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1.  p53-dependent Fas expression is critical for Ginsenoside Rh2 triggered caspase-8 activation in HeLa cells 
Protein & Cell  2014;5(3):224-234.
We have recently reported that Ginsenoside Rh2 (G-Rh2) induces the activation of two initiator caspases, caspase-8 and caspase-9 in human cancer cells. However, the molecular mechanism of its death-inducing function remains unclear. Here we show that G-Rh2 stimulated the activation of both caspase-8 and caspase-9 simultaneously in HeLa cells. Under G-Rh2 treatment, membrane death receptors Fas and TNFR1 are remarkably upregulated. However, the induced expression of Fas but not TNFR1 was contributed to the apoptosis process. Moreover, significant increases in Fas expression and caspase-8 activity temporally coincided with an increase in p53 expression in p53-non-mutated HeLa and SK-HEP-1 cells upon G-Rh2 treatment. In contrast, Fas expression and caspase-8 activity remained constant with G-Rh2 treatment in p53-mutated SW480 and PC-3 cells. In addition, siRNA-mediated knockdown of p53 diminished G-Rh2-induced Fas expression and caspase-8 activation. These results indicated that G-Rh2-triggered extrinsic apoptosis relies on p53-mediated Fas over-expression. In the intrinsic apoptotic pathway, G-Rh2 induced strong and immediate translocation of cytosolic BAK and BAX to the mitochondria, mitochondrial cytochrome c release, and subsequent caspase-9 activation both in HeLa and in SW480 cells. p53-mediated Fas expression and subsequent downstream caspase-8 activation as well as p53-independent caspase-9 activation all contribute to the activation of the downstream effector caspase-3/-7, leading to tumor cell death. Taken together, we suggest that G-Rh2 induces cancer cell apoptosis in a multi-path manner and is therefore a promising candidate for anti-tumor drug development.
Electronic supplementary material
The online version of this article (doi:10.1007/s13238-014-0027-2) contains supplementary material, which is available to authorized users.
doi:10.1007/s13238-014-0027-2
PMCID: PMC3967063  PMID: 24622841
G-Rh2; Fas; p53; apoptosis
2.  p53-dependent Fas expression is critical for Ginsenoside Rh2 triggered caspase-8 activation in HeLa cells 
Protein & Cell  2014;5(3):224-234.
We have recently reported that Ginsenoside Rh2 (G-Rh2) induces the activation of two initiator caspases, caspase-8 and caspase-9 in human cancer cells. However, the molecular mechanism of its death-inducing function remains unclear. Here we show that G-Rh2 stimulated the activation of both caspase-8 and caspase-9 simultaneously in HeLa cells. Under G-Rh2 treatment, membrane death receptors Fas and TNFR1 are remarkably upregulated. However, the induced expression of Fas but not TNFR1 was contributed to the apoptosis process. Moreover, significant increases in Fas expression and caspase-8 activity temporally coincided with an increase in p53 expression in p53-non-mutated HeLa and SK-HEP-1 cells upon G-Rh2 treatment. In contrast, Fas expression and caspase-8 activity remained constant with G-Rh2 treatment in p53-mutated SW480 and PC-3 cells. In addition, siRNA-mediated knockdown of p53 diminished G-Rh2-induced Fas expression and caspase-8 activation. These results indicated that G-Rh2-triggered extrinsic apoptosis relies on p53-mediated Fas over-expression. In the intrinsic apoptotic pathway, G-Rh2 induced strong and immediate translocation of cytosolic BAK and BAX to the mitochondria, mitochondrial cytochrome c release, and subsequent caspase-9 activation both in HeLa and in SW480 cells. p53-mediated Fas expression and subsequent downstream caspase-8 activation as well as p53-independent caspase-9 activation all contribute to the activation of the downstream effector caspase-3/-7, leading to tumor cell death. Taken together, we suggest that G-Rh2 induces cancer cell apoptosis in a multi-path manner and is therefore a promising candidate for anti-tumor drug development.
Electronic supplementary material
The online version of this article (doi:10.1007/s13238-014-0027-2) contains supplementary material, which is available to authorized users.
doi:10.1007/s13238-014-0027-2
PMCID: PMC3967063  PMID: 24622841
G-Rh2; Fas; p53; apoptosis
3.  Prognosis of Unresectable Hepatocellular Carcinoma: Comparison of Seven Staging Systems (TNM, Okuda, BCLC, CLIP, CUPI, JIS, CIS) in a Chinese Cohort 
PLoS ONE  2014;9(3):e88182.
Background
Many liver staging systems that include the tumor stage and the extent of liver function have been developed. However, prognosis assessment for hepatocellular carcinoma (HCC) remains controversial. In this study, the performances of 7 staging systems were compared in a cohort of patients with HCC who underwent non-surgical treatment.
Methods
A total of 196 consecutive patients with HCC who underwent non-surgical treatment seen between January 1, 2004, and December 31, 2007, were included. Performances of TNM sixth edition, Okuda, Barcelona Clinic Liver Cancer (BCLC), Cancer of the Liver Italian Program (CLIP), Chinese University Prognostic Index (CUPI), Japan Integrated Staging (JIS), and China integrated score (CIS) have been compared and ranked using concordance index (c-index). Predictors of survival were identified using univariate and multivariate Cox model analyses.
