extracellular space and plasma Kep, the extravascular extracellular volume Ve and the fractional plasma volume Vp were measured within the entire contrast-enhancing tumor by extended Tofts model. A one-way analysis of variance was used to compare all of the parameters among these three tumors, followed by the post-hoc test. Receiver operating characteristic curves were constructed to evaluate the diagnostic performance of the permeability parameters. RESULTS Mean K(trans) value and Ve value were significantly higher in PCNSLs than in GBMs (P<0.001 and P=0.011) and MTs (P<0.001 and P<0.001). No significant difference was observed in all of the permeability parameters between GBMs and MTs. According to the receiver operating characteristic analyses, both K(trans) and Ve had good diagnostic performance for discriminating between PCNSLs and GBMs (the area under the curve: 0.847 and 0.785, respectively), as well as between PCNSLs and MTs (the area under the curve: 0.851 and 0.884, respectively). CONCLUSIONS The K(trans) and Ve derived from dynamic contrast-enhanced MRI facilitate the differentiation of PCNSLs from GBMs and MTs.

Mammary Fat of Breast Cancer: Gene Expression Profiling and Functional Characterization

Mammary fat is the main composition of breast, and is the most probable candidate to affect tumor behavior because the fat produces hormones, growth factors and adipokines, a heterogeneous group of signaling molecules. Gene expression profiling and functional characterization of mammary fat in Chinese women has not been reported. Thus, we collected the mammary fat tissues adjacent to breast tumors from 60 subjects, among which 30 subjects had breast cancer and 30 had benign lesions. We isolated and cultured the stromal vascular cell fraction from mammary fat. The expression of genes related to adipose function (including adipogenesis and secretion) was detected at both the tissue and the cellular level. We also studied mammary fat browning. The results indicated that fat tissue close to malignant and benign lesions exhibited distinctive gene expression profiles and functional characteristics. Although the mammary fat of breast tumors atrophied, it secreted tumor growth stimulatory factors. Browning of mammary fat was observed and browning activity of fat close to malignant breast tumors was greater than that close to benign lesions. Understanding the diversity between these two fat depots may possibly help us improve our understanding of breast cancer pathogenesis and find the key to unlock new anticancer therapies.

Use of FLAIR Imaging to Identify Onset Time of Cerebral Ischemia in a Canine Model

After an infarction-inducing procedure, 20 dogs were imaged at 3, 4, 5, 6, and 24 hours with FLAIR and DWI. A mismatch between the 2 sequences (positive DWI and negative FLAIR) was found to reliably predict the time of infarct onset. By 6 hours, 95% of dogs had FLAIR abnormalities and by 24 hours all did. However, at 3 hours only 15% of dogs showed positive FLAIR studies. These results could serve as guidelines to estimate the time of onset of ischemic events. BACKGROUND AND PURPOSE: Stroke is a leading cause of death and disability, and many studies have focused on the evolution of FLAIR imaging in the acute and chronic time window. The purpose of this study was to evaluate the potential efficacy of FLAIR-related techniques in identifying the onset time of cerebral ischemia in a canine embolic stroke model. MATERIALS AND METHODS: An embolic ischemic model was generated through the use of an autologous clot in 20 beagle dogs. Both FLAIR and DWI were performed at 3 hours, 4 hours, 5 hours, 6 hours, and 24 hours after embolization, respectively. Visual “DWI-FLAIR mismatch” was defined as hyperintense signal detected on DWI but not on FLAIR. The relative signal intensity of FLAIR-positive lesions and the degree of DWI-FLAIR mismatch was calculated as relative FLAIR = relative signal intensity of FLAIR positive lesions, mismatch degree = (100−VFLAIR/VDWI) × 100%. RESULTS: The ischemic model was successfully established in all animals. FLAIR-positive lesions were seen in 3, 11, 16, 19, and 20 beagle dogs at 5 time points after embolization, respectively. There was significant correlation between the relative FLAIR, degree of DWI-FLAIR mismatch, and the onset time (relative FLAIR: r = +0.42; 95% CI, 0.20–0.60; mismatch degree: r = −0.85; 95% CI, 0.89–0.78). Receiver operating characteristic curves showed that the degree of DWI-FLAIR mismatch could identify the hyperacute ischemic lesions with a sensitivity range from 1.00–0.76; visual DWI-FLAIR mismatch sensitivity ranged from 0.85–0.39, whereas specificity was 0.83–0.95 versus 0.85–1.00. CONCLUSIONS: The relative FLAIR and DWI-FLAIR mismatch values were useful in predicting the onset time in our canine embolic stroke model. The degree of DWI-FLAIR mismatch proposed in our study could be a good indicator with high sensitivity for identifying the hyperacute ischemic stroke.

Development of Resistance to Pyrethroid in Culex pipiens pallens Population under Different Insecticide Selection Pressures

Current vector control programs are largely dependent on pyrethroids, which are the most commonly used and only insecticides recommended by the World Health Organization for insecticide-treated nets (ITNs). However, the rapid spread of pyrethroid resistance worldwide compromises the effectiveness of control programs and threatens public health. Since few new insecticide classes for vector control are anticipated, limiting the development of resistance is crucial for prolonging efficacy of pyrethroids. In this study, we exposed a field-collected population of Culex pipiens pallens to different insecticide selection intensities to dynamically monitor the development of resistance. Moreover, we detected kdr mutations and three detoxification enzyme activities in order to explore the evolutionary mechanism of pyrethroid resistance. Our results revealed that the level of pyrethroid resistance was proportional to the insecticide selection pressure. The kdr and metabolic resistance both contributed to pyrethroid resistance in the Cx. pipiens pallens populations, but they had different roles under different selection pressures. We have provided important evidence for better understanding of the development and mechanisms of pyrethroid resistance which may guide future insecticide use and vector management in order to avoid or delay resistance.

Correlation of standard diffusion-weighted imaging and diffusion kurtosis imaging with distant metastases of rectal carcinoma.

To investigate the correlation of standard diffusion‐weighted imaging (DWI) and diffusion kurtosis imaging (DKI) with distant metastases of rectal carcinoma.