Qiu B.,Agency for Science, Technology and Research Singapore |
Shi X.,Agency for Science, Technology and Research Singapore |
Wong E.,Agency for Science, Technology and Research Singapore |
Lim J.,Agency for Science, Technology and Research Singapore |
And 19 more authors.
Cell Reports | Year: 2014
Although much is known about the molecular players in insulin signaling, there is scant information about transcriptional regulation of its key components. We now find that NUCKS is a transcriptional regulator of the insulin signaling components, including the insulin receptor (IR). Knockdown of NUCKS leads to impaired insulin signaling in endocrine cells. NUCKS knockout mice exhibit decreased insulin signaling and increased body weight/fat mass along with impaired glucose tolerance and reduced insulin sensitivity, all of which are further exacerbated by a high-fat diet (HFD). Genome-wide ChIP-seq identifies metabolism and insulin signaling as NUCKS targets. Importantly, NUCKS is downregulated in individuals with a high body mass index and in HFD-fed mice, and conversely, its levels increase upon starvation. Altogether, NUCKS is a physiological regulator of energy homeostasis and glucose metabolism that works by regulating chromatin accessibility and RNA polymerase II recruitment to the promoters of IR and other insulin pathway modulators. © 2014 The Authors.
Dou H.,State Key Laboratory of Pharmaceutical Biotechnology |
Dou H.,Nanjing University |
Song Y.,State Key Laboratory of Pharmaceutical Biotechnology |
Liu X.,State Key Laboratory of Pharmaceutical Biotechnology |
And 7 more authors.
American Journal of Respiratory Cell and Molecular Biology | Year: 2014
We designed and synthesized a novel benzenediamine derivate, FC-99, that was tested for its ability to protect mice from experimental sepsis. Moreover, we sought to determine whether FC-99 could control a bacterial infection and to clarify the mechanism by which FC-99 inhibited LPS-activated macrophages. The effects of FC-99 on inflammation were evaluated in two experimental sepsismodels and in cultured macrophages. Microarrays and docking and molecular dynamics simulations were used to determine the target of FC-99. Surface plasmon resonance and molecular detectionwere performed to confirmthe direct interaction of FC-99 with its target. FC-99 protectedmice from experimental sepsis. The mice that received FC-99 exhibited a diminished inflammatory response, had a lower local bacterial burden, and experienced a significantly improved survival rate. Genome-wide transcriptional profiling of FC-99-treated macrophages identified IRAK4 as a drug-regulated gene involved in LPS/TLR4 signaling. A computer search and calculations indicated that IRAK4 directly interacted with FC-99. Surface plasmon resonance, IRAK4-regulated signaling pathway analysis, and gene expression profiling of proinflammatory mediators confirmed the direct interaction between FC-99 and IRAK4. FC-99 is a potential therapeutic molecule for sepsis that alleviated experimental sepsis by directly inhibiting IRAK4 activation, which represents a novel target for sepsis therapy. Copyright © 2014 by the American Thoracic Society.
PubMed | Agency for Science, Technology and Research Singapore, State Key Laboratory of Pharmaceutical Biotechnology, University of Hong Kong, National University of Singapore and Osaka University
Type: Journal Article | Journal: Cell reports | Year: 2014
Although much is known about the molecular players in insulin signaling, there is scant information about transcriptional regulation of its key components. We now find that NUCKS is a transcriptional regulator of the insulin signaling components, including the insulin receptor (IR). Knockdown of NUCKS leads to impaired insulin signaling in endocrine cells. NUCKS knockout mice exhibit decreased insulin signaling and increased body weight/fat mass along with impaired glucose tolerance and reduced insulin sensitivity, all of which are further exacerbated by a high-fat diet (HFD). Genome-wide ChIP-seq identifies metabolism and insulin signaling as NUCKS targets. Importantly, NUCKS is downregulated in individuals with a high body mass index and in HFD-fed mice, and conversely, its levels increase upon starvation. Altogether, NUCKS is a physiological regulator of energy homeostasis and glucose metabolism that works by regulating chromatin accessibility and RNA polymerase II recruitment to the promoters of IR and other insulin pathway modulators.
Wu G.,Shanghai JiaoTong University |
Li H.,Shanghai JiaoTong University |
Fang Q.,Shanghai JiaoTong University |
Jiang S.,Shanghai JiaoTong University |
And 8 more authors.