Results
The median survival time for the cohort was 7.6 months (95% CI 5.6–9.7). The independent predictors of survival were performance status (P<.001), serum sodium (P<.001), alkaline phosphatase (P<.001), tumor diameter greater than 5 cm (P = .001), portal vein invasion (P<.001), lymph node metastasis (P = .025), and distant metastasis (P = .004). CUPI staging system had the best independent predictive power for survival when compared with the other six prognostic systems. Performance status and serum sodium improved the discriminatory ability of CUPI.
Conclusion
In our selected patient population whose main etiology is hepatitis B, CUPI was the most suitable staging system in predicting survival in patients with unresectable HCC. BCLC was the second top-ranking staging system. CLIP, JIS, CIS, and TNM sixth edition were not helpful in predicting survival outcome, and their use is not supported by our data.
doi:10.1371/journal.pone.0088182
PMCID: PMC3946426  PMID: 24609114
4.  Effects of three blood purification methods on serum fibroblast growth factor-23 clearance in patients with hyperphosphatemia undergoing maintenance hemodialysis 
The aim of the present study was to investigate the effects of three blood purification methods on fibroblast growth factor-23 (FGF-23) clearance in patients with hyperphosphatemia undergoing maintenance hemodialysis (MHD). In addition, the correlation between serum FGF-23 and phosphorus (Pi) levels and the clinical implications were identified. Sixty-five MHD patients with hyperphosphatemia were randomly divided into three groups: Hemodialysis, HD (n=23); hemodiafiltration, HDF (n=21); and hemodialysis+hemoperfusion, HD+HP (n=21) groups. Serum Pi, FGF-23, blood urea nitrogen, serum creatinine and associated bio-marker levels were measured prior to and following treatment. The expression level of serum FGF-23 was observed to be positively correlated with Pi (r=0.45, P<0.01). The three blood purification methods that were adopted for the present study exhibited significant and effective clearance of serum Pi (P<0.05). The post-treatment serum FGF-23 levels were significantly decreased in the HDF and HD+HP groups (P<0.05). Therefore, HDF may be an effective method for clearing serum FGF-23 in MHD patients exhibiting hyperphosphatemia.
doi:10.3892/etm.2014.1543
PMCID: PMC3964936  PMID: 24669256
hyperphosphatemia; fibroblast growth factor-23; hemodialysis; hemodiafiltration; hemoperfusion
5.  HGF Accelerates Wound Healing by Promoting the Dedifferentiation of Epidermal Cells through β1-Integrin/ILK Pathway 
BioMed Research International  2014;2013:470418.
Skin wound healing is a critical and complex biological process after trauma. This process is activated by signaling pathways of both epithelial and nonepithelial cells, which release a myriad of different cytokines and growth factors. Hepatocyte growth factor (HGF) is a cytokine known to play multiple roles during the various stages of wound healing. This study evaluated the benefits of HGF on reepithelialization during wound healing and investigated its mechanisms of action. Gross and histological results showed that HGF significantly accelerated reepithelialization in diabetic (DB) rats. HGF increased the expressions of the cell adhesion molecules β1-integrin and the cytoskeleton remodeling protein integrin-linked kinase (ILK) in epidermal cells in vivo and in vitro. Silencing of ILK gene expression by RNA interference reduced expression of β1-integrin, ILK, and c-met in epidermal cells, concomitantly decreasing the proliferation and migration ability of epidermal cells. β1-Integrin can be an important maker of poorly differentiated epidermal cells. Therefore, these data demonstrate that epidermal cells become poorly differentiated state and regained some characteristics of epidermal stem cells under the role of HGF after wound. Taken together, the results provide evidence that HGF can accelerate reepithelialization in skin wound healing by dedifferentiation of epidermal cells in a manner related to the β1-integrin/ILK pathway.
doi:10.1155/2013/470418
PMCID: PMC3899705  PMID: 24490163
6.  Triazole-dithiocarbamate based, selective LSD1 inactivators inhibit gastric cancer cell growth, invasion and migration 
Journal of medicinal chemistry  2013;56(21):10.1021/jm401002r.
Lysine specific demethylase 1 (LSD1), the first identified histone demethylase, plays an important role in epigenetic regulation of gene activation and repression. The up-regulated LSD1's expression has been reported in several malignant tumors. In the current study, we designed and synthesized five series of 1, 2, 3-triazole-dithiocarbamate hybrids and screened their inhibitory activity toward LSD1. We found that some of these compounds, especially compound 26, exhibited the most specific and robust inhibition of LSD1. Interestingly, compound 26 also showed potent and selective cytotoxicity against LSD1 overexpressing gastric cancer cell lines MGC-803 and HGC-27, as well as marked inhibition of cell migration and invasion, compared to 2-PCPA. Furthermore, compound 26 effectively reduced the tumor growth bared by human gastric cancer cells in vivo with no signs of adverse side effects. These findings suggested that compound 26 deserves further investigation as a lead compound in the treatment of LSD1 overexpressing gastric cancer.
doi:10.1021/jm401002r
PMCID: PMC3881423  PMID: 24131029
7.  Deep Sequencing-Based Analysis of the Cymbidium ensifolium Floral Transcriptome 
PLoS ONE  2013;8(12):e85480.
