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author:("Huang, anqing")
1.  FRS2α-mediated FGF signals suppress premature differentiation of cardiac stem cells through regulating autophagy activity 
Circulation research  2011;110(4):e29-e39.
Rational
Although the fibroblast growth factor (FGF) signaling axis plays important roles in heart development, the molecular mechanism by which the FGF regulates cardiogenesis is not fully understood.
Objective
To investigate the mechanism by which FGF signaling regulates cardiac progenitor cell differentiation.
Methods and results
Using mice with tissue-specific ablation of FGF receptors and FGF receptor substrate 2α (Frs2α) in heart progenitor cells, we demonstrate that that disruption of FGF signaling leads to premature differentiation of cardiac progenitor cells in mice. Using embryoid body (EB) cultures of mouse embryonic stem cells (ESCs), we reveal that FGF signaling promotes mesoderm differentiation in ESCs, but inhibits cardiomyocyte differentiation of the mesoderm cells at later stages. Furthermore, we also report that inhibiting FRS2α-mediated signals increases autophagy and that activating autophagy promotes myocardial differentiation and vice versa.
Conclusions
The results indicate that the FGF/FRS2α-mediated signals prevent premature differentiation of heart progenitor cells through suppressing autophagy. The findings provide the first evidence that autophagy plays a role in heart progenitor differentiation.
doi:10.1161/CIRCRESAHA.111.255950
PMCID: PMC3677753  PMID: 22207710
FGF; autophagy; heart development; second heart field; premature differentiation; heart defect
2.  FGFR1 Abrogates Inhibitory Effect of Androgen Receptor Concurrent with Induction of Androgen-receptor Variants in Androgen Receptor-negative Prostate Tumor Epithelial Cells 
The Prostate  2011;71(15):1691-1700.
BACKGROUND
Despite dramatic positive effects, there is evidence that the androgen receptor (AR) may negatively influence prostate tumor progression. Understanding the AR repressor function and how it is subverted is of particular importance in anti-androgen and AR intervention strategies.
METHODS
AR, resident FGFR2IIIb and ectopic FGFR1 were expressed by transfection in the AR-negative epithelial cell line DTE that predominates in cell culture of AR-positive androgen-responsive model Dunning R3327 rat prostate tumors. Androgen-responsiveness at transcription was measured by a luciferase reporter. Cell population growth rates were assessed by cell counts, DNA synthesis and expression of cell cycle genes. AR variants (ARVs) were assessed by immunochemistry and nuclease protection of mRNA.
RESULTS
Expression of AR inhibited cell population growth of AR-negative DTE cells at the G1 to S phase of the cell cycle. Ectopic FGFR1, but not resident FGFR2IIIb abrogated the growth inhibitory effects of AR. Appearance of ARVs was coincident with co-expression of FGFR1 and AR and abrogation of the AR-dependent inhibition of cell growth.
CONCLUSIONS
DTE cells may represent nonmalignant AR-negative progenitors whose population is restricted by activation of AR in vivo. Ectopic expression of epithelial FGFR1, a common observation in tumors, overrides the inhibition of AR and thus may contribute to evolution of androgen and AR independent tumors. These results are consistent with the notion that some tumor cells are negatively restricted by AR and are unleased by androgen-deprivation or ectopic expression of FGFR1. ARV’s may play a role in the bypass of the negative restrictions of AR.
doi:10.1002/pros.21386
PMCID: PMC3513346  PMID: 21446013
castration-resistance; fibroblast growth factor signaling; stem cells; tumor suppression; tyrosine kinases
3.  Dietary Available Phosphorus Affected Growth Performance, Body Composition, and Hepatic Antioxidant Property of Juvenile Yellow Catfish Pelteobagrus fulvidraco 
The Scientific World Journal  2012;2012:987570.
An 8-week feeding trial was carried out with juvenile yellow catfish to study the effects of dietary available phosphorus (P) on growth performance, body composition, and hepatic antioxidant property. Six pellet diets were formulated to contain graded available P levels at 0.33, 0.56, 0.81, 1.15, 1.31, and 1.57% of dry matter, respectively. Triplicate tanks with each tank containing 60 juveniles (3.09 ± 0.03 g) were fed one of the six experimental diets for 8 weeks. Specific growth rate, feeding rate, and protein efficiency ratio were significantly higher at 0.81% dietary available P. Efficiency of P utilization distinctly decreased with increasing P level. Body lipid content significantly decreased while body ash and feces P content significantly increased with increasing P level. Quadratic regression analysis indicated that vertebrae P content was maximized at 1.21% dietary available P. Fish fed 1.57% dietary available P had highest activity of hepatic superoxide dismutase and catalase and malonaldehyde content. In conclusion, decreasing dietary available P increased P utilization efficiency and body lipid content while decreased vertebrae P content. Juvenile yellow catfish were subjected to oxidative damage under the condition of high dietary P content (1.57%), and the damage could not be eradicated by their own antioxidant defense system.