Arteriosclerosis, Thrombosis, and Vascular Biology | Year: 2014
Objective-Adipose tissue inflammation and perturbation of adipokine secretion may contribute to the pathogenesis of cardiovascular diseases (CVD). Lipocalin-2 (LCN2), mainly released from adipocytes, has been shown to be positively associated with CVD in cross-sectional studies. We aimed to evaluate the association of LCN2 with CVD involving a population-based cohort recruited from the Shanghai Diabetes Study.Approach and Results-Serum LCN2 levels were measured using ELISA. Independent predictors of CVD development were identified using Cox proportion hazards regression. The predictive performances of the various models were assessed by Kaplan-Meier analysis. At baseline, circulating LCN2 was significantly associated with a cluster of traditional cardiovascular risk factors. Baseline LCN2 levels in male subjects who developed CVD events during follow-up were significantly higher than those who did not develop CVD events (P=0.012). However, such difference was not significant in female subjects. LCN2 was a predictor of CVD in men, which remained statistically significant after adjustment for traditional cardiovascular risk factors (hazard ratio, 1.038 [95% confidence interval, 1.017-1.060]). LCN2 remained significantly associated with incident CVD even after adjustment for renal function, adiponectin, and high-sensitivity C-reactive protein levels. Kaplan-Meier analysis suggested combination of LCN2 and high-sensitivity C-reactive protein might improve the prediction of CVD events in male subjects.Conclusions-Elevated circulating LCN2 level is an independent predictor of CVD events in men in a population-based cohort and adds to the prognostic value of high-sensitivity C-reactive protein, which is currently the most extensively studied biomarker of CVD. Measurement of serum LCN2 might be useful for early detection and intervention of CVD. © 2014 American Heart Association, Inc.
Fang K.,Nanjing Southeast University |
Fang K.,State Key Laboratory of Pharmaceutical Biotechnology |
Yang F.,Nanjing Southeast University |
Zhang Q.,Nanjing Southeast University |
And 2 more authors.
Materials Letters | Year: 2014
A modified water-oil-water double emulsion solvent evaporation method was used to prepare cationic poly (lactic-co-glycolic acid) microspheres. Polyethyleneimine in external water phase was used to stabilize the microspheres and ammonium bicarbonate in internal aqueous phase was adopted to facilitate the formation of pores. It is found that the microspheres with or without pores could be manipulated by easily adjusting the polyethyleneimine concentration. In order to understand the drug delivery potential of the porous microspheres, the model macromolecule agent, fluorescein isothiocyanate-dextran was used. The results show that the porous microspheres obtained by emulsion processing have higher absorption capability compared with non-porous ones. Therefore, the as-obtained porous microspheres could be the suitable platforms for the delivery of bioactive agents. © 2013 Published by Elsevier B.V.
Hung V.K.L.,University of Hong Kong |
Yeung P.K.K.,University of Hong Kong |
Lai A.K.W.,University of Hong Kong |
Ho M.C.Y.,University of Hong Kong |
And 7 more authors.
Journal of Cerebral Blood Flow and Metabolism | Year: 2015
Endothelin-1 (ET-1) is synthesized by endothelial cells and astrocytes in stroke and in brains of Alzheimer's disease patients. Our transgenic mice with ET-1 overexpression in the endothelial cells (TET-1) showed more severe blood-brain barrier (BBB) breakdown, neuronal apoptosis, and glial reactivity after 2-hour transient middle cerebral artery occlusion (tMCAO) with 22-hour reperfusion and more severe cognitive deficits after 30 minutes tMCAO with 5 months reperfusion. However, the role of astrocytic ET-1 in contributing to poststroke cognitive deficits after tMCAO is largely unknown. Therefore, GET-1 mice were challenged with tMCAO to determine its effect on neurologic and cognitive deficit. The GET-1 mice transiently displayed a sensorimotor deficit after reperfusion that recovered shortly, then more severe deficit in spatial learning and memory was observed at 3 months after ischemia compared with that of the controls. Upregulation of TNF-α, cleaved caspase-3, and Thioflavin-S-positive aggregates was observed in the ipsilateral hemispheres of the GET-1 brains as early as 3 days after ischemia. In an in vitro study, ET-1 overexpressing astrocytic cells showed amyloid secretion after hypoxia/ischemia insult, which activated endothelin A (ETA) and endothelin B (ETB) receptors in a PI3K/AKT-dependent manner, suggesting role of astrocytic ET-1 in dementia associated with stroke by astrocyte-derived amyloid production. © 2015 ISCBFM.