Cymbidium ensifolium is a Chinese Cymbidium with an elegant shape, beautiful appearance, and a fragrant aroma. C. ensifolium has a long history of cultivation in China and it has excellent commercial value as a potted plant and cut flower. The development of C. ensifolium genomic resources has been delayed because of its large genome size. Taking advantage of technical and cost improvement of RNA-Seq, we extracted total mRNA from flower buds and mature flowers and obtained a total of 9.52 Gb of filtered nucleotides comprising 98,819,349 filtered reads. The filtered reads were assembled into 101,423 isotigs, representing 51,696 genes. Of the 101,423 isotigs, 41,873 were putative homologs of annotated sequences in the public databases, of which 158 were associated with floral development and 119 were associated with flowering. The isotigs were categorized according to their putative functions. In total, 10,212 of the isotigs were assigned into 25 eukaryotic orthologous groups (KOGs), 41,690 into 58 gene ontology (GO) terms, and 9,830 into 126 Arabidopsis Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways, and 9,539 isotigs into 123 rice pathways. Comparison of the isotigs with those of the two related orchid species P. equestris and C. sinense showed that 17,906 isotigs are unique to C. ensifolium. In addition, a total of 7,936 SSRs and 16,676 putative SNPs were identified. To our knowledge, this transcriptome database is the first major genomic resource for C. ensifolium and the most comprehensive transcriptomic resource for genus Cymbidium. These sequences provide valuable information for understanding the molecular mechanisms of floral development and flowering. Sequences predicted to be unique to C. ensifolium would provide more insights into C. ensifolium gene diversity. The numerous SNPs and SSRs identified in the present study will contribute to marker development for C. ensifolium.
doi:10.1371/journal.pone.0085480
PMCID: PMC3877369  PMID: 24392013
8.  Experimental gastritis leads to anxiety- and depression-like behaviors in female but not male rats 
Human and animals studies support the idea that there is a gender-related co-morbidity of pain-related and inflammatory gastrointestinal (GI) diseases with psychological disorders. This co-morbidity is the evidence for the existence of GI-brain axis which consists of immune (cytokines), neural (vagus nerve) and neuroendocrine (HPA axis) pathways. Psychological stress causes disturbances in GI physiology, such as altered GI barrier function, changes in motility and secretion, development of visceral hypersensitivity, and dysfunction of inflammatory responses. Whether GI inflammation would exert impact on psychological behavior is not well established. We examined the effect of experimental gastritis on anxiety- and depression-like behaviors in male and female Sprague–Dawley rats, and evaluated potential mechanisms of action. Gastritis was induced by adding 0.1% (w/v) iodoacetamide (IAA) to the sterile drinking water for 7 days. Sucrose preference test assessed the depression-like behavior, open field test and elevated plus maze evaluated the anxiety-like behavior. IAA treatment induced gastric inflammation in rats of either gender. No behavioral abnormality or dysfunction of GI-brain axis was observed in male rats with IAA-induced gastritis. Anxiety- and depression-like behaviors were apparent and the HPA axis was hyperactive in female rats with IAA-induced gastritis. Our results show that gastric inflammation leads to anxiety- and depression-like behaviors in female but not male rats via the neuroendocrine (HPA axis) pathway, suggesting that the GI inflammation can impair normal brain function and induce changes in psychological behavior in a gender-related manner through the GI-to-brain signaling.
doi:10.1186/1744-9081-9-46
PMCID: PMC3878489  PMID: 24345032
Gastrointestinal-brain axis; Iodoacetamide-induced gastritis; Anxiety; Depression; Gender difference
9.  CDK inhibitor p57Kip2 is negatively regulated by COP9 signalosome subunit 6 
Cell Cycle  2012;11(24):4633-4641.
Subunit 6 of the COP9 signalosome complex, CSN6, is known to be critical to the regulation of the MDM2-p53 axis for cell proliferation and anti-apoptosis, but its many targets remain unclear. Here we show that p57Kip2 is a target of CSN6, and that CSN6 is a negative regulator of p57Kip2. CSN6 associates with p57Kip2, and its overexpression can decrease the steady-state expression of p57Kip2; accordingly, CSN6 deficiency leads to p57Kip2 stabilization. Mechanistic studies show that CSN6 associates with p57Kip2 and Skp2, a component of the E3 ligase, which, in turn, facilitates Skp2-mediated protein ubiquitination of p57Kip2. Loss of Skp2 compromised CSN6-mediated p57Kip2 destabilization, suggesting collaboration between Skp2 and CSN6 in degradation of p57Kip2. CSN6’s negative impact on p57Kip2 elevation translates into cell growth promotion, cell cycle deregulation and potentiated transformational activity. Significantly, univariate Kaplan-Meier analysis of tumor samples demonstrates that high CSN6 expression or low p57 expression is associated with poor overall survival. These data suggest that CSN6 is an important negative regulator of p57Kip2, and that overexpression of CSN6 in many types of cancer could lead to decreased expression of p57Kip2 and result in promoted cancer cell growth.
doi:10.4161/cc.22887
PMCID: PMC3562308  PMID: 23187808
COP9; CSN6; Skp2; cell cycle; p57
10.  Si-RNA mediated knockdown of CELF1 gene suppressed the proliferation of human lung cancer cells 
Background
Lung cancer is the leading cause of cancer-related death in the world, with metastasis as the main reason for the mortality. CELF1 is an RNA-binding protein controlling the post-transcriptional regulation of genes related to cell survival. As yet, there is little knowledge of CELF1 expression and biological function in lung cancer. This study investigated the expression levels of CELF1 in lung cancer tissues and the biological function of CELF1 in lung cancer cells.