doi:10.1100/2012/987570
PMCID: PMC3419402  PMID: 22924032
4.  The FGF-BMP signaling axis regulates outflow tract valve primordium formation by promoting cushion neural crest cell differentiation 
Circulation research  2010;107(10):1209-1219.
Rationale
Heart valves develop from precursor structures called cardiac cushions, an endothelial-lined cardiac jelly that resides in the inner side of the heart tube. The cushions are then invaded by cells from different sources, undergo a series of complicated and poorly understood remodeling processes, and give rise to valves. Disruption of the fibroblast growth factor (FGF) signaling axis impairs morphogenesis of the outflow tract (OFT). Yet, whether FGF signaling regulates OFT valve formation is unknown.
Objective
To study how OFT valve formation is regulated and how aberrant cell signaling causes valve defects.
Methods and results
By employing mouse genetic manipulation, cell lineage tracing, ex vivo heart culture, and molecular biology approaches, we demonstrated that FGF signaling in the OFT myocardium upregulated Bmp4 expression, which then enhanced smooth muscle differentiation of neural crest cells (NCCs) in the cushion. FGF signaling also promoted OFT myocardial cell invasion to the cushion. Disrupting FGF signaling interrupted cushion remodeling with reduced NCCs differentiation into smooth muscle and less cardiomyocyte invasion, and resulted in malformed OFT valves.
Conclusions
The results demonstrate a novel mechanism by which the FGF-BMP signaling axis regulates formation of OFT valve primordia by controlling smooth muscle differentiation of cushion NCCs.
doi:10.1161/CIRCRESAHA.110.225318
PMCID: PMC3052773  PMID: 20847311
FGF; BMP; heart development; NCC differentiation; cardiac valve defect
5.  Development of Silymarin Self-Microemulsifying Drug Delivery System with Enhanced Oral Bioavailability 
AAPS PharmSciTech  2010;11(2):672-678.
The objective of this work was to develop a self-microemulsifying drug delivery system (SMEDDS) for improving oral absorption of poorly water-soluble drug, silymarin. The pseudo-ternary phase diagrams were constructed using ethyl linoleate, Cremophor EL, ethyl alcohol, and normal saline to identify the efficient self-microemulsification region. The particle size and its distribution of the resultant microemulsions were determined using dynamic light scattering. The optimal formulation with the best self-microemulsifying and solubilization ability consisted of 10% (w/w) of ethyl linoleate, 30% of Cremophor EL, and 60% of ethyl alcohol. The release of silymarin from SMEDDS was significantly faster than that from the commercial silymarin preparation hard capsule (Legalon®). The bioavailability results indicated that the oral absorption of silymarin SMEDDS was enhanced about 2.2-fold compared with the hard capsule in fasted dogs. It could be concluded that SMEDDS would be a promising drug delivery system for poorly water-soluble drugs by the oral route.
doi:10.1208/s12249-010-9432-x
PMCID: PMC2902333  PMID: 20405254
bioavailability; microemulsion; self-microemulsifying drug delivery system; silymarin
6.  Preparation and Evaluation of Poly(Ethylene Glycol)–Poly(Lactide) Micelles as Nanocarriers for Oral Delivery of Cyclosporine A 
Nanoscale Research Letters  2010;5(6):917-925.
A series of monomethoxy poly(ethylene glycol)–poly(lactide) (mPEG–PLA) diblock copolymers were designed according to polymer–drug compatibility and synthesized, and mPEG–PLA micelle was fabricated and used as a nanocarrier for solubilization and oral delivery of Cyclosporine A (CyA). CyA was efficiently encapsulated into the micelles with nanoscaled diameter ranged from 60 to 96 nm with a narrow size distribution. The favorable stabilities of CyA-loaded polymeric micelles were observed in simulated gastric and intestinal fluids. The in vitro drug release investigation demonstrated that drug release was retarded by polymeric micelles. The enhanced intestinal absorption of CyA-loaded polymeric micelles, which was comparable to the commercial formulation of CyA (Sandimmun Neoral®), was found. These suggested that polymeric micelles might be an effective nanocarrier for solubilization of poorly soluble CyA and further improving oral absorption of the drug.