Yin Y.,State Key Laboratory of Pharmaceutical Biotechnology |
Kou L.,State Key Laboratory of Pharmaceutical Biotechnology |
Wang J.-J.,State Key Laboratory of Pharmaceutical Biotechnology |
Xu G.-X.,Nanjing Medical University |
Xu G.-X.,Jiangsu Research Center
Experimental and Therapeutic Medicine | Year: 2012
Interleukin-2 (IL-2), as an important cytokine in immune response, has been demonstrated to have therapeutic activity in several cancer models. In our previous study, we showed that the pBV22210 vector containing a chloramphenicol resistance gene and the cryptic plasmid, pMB1, from the Bifidobacterium longum (B. longum) strain could stably replicate and did not significantly affect the biological characteristics of B. longum. In this study, B. longum was transfected by electroporation with pBV22210 containing IL-2 (B.longum-pBV22210-IL-2), its growth curve was determined, and its inhibitory effect on tumor xenografts in mice was examined. The results showed that B. longum-pBV22210-IL-2 reduced the tumor size and prolonged the survival time of H22 tumorbearing mice. In addition, when cyclophosphamide (CTX), B. longum-pBV22210-endostatin, or B. longum-pBV22210-TRAIL was combined with B.longum-pBV22210-IL-2, the antitumor effect was significantly enhanced. The survival times of the mice in the combination groups of B. longum-pBV22210-endostatin or B. longum-pBV22210-TRAIL were longer than those of the mice in the B.longum-pBV22210-IL-2 alone group. However, when CTX was added, the survival times of the mice showed no statistically significant difference compared with those of the mice in the dextrose-saline solution group. These results suggest that B.longum-pBV22210-IL-2 has potent antitumor effects that could be enhanced when combined with chemotherapeutic drugs or other antitumor genes.
Huang Z.,State Key Laboratory of Pharmaceutical Biotechnology |
Wang Z.,State Key Laboratory of Pharmaceutical Biotechnology |
Long S.,State Key Laboratory of Pharmaceutical Biotechnology |
Jiang H.,State Key Laboratory of Pharmaceutical Biotechnology |
And 5 more authors.
Molecular Pharmaceutics | Year: 2014
Functional engineered nanoparticles are promising drug delivery carriers. As the construction of a functional nanocarrier always needs the optimization of multiple technical variables, efficient in vitro high-throughput evaluation methods would help to shorten the development cycle. In the present study, we generated a tissue mimic of the colon of inflammatory bowel disease (IBD) patients. Generally, Caco-2 cells and THP-1 cells were grown in a 3-D matrix with different number, spatial distribution and specific extracellular cell matrix (ECM) composition according to real healthy and inflamed animal colon tissues. After interlerukin-1β/lipopolysaccharide (LPS) stimulation, the artificial model closely resembled the pathological features of IBD patients colon, including massive cytokines and mucus production, epithelium defect and leukocytic infiltration. The tissue and cellular uptake of three different nanoparticles in the artificial model was similar to that in 2,4,6-trinitrobenzenesulfonic acid (TNBS) colitic mice. Most importantly, our artificial tissue can be placed into 96-well plates for high-throughput screening of drug delivery carriers for the treatment of IBD. Our study suggested a readily achievable way to improve current methodologies for the development of colon targeted drug delivery systems. © 2014 American Chemical Society.
PubMed | Wannan Medical College, State Key Laboratory of Pharmaceutical Biotechnology and Nanjing Normal University
Type: Journal Article | Journal: Cellular signalling | Year: 2016
Nonalcoholic fatty liver disease (NAFLD) has become the major liver disease worldwide. Recently, several studies have identified that the activation of autophagy attenuates hepatic steatosis. Heat shock protein 27 (Hsp27) is involved in autophagy in response to various stimuli. In this study, we demonstrate that phosphorylated Hsp27 stimulates autophagy and lipid droplet clearance and interacts with STAT3. In vivo study showed that high fat diet (HFD) feeding increased Hsp25 (mouse orthology of Hsp27) phosphorylation and autophagy in mouse livers. Inhibition of Hsp25 phosphorylation exacerbated HFD-induced hepatic steatosis in mice. In vitro study showed that palmitate-induced lipid overload in hepatic cells was enhanced by Hsp27 knockdown, KRIBB3 treatment and Hsp27-3A (non-phosphorylatable) overexpression but was prevented by Hsp27-WT (wild type) and Hsp27-3D (phosphomimetic) overexpression. Mechanism analysis demonstrated that palmitate could induce Hsp27 phosphorylation which promoted palmitate-induced autophagy. Phosphorylated Hsp27 interacted with STAT3 in response to palmitate treatment, and disrupted the STAT3/PKR complexes, facilitated PKR-dependent eIF2 phosphorylation, and thus stimulated autophagy. To conclude, our study provides a novel mechanism by which the phosphorylated Hsp27 promotes hepatic lipid clearance and suggests a new insight for therapy of steatotic diseases such as nonalcoholic fatty liver disease (NAFLD).
Zhang X.,State Key Laboratory of Pharmaceutical Biotechnology |
Wei W.,State Key Laboratory of Pharmaceutical Biotechnology |
Tan R.,State Key Laboratory of Pharmaceutical Biotechnology
Science China Chemistry | Year: 2015
Symbionts are microorganisms residing in multicellular hosts (e.g., plants and animals), and they have been witnessed to be a rich source of diverse functional molecules. This review describes structures and biological activities of symbiont-derived secondary metabolites commonly referred to as “natural products”, and highlights that symbiotic microbes represent an under-explored reservoir of natural products with unique scaffolds and promising significance in managing human healthcare and agricultural production. © 2015 Science China Press and Springer-Verlag Berlin Heidelberg