Methods
CELF1 mRNA expression was determined in lung cancer and normal tissues, and the relationship between the expression level of CELF1 and clinicopathological parameters was evaluated. The biological function of CELF1 in A549 and H1299 lung cancer cell lines growth was examined.
Results
The expression of CELF1 was higher in human lung cancer tissues compared with the normal lung tissue. Lentiviral-mediated transfection of CELF1 siRNA effectively silenced the expression of CELF1 in both A549 and H1299 cells. Moreover, CELF1 knockdown markedly reduced the survival rate of lung cancer cells. Colony formation assays revealed a reduction in the number and size of lung cancer cell colonies from CELF1 knockdown.
Conclusion
These results indicated that CELF1 may have significant roles in the progression of lung cancer, and suggested that siRNA mediated silencing of CELF1 could be an effective tool in lung cancer treatment.
doi:10.1186/1475-2867-13-115
PMCID: PMC3842801  PMID: 24237593
Lung cancer; CELF1 gene; Proliferation
11.  RPS8—a New Informative DNA Marker for Phylogeny of Babesia and Theileria Parasites in China 
PLoS ONE  2013;8(11):e79860.
Piroplasmosis is a serious debilitating and sometimes fatal disease. Phylogenetic relationships within piroplasmida are complex and remain unclear. We compared the intron–exon structure and DNA sequences of the RPS8 gene from Babesia and Theileria spp. isolates in China. Similar to 18S rDNA, the 40S ribosomal protein S8 gene, RPS8, including both coding and non-coding regions is a useful and novel genetic marker for defining species boundaries and for inferring phylogenies because it tends to have little intra-specific variation but considerable inter-specific difference. However, more samples are needed to verify the usefulness of the RPS8 (coding and non-coding regions) gene as a marker for the phylogenetic position and detection of most Babesia and Theileria species, particularly for some closely related species.
doi:10.1371/journal.pone.0079860
PMCID: PMC3820542  PMID: 24244571
12.  Endoscopic retrograde cholangiopancreatography and laparoscopic cholecystectomy during the same session: Feasibility and safety 
AIM: To explore the feasibility and safety of endoscopic retrograde cholangiopancreatography and laparoscopic cholecystectomy (LC) performed during the same session.
METHODS: Between July 2010 and May 2013, 156 patients with gallstones and common bile duct (CBD) stones were enrolled in this retrospective study. According to the sequence of endoscopic procedures and LC, patients were classified into two groups: in group 1, patients underwent endoscopic stone extraction and LC during the same session, and in group 2, patients underwent LC at least 3 d after endoscopic stone extraction. Outcomes of the endoscopic procedures and LC were compared between the two groups, respectively.
RESULTS: There were 91 patients in group 1 and 65 patients in group 2. The characteristics of the two groups were similar. The mean duration of the endoscopic procedures was 34.9 min in group 1 and 35.3 min in group 2. There were no significant differences in the success rate of the endoscopic procedures (97.8% for group 1 vs 98.5% for group 2), the total rate of endoscopic complications (4.40% for group 1 vs 4.62% for group 2) and CBD stone clearance rate (96.7% for group 1 vs 96.9% for group 2). Duration of LC was 53.6 min in group 1 and 52.8 min in group 2. There were no significant differences in the overall LC-related morbidity and postoperative hospital stay.
CONCLUSION: Endoscopic stone extraction and LC performed during the same session was feasible and safe in patients with gallstones and concomitant CBD stones.
doi:10.3748/wjg.v19.i36.6093
PMCID: PMC3785632  PMID: 24106411
Cholecystectomy; Laparoscopic; Endoscopic; Therapy
13.  Co-expression of the Arabidopsis SOS genes enhances salt tolerance in transgenic tall fescue (Festuca arundinacea Schreb.) 
Protoplasma  2013;251:219-231.
Crop productivity is greatly affected by soil salinity; therefore, improvement in salinity tolerance of crops is a major goal in salt-tolerant breeding. The Salt Overly Sensitive (SOS) signal-transduction pathway plays a key role in ion homeostasis and salt tolerance in plants. Here, we report that overexpression of Arabidopsis thaliana SOS1+SOS2+SOS3 genes enhanced salt tolerance in tall fescue. The transgenic plants displayed superior growth and accumulated less Na+ and more K+ in roots after 350 mM NaCl treatment. Moreover, Na+ enflux, K+ influx, and Ca2+ influx were higher in the transgenic plants than in the wild-type plants. The activities of the enzyme superoxide dismutase, peroxidase, catalase, and proline content in the transgenic plants were significantly increased; however, the malondialdehyde content decreased in transgenic plants compared to the controls. These results suggested that co-expression of A. thaliana SOS1+SOS2+SOS3 genes enhanced the salt tolerance in transgenic tall fescue.