doi:10.1007/s11671-010-9583-4
PMCID: PMC2893821  PMID: 20671795
Monomethoxy poly(ethylene glycol)–poly(lactide); Polymeric micelles; Cyclosporine A; Solubility parameter; In vitro release; Intestinal absorption
7.  Preparation and Evaluation of Poly(Ethylene Glycol)–Poly(Lactide) Micelles as Nanocarriers for Oral Delivery of Cyclosporine A 
Nanoscale Research Letters  2010;5(6):917-925.
A series of monomethoxy poly(ethylene glycol)–poly(lactide) (mPEG–PLA) diblock copolymers were designed according to polymer–drug compatibility and synthesized, and mPEG–PLA micelle was fabricated and used as a nanocarrier for solubilization and oral delivery of Cyclosporine A (CyA). CyA was efficiently encapsulated into the micelles with nanoscaled diameter ranged from 60 to 96 nm with a narrow size distribution. The favorable stabilities of CyA-loaded polymeric micelles were observed in simulated gastric and intestinal fluids. The in vitro drug release investigation demonstrated that drug release was retarded by polymeric micelles. The enhanced intestinal absorption of CyA-loaded polymeric micelles, which was comparable to the commercial formulation of CyA (Sandimmun Neoral®), was found. These suggested that polymeric micelles might be an effective nanocarrier for solubilization of poorly soluble CyA and further improving oral absorption of the drug.
doi:10.1007/s11671-010-9583-4
PMCID: PMC2893821  PMID: 20671795
Monomethoxy poly(ethylene glycol)–poly(lactide); Polymeric micelles; Cyclosporine A; Solubility parameter; In vitro release; Intestinal absorption
8.  Effects of S-adenosylmethionine on liver methionine metabolism and steatosis with ethanol-induced liver injury in rats 
Hepatology International  2008;2(3):346-352.
Background
Hyperhomocysteinemia is implicated in the pathogenesis of various liver diseases. In this study, the effects of S-adenosylmethionine (SAM) on hyperhomocysteinemia and steatosis with ethanol-induced liver injury in rats were examined and their mechanisms were explored.
Methods
Forty-eight female Sprague–Dawley rats were randomly divided into four groups as control, model, low-dose, and high-dose SAM groups. Except the control group, all rats were fed high-fat-containing diet plus ethanol and fish oil gavaged for 8 weeks. SAM was administered by intraperitoneal injection after the 4 weeks’ exposure of ethanol. Serum homocysteine (Hcy), alanine aminotransferase (ALT), aspartate aminotransferase (AST), total cholesterol (TC), triglyceride (TG), tumor necrosis factor α (TNF-α), and transforming growth factor β1 (TGF-β1) levels were determined. The contents of liver malondialdehyde (MDA) and glutathione (GSH) were assayed. Liver histology was also examined. The expressions of TNF-α and TGF-β1 mRNAs in the liver were detected by the reverse transcriptase-polymerase chain reaction assay.
Results
Compared with the control group, the model group rats developed marked liver damage, accompanied by an increase in Hcy, ALT, AST, TC, TG, TNF-α, TGF-β1, and MDA levels. However, the levels of GSH were decreased. These responses were associated with the increased expression of TNF-α and TGF-β1 mRNAs in the livers, as well as the existence of hepatocellular necrosis and neutrophil infiltration in the livers. In treatment groups, SAM provided significant protection from the liver injury induced by alcohol, resulting in a decrease in serum TNF-α, TGF-β1 levels, lipid peroxidation, and the expressions of TNF-α and TGF-β1 mRNAs in the livers, as well as an increase in GSH levels. However, no statistical difference was observed in these parameters between the two different dose treatment groups. In the study, SAM did not affect plasma total homocysteine (tHcy) levels significantly.
Conclusion
SAM prevents alcohol-induced liver injury in rats by reducing liver lipid peroxidation, anti-inflammation, and antihyperplasia. In addition, it does not affect the plasma tHcy levels.
doi:10.1007/s12072-008-9082-1
PMCID: PMC2716886  PMID: 19669264
Alcohol-induced liver injury; S-Adenosylmethionine; Lipid peroxidation; TNF-α; TGF-β1; Hyperhomocysteinemia
9.  Cleavage of Host Keratin 8 by a Chlamydia-Secreted Protease  
Infection and Immunity  2004;72(7):3863-3868.