Electronic supplementary material
The online version of this article (doi:10.1007/s00709-013-0540-9) contains supplementary material, which is available to authorized users.
doi:10.1007/s00709-013-0540-9
PMCID: PMC3893463  PMID: 24022678
SOS pathway genes; Salt stress; Transgenic tall fescue
14.  A novel surgical procedure: scaffold-pulmonary autograft transplantation 
Mitral valve-related operations are easy to perform and show good results, but to prevent severe thromboembolism or a high ratio of prosthetic valve destruction by tissue, lifetime anticoagulant therapy is essential after the operation. Thus, identifying a new type of surgical procedure and prosthetic valve to cure mitral valve diseases is necessary. Pulmonary valve autograft transplantation (Ross II) with the “top hat” transplantation technique was first reported by Ross DN to cure mitral disease. Because the “top hat” procedure has some shortcomings, we designed the scaffold-pulmonary autograft transplantation procedure and performed animal experiments to confirm the feasibility and effectiveness of the procedure. A total of 13 minipigs, weighing 20-25 kg, were employed as experimental animals to undergo scaffold-pulmonary autograft valve transplantation in our surgical animal lab. The surgical procedure was performed under hypothermic general anaesthesia and extracorporeal circulation (or cardiopulmonary bypass, CPB). Briefly, the chest cave was opened through the left intercostal, the pulmonary valve autograft was harvested during on-pump beating heart, and the pulmonary valve autograft was mounted in a self-made pulmonary valve scaffold and transferred to the mitral valve annulus without removing the mitral instruments. Finally, the outflow tract of the right ventricle was re-established with a pig pulmonary homograft. After finishing data collection, all animals were executed 1 hour after removal from the CPB. For the 13 minipigs that underwent the operation, the CPB time was 182.4 ± 23.4 min. Two of the thirteen cases died of bleeding during the operation and of a post-operative pulmonary embolism, and the remaining eleven survived for one hour. The pressure of the left atrium did not increase significantly (P = 1.00), and the ultrasonic cardiograph (UCG) showed good function of the new mitral valves, with mean ejection fraction (EF) values of 63.6%. The mitral valve orifice areas were 1.10 ± 0.13 cm2 (pre-operation) and 1.01 ± 0.08 cm2 (post-operation) (P = 0.013). The function and structure of the new mitral valves were normal. We preliminarily consider scaffold-pulmonary autograft valve transplantation to be a new alternative to cure mitral valve disease, but advanced chronic animal experiments will be needed to confirm the long-term results of the operation. The results showed it could be a new alternative to cure mitral valve disease.
PMCID: PMC3762621  PMID: 24040474
Mitral valve disease; scaffold-pulmonary autograft valve transplantation; minipig
15.  Preparation and characterization of monomethoxy poly(ethylene glycol)-poly(ε-caprolactone) micelles for the solubilization and in vivo delivery of luteolin 
Luteolin (Lu) is one of the flavonoids with anticancer activity, but its poor water solubility limits its use clinically. In this work, we used monomethoxy poly(ethylene glycol)-poly(e-caprolactone) (MPEG-PCL) micelles to encapsulate Lu by a self-assembly method, creating a water-soluble Lu/MPEG-PCL micelle. These micelles had a mean particle size of 38.6 ± 0.6 nm (polydispersity index = 0.16 ± 0.02), encapsulation efficiency of 98.32% ± 1.12%, and drug loading of 3.93% ± 0.25%. Lu/MPEG-PCL micelles could slowly release Lu in vitro. Encapsulation of Lu in MPEG-PCL micelles improved the half-life (t½; 152.25 ± 49.92 versus [vs] 7.16 ± 1.23 minutes, P = 0.007), area under the curve (0-t) (2914.05 ± 445.17 vs 502.65 ± 140.12 mg/L/minute, P = 0.001), area under the curve (0–∞) (2989.03 ± 433.22 vs 503.81 ± 141.41 mg/L/minute, P = 0.001), and peak concentration (92.70 ± 11.61 vs 38.98 ± 7.73 mg/L, P = 0.003) of Lu when the drug was intravenously administered at a dose of 30 mg/kg in rats. Also, Lu/MPEG-PCL micelles maintained the cytotoxicity of Lu on 4T1 breast cancer cells (IC50 = 6.4 ± 2.30 μg/mL) and C-26 colon carcinoma cells (IC50 = 12.62 ± 2.17 μg/mL) in vitro. These data suggested that encapsulation of Lu into MPEG-PCL micelles created an aqueous formulation of Lu with potential anticancer effect.
doi:10.2147/IJN.S45062
PMCID: PMC3748903  PMID: 23990719
luteolin; micelle; MPEG-PCL; cancer therapy
16.  Role of the NT-proBNP level in the diagnosis of pediatric heart failure and investigation of novel combined diagnostic criteria 
The aim of this study was to investigate the modified Ross criteria score and the diagnostic cut-off level for plasmatic amino-terminal pro-brain natriuretic peptide (NT-proBNP) in the diagnosis of pediatric heart failure, by analyzing the receiver operating characteristic (ROC) curve. The plasma NT-proBNP level was measured in 80 children diagnosed with heart failure according to the modified Ross criteria, 80 children with non-cardiogenic dyspnea and 80 healthy children. The NT-proBNP levels were then compared using an F-test. The cut-off score for heart failure in the modified Ross criteria and the diagnostic cut-off level for plasmatic NT-proBNP in pediatric heart failure were determined by ROC curve analysis. The results demonstrated that the NT-proBNP level was markedly increased in 76 of the 80 children with heart failure, and the correlation with the modified Ross criteria was 95%. Based on ROC curve analysis, the diagnosis of pediatric heart failure was most accurate when the modified Ross criteria score was ≥4 and the plasmatic NT-proBNP level was ≥598 ng/l. The NT-proBNP level was normal (0–300 ng/l) in the children with non-cardiogenic dyspnea and the healthy children. Significant differences were observed in the comparison of the three groups (P<0.01). In conclusion, a NT-proBNP level of ≥598 ng/l, combined with a modified Ross criteria score ≥4, is highly diagnostic of heart failure in children.
doi:10.3892/etm.2013.1250
PMCID: PMC3797316  PMID: 24137304
heart failure; amino-terminal pro-B-type natriuretic peptide; diagnostic criteria; children
17.  Genome Array of Hair Follicle Genes in Lambskin with Different Patterns 
PLoS ONE  2013;8(7):e68840.
Hu sheep lambskin comes from a specific breed of sheep of China. Hu sheep are considered a protected breed by the Chinese government. The hair follicles of these sheep have three types of waves, large, medium, and small. There are only few histological reports of Hu sheep lambskin, and there are no modern molecular or biological studies, so the molecular mechanisms underlying the formation of hair follicles with different patterns are not currently known. The aim of this article was to study the molecular mechanism of the formation of these types of hair follicles in Hu sheep. Histological and microscopic analysis indicated that the number of follicles with small waves was not significantly higher than the number of follicles with large waves (P>0.05). The diameters of primary and secondary small-wave follicles were significantly smaller than those of large-wave follicles (P<0.05; P<0.01). The ratio between the number primary follicles and the number of secondary follicles was significantly higher among small-wave follicles than among large-wave follicles (P<0.05). Differentially expressed genes in the skin tissue were screened using an Agilent gene chip and RT-PCR. Differential expression analysis revealed 3 groups of large waves and small waves; 1067, 2071, and 3879 differentially expressed genes; and 137 genes common to all 3 groups. Differentially expressed genes were classified using gene ontology. They were found to be mainly involved in cell differentiation, proliferation, apoptosis, growth, immune response, and ion transport. RT-PCR results of 4 differentially expressed genes were consistent with gene chip results. Combined with related literature, our results suggest that BMP7, MMP2, SNAI1, SFXN1, CDKNIC, MT3, and POU1F1 may have important effects on the formation of large-wave and small-wave hair follicles. This study may enrich knowledge of hair follicle development, and may identify the genes responsible for the formation of hair follicles with different patterns.
doi:10.1371/journal.pone.0068840
PMCID: PMC3728312  PMID: 23935896
18.  Cytotoxic and Antibacterial Beilschmiedic Acids from a Gabonese Species of Beilschmiedia 
Journal of natural products  2012;75(7):1319-1325.
High-throughput natural products chemistry methods have facilitated the isolation of eight new (1–8) and two known (9 and 10) beilschmiedic acid derivatives from the leaves of a Gabonese species of Beilschmiedia. Compounds 3–10 were isolated in microgram quantities, and the NMR data for structure elucidation and dereplication were acquired utilizing a Bruker BioSpin TCI 1.7 mm MicroCryoProbe. All of the compounds were screened for cytotoxic and antibacterial activity against NCI-H460 human lung cancer cells and a clinical isolate of methicillin-resistant Staphylococcus aureus, respectively. This is the first report of cytotoxic activity for the endiandric/beilschmiedic acid class of compounds.
doi:10.1021/np300241d
PMCID: PMC3424616  PMID: 22758788
19.  Glycemic variability in relation to oral disposition index in the subjects with different stages of glucose tolerance 
Background
Glucose variability could be an independent risk factor for diabetes complications in addition to average glucose. The deficiency in islet β cell secretion and insulin sensitivity, the two important pathophysiological mechanisms of diabetes, are responsible for glycemic disorders. The oral disposition index evaluated by product of insulin secretion and sensitivity is a useful marker of islet β cell function. The aim of the study is to investigate glycemic variability in relation to oral disposition index in the subjects across a range of glucose tolerance from the normal to overt type 2 diabetes.
Methods
75-g oral glucose tolerance test (OGTT) was performed in total 220 subjects: 47 with normal glucose regulation (NGR), 52 with impaired glucose metabolism (IGM, 8 with isolated impaired fasting glucose [IFG], 18 with isolated impaired glucose tolerance [IGT] and 26 with combined IFG and IGT), 61 screen-diagnosed diabetes by isolated 2-h glucose (DM2h) and 60 newly diagnosed diabetes by both fasting and 2-h glucose (DM). Insulin sensitivity index (Matsuda index, ISI), insulin secretion index (ΔI30/ΔG30), and integrated β cell function measured by the oral disposition index (ΔI30/ΔG30 multiplied by the ISI) were derived from OGTT. All subjects were monitored using the continuous glucose monitoring system for consecutive 72 hours. The multiple parameters of glycemic variability included the standard deviation of blood glucose (SD), mean of blood glucose (MBG), high blood glucose index (HBGI), continuous overlapping net glycemic action calculated every 1 h (CONGA1), mean of daily differences (MODD) and mean amplitude of glycemic excursions (MAGE).