Chlamydiae have to replicate within a cytoplasmic vacuole in eukaryotic cells. Expansion of the chlamydia-laden vacuole is essential for chlamydial intravacuolar replication, which inevitably causes host cell cytoskeleton rearrangements. A cleavage fragment of keratin 8 corresponding to the central rod region was detected in the soluble fraction of chlamydia-infected cells. Since keratin 8 is a major component of the intermediate filaments in simple epithelial cells, cleavage of keratin 8 may increase the solubility of the host cell cytoskeleton and thus permit vacuole expansion in chlamydia-infected cells. A chlamydia-secreted protease designated CPAF (chlamydial protease/proteasome-like activity factor) was both necessary and sufficient for keratin 8 cleavage in chlamydia-infected cells, suggesting that chlamydiae have evolved specific mechanisms for modifying the host cell cytoskeleton.
doi:10.1128/IAI.72.7.3863-3868.2004
PMCID: PMC427399  PMID: 15213128
10.  Chlamydia-Infected Cells Continue To Undergo Mitosis and Resist Induction of Apoptosis  
Infection and Immunity  2004;72(1):451-460.
Both anti- and proapoptotic activities have been reported to occur during chlamydial infection. To reconcile the apparent controversy, we compared host cell apoptotic responses to infection with 17 different chlamydial serovars and strains. None of the serovars caused any biologically significant apoptosis in the infected host cells. Host cells in chlamydia-infected cultures can continue to undergo DNA synthesis and mitosis. Chlamydia-infected cells are resistant to apoptosis induction, although the extent of the antiapoptotic ability varied between serovars. These observations have demonstrated that an anti- but not proapoptotic activity is the prevailing event in chlamydia-infected cultures.
doi:10.1128/IAI.72.1.451-460.2004
PMCID: PMC343958  PMID: 14688126
12.  Chlamydia pneumoniae Secretion of a Protease-Like Activity Factor for Degrading Host Cell Transcription Factors Is Required for Major Histocompatibility Complex Antigen Expression  
Infection and Immunity  2002;70(1):345-349.
Chlamydia pneumoniae is a causative agent for many respiratory infections and has been associated with cardiovascular diseases in humans. The pathogenicity of C. pneumoniae is thought to depend on its ability to cause persistent infection and to evade host defense. Genome sequence analysis indicates that C. pneumoniae encodes a homologue of a chlamydial protease-like activity factor from C. trachomatis (CPAFct). We designated the C. pneumoniae homologue as CPAFcp. Recombinant CPAFcp was produced and found to degrade RFX5, a host transcription factor required for major histocompatibility complex (MHC) antigen expression. The degradation was inhibitable by lactacystin, an irreversible proteasome inhibitor. Furthermore, CPAFcp was secreted into host cytosol by C. pneumoniae organisms. Depletion of the C. pneumoniae-secreted CPAFcp with specific antibodies completely ablated the RFX5 degradation activity in the infected cells, suggesting that CPAFcp is necessary for the degradation of host transcription factors required for MHC antigen expression during C. pneumoniae infection. These observations have revealed a unique molecular mechanism for C. pneumoniae to evade host adaptive immunity that may aid in its persistence.
doi:10.1128/IAI.70.1.345-349.2002
PMCID: PMC127637  PMID: 11748200
13.  Identification of a Chlamydial Protease–Like Activity Factor Responsible for the Degradation of Host Transcription Factors 
Microbial pathogens have been selected for the capacity to evade or manipulate host responses in order to survive after infection. Chlamydia, an obligate intracellular pathogen and the causative agent for many human diseases, can escape T lymphocyte immune recognition by degrading host transcription factors required for major histocompatibility complex (MHC) antigen expression. We have now identified a chlamydial protease– or proteasome–like activity factor (CPAF) that is secreted into the host cell cytosol and that is both necessary and sufficient for the degradation of host transcription factors RFX5 and upstream stimulation factor 1 (USF-1). The CPAF gene is highly conserved among chlamydial strains, but has no significant overall homology with other known genes. Thus, CPAF represents a unique secreted protein produced by an obligate intracellular bacterial pathogen to interfere with effective host adaptive immunity.
PMCID: PMC2193410  PMID: 11304554
chlamydial enzyme; degradation; transcription factors; antigen presentation; immune evasion

Results 1-13 (13)