Results
From the NGR to IGM to DM2h to DM group, the respective values of SD (mean ± SD) (0.9 ± 0.3, 1.5 ± 0.5, 1.9 ± 0.6 and 2.2 ± 0.6 mmol/), MBG (5.9 ± 0.5, 6.7 ± 0.7, 7.7 ± 1.0 and 8.7 ± 1.5 mmol/L), HGBI [median(Q1–Q3)][0.8(0.2–1.2), 2.0(1.2–3.7), 3.8(2.4–5.6) and 6.4(3.2–9.5)], CONGA1 (1.0 ± 0.2, 1.3 ± 0.2, 1.5 ± 0.3 and 1.8 ± 0.4 mmol/L), MODD (0.9 ± 0.3, 1.4 ± 0.4, 1.8 ± 0.7 and 2.1 ± 0.7 mmol/L) and MAGE (2.1 ± 0.6, 3.3 ± 1.0, 4.3 ± 1.4 and 4.8 ± 1.6 mmol/L) were all increased progressively (all p < 0.05), while their oral disposition indices [745(546–947), 362(271–475), 203(134–274) and 91(70–139)] were decreased progressively (p < 0.05). In addition, SD, MBG, HGBI, CONGA1, MODD and MAGE were all negatively associated with the oral disposition index in each group (all p < 0.05) and in the entire data set (r = −0.66, –0.66, –0.72, –0.59, –0.61 and −0.65, respectively, p < 0.05).
Conclusions
Increased glycemic variability parameters are consistently associated with decreased oral disposition index in subjects across the range of glucose tolerance from the NGR to IGM to DM2h to DM group.
doi:10.1186/1758-5996-5-38
PMCID: PMC3728076  PMID: 23876034
Glycemic variability; Continuous glucose monitoring; Oral disposition index; Type 2 diabetes
20.  Buried in Sands: Environmental Analysis at the Archaeological Site of Xiaohe Cemetery, Xinjiang, China 
PLoS ONE  2013;8(7):e68957.
Palynomorphs extracted from the mud coffins and plant remains preserved at the archaeological site of Xiaohe Cemetery (Cal. 3980 to 3540 years BP) in Lop Nur Desert of Xinjiang, China were investigated for the reconstruction of the ancient environments at the site. The results demonstrate that the Xiaohe People lived at a well-developed oasis, which was surrounded by extensive desert. The vegetation in the oasis consisted of Populus, Phragmites, Typha and probably of Gramineae, while the desert surrounding the oasis had some common drought-resistant plants dominated by Ephedra, Tamarix, Artemisia and Chenopodiaceae. This present work provides the first data of the environmental background at this site for further archaeological investigation.
doi:10.1371/journal.pone.0068957
PMCID: PMC3718815  PMID: 23894382
21.  Research on Effects of the Thermal Stimulation by Moxibustion at Different Temperatures on Cardiac Function in Rats and on Mast Cells in the Local Site of Moxibustion 
Objective. To observe effects of the thermal stimulation by moxibustion at different temperatures on cardiac function in brachycardia rat model and on mast cells in the local site of moxibustion at the Ximen Acupoint and to compare the differences of the effects of moxibustion at different temperatures. Method. Establish the brachycardia rat model with propranolol and observe effects of the thermal stimulation by moxibustion at different temperatures (38°C and 46°C). Results. The thermal stimulation by moxibustion at 2 temperatures may increase HR, MAP, LVSP, and +dp/dtmax and reduce t-dp/dtmax in brachycardia rats; the 46°C moxibustion group shows greater regulating effects on cardiac function in rats than that in the 38°C moxibustion group (P < 0.05). The thermal stimulation by moxibustion at 2 temperatures may promote degranulation of mast cells in the local site of moxibustion at the Ximen Acupoint; the degranulation rate in the 46°C moxibustion group is higher than that in the 38°C moxibustion group (P < 0.05). Conclusion. There is a certain association between the effect on the target organ and the effect in the local site of moxibustion. The moxibustion effect possibly resulted from local mast cells degranulation and different thermoreceptors activated by the thermal stimulation at different temperatures.
doi:10.1155/2013/545707
PMCID: PMC3732631  PMID: 23970933
22.  Narrow-band UVB radiation promotes dendrite formation by activating Rac1 in B16 melanoma cells 
Molecular and Clinical Oncology  2013;1(5):858-862.
Melanocytes are found scattered throughout the basal layer of the epidermis. Following hormone or ultraviolet (UV) light stimulation, the melanin pigments contained in melanocytes are transferred through the dendrites to the surrounding keratinocytes to protect against UV light damage or carcinogenesis. This has been considered as a morphological indicator of melanocytes and melanoma cells. Small GTPases of the Rho family have been implicated in the regulation of actin reorganization underlying dendrite formation in melanocytes and melanoma cells. It has been proven that ultraviolet light plays a pivotal role in melanocyte dendrite formation; however, the molecular mechanism underlying this process has not been fully elucidated. The effect of small GTPases, such as Rac1 and RhoA, on the morphology of B16 melanoma cells treated with narrow-band UVB radiation was investigated. The morphological changes were observed under a phase contrast microscope and the F-actin microfilament of the cytoskeleton was observed under a laser scanning confocal microscope. The pull-down assay was performed to detect the activity of the small GTPases Rac1 and RhoA. The morphological changes were evident, with globular cell bodies and increased numbers of tree branch-like dendrites. The cytoskeletal F-actin appeared disassembled following narrow-band UVB irradiation of B16 melanoma cells. Treatment of B16 melanoma cells with narrow-band UVB radiation resulted in the activation of Rac1 in a time-dependent manner. In conclusion, the present study may provide a novel method through which narrow-band UVB radiation may be used to promote dendrite formation by activating the Rac1 signaling pathway, resulting in F-actin rearrangement in B16 melanoma cells.
doi:10.3892/mco.2013.145
PMCID: PMC3916207  PMID: 24649261
narrow-band ultraviolet B radiation; Rac1; F-actin rearrangement; dendricity; B16 melanoma cells
23.  Effects of Moxibustion Temperature on Blood Cholesterol Level in a Mice Model of Acute Hyperlipidemia: Role of TRPV1 
Objectives. To compare the effects of moxibustion at two different temperatures (38°C and 46°C) on the blood cholesterol level in a mice model of acute hyperlipidemia, to detect the different expression levels of transient receptor potential vanilloid subfamily 1 (TRPV1) in the dorsal root ganglions of the wild mice, and to explore the correlation between TRPV1 and moxibustion's cholesterol-lowering effects. Method. Two different mice models were used: C57BL/6J wild type (WT) and TRPV1 gene knockout (TRPV1−/−). Each model was randomly divided into control group and model group with three subgroups after acute hyperlipidemia was established: model control group, 38°C moxibustion group, and 46°C moxibustion group. The mice in 38°C group and 46°C group were subject to moxibustion. After the therapy, the cholesterol concentration in serum was measured, and the expression of TRPV1 was quantified. Results. In WT mice, moxibustion caused a decrease in blood cholesterol level and upregulation of TRPV1 at the mRNA level, which was significantly greater in the 46°C group. In contrast, in TRPV1−/− mice, the differences of cholesterol-lowering effects of moxibustion were lost. Conclusions. Temperature is one of the important factors affecting the effects of moxibustion, and the cholesterol -lowering effect of moxibustion is related to the activation of TRPV1.
doi:10.1155/2013/871704
PMCID: PMC3713370  PMID: 23935685
24.  Activation of TRPV1 Prevents OxLDL-Induced Lipid Accumulation and TNF-α-Induced Inflammation in Macrophages: Role of Liver X Receptor α 
Mediators of Inflammation  2013;2013:925171.
The transient receptor potential vanilloid type 1 (TRPV1) is crucial in the pathogenesis of atherosclerosis; yet its role and underlying mechanism in the formation of macrophage foam cells remain unclear. Here, we show increased TRPV1 expression in the area of foamy macrophages in atherosclerotic aortas of apolipoprotein E-deficient mice. Exposure of mouse bone-marrow-derived macrophages to oxidized low-density lipoprotein (oxLDL) upregulated the expression of TRPV1. In addition, oxLDL activated TRPV1 and elicited calcium (Ca2+) influx, which were abrogated by the pharmacological TRPV1 antagonist capsazepine. Furthermore, oxLDL-induced lipid accumulation in macrophages was ameliorated by TRPV1 agonists but exacerbated by TRPV1 antagonist. Treatment with TRPV1 agonists did not affect the internalization of oxLDL but promoted cholesterol efflux by upregulating the efflux ATP-binding cassette (ABC) transporters ABCA1 and ABCG1. Moreover, the upregulation of ABC transporters was mainly through liver X receptor α- (LXRα-) dependent regulation of transcription. Moreover, the TNF-α-induced inflammatory response was alleviated by TRPV1 agonists but aggravated by the TRPV1 antagonist and LXRα siRNA in macrophages. Our data suggest that LXRα plays a pivotal role in TRPV1-activation-conferred protection against oxLDL-induced lipid accumulation and TNF-α-induced inflammation in macrophages.
doi:10.1155/2013/925171
PMCID: PMC3710635  PMID: 23878415
25.  Haptoglobin 2-2 Genotype Is Associated with Increased Risk of Type 2 Diabetes Mellitus in Northern Chinese 
The aim of this study was to investigate the association between haptoglobin (Hp) gene polymorphism and occurrence of type 2 diabetes mellitus (T2DM) in a northern Chinese population. We studied the association of the Hp gene polymorphism with T2DM in 584 unrelated T2DM patients and 690 control subjects with normal glucose tolerance among northern Chinese. The patients were diagnosed in accordance with the guidelines of the American Diabetes Association. The clinical characteristics of the study population were recorded, and the Hp genotype was determined. The frequencies of the genotypes in the group of T2DM patients and the controls were as follows: Hp2-2, 51.7% and 44.1%; Hp2-1, 39.7% and 45.1%; and Hp1-1, 8.6% and 10.9%, respectively. There was significant difference for the genotypic and allelic distribution between the two groups (p=0.021 and p=0.007, respectively). Even after readjusting for the confounding effects of age, gender, and body mass index, a significant effect of genotypes on T2DM was still found in the recessive model for the Hp2 allele tested (p=0.002). Those who had the Hp2-2 genotype had a significantly higher risk for T2DM than those with other genotypes (odds ratio=1.441, 95% confidence interval=1.143–1.817). The results showed that the Hp2-2 genotype is associated with increased risk of T2DM in the northern Chinese Han population.
doi:10.1089/gtmb.2011.0246
PMCID: PMC3378027  PMID: 22300541

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