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1.  Enhanced oral absorption of 20(S)-protopanaxadiol by self-assembled liquid crystalline nanoparticles containing piperine: in vitro and in vivo studies 
Background
20(S)-protopanaxadiol (PPD), similar to several other anticancer agents, has low oral absorption and is extensively metabolized. These factors limit the use of PPD for treatment of human diseases.
Methods
In this study, we used cubic nanoparticles containing piperine to improve the oral bioavailability of PPD and to enhance its absorption and inhibit its metabolism. Cubic nanoparticles loaded with PPD and piperine were prepared by fragmentation of glyceryl monoolein (GMO)/poloxamer 407 bulk cubic gel and verified using transmission electron microscopy and differential scanning calorimetry. We evaluated the in vitro release of PPD from these nanoparticles and its absorption across the Caco-2 cell monolayer model, and subsequently, we examined the bioavailability and metabolism of PPD and its nanoparticles in vivo.
Results
The in vitro release of PPD from these nanoparticles was less than 5% at 12 hours. PPD-cubosome and PPD-cubosome loaded with piperine (molar ratio PPD/piperine, 1:3) increased the apical to basolateral permeability values of PPD across the Caco-2 cell monolayer from 53% to 64%, respectively. In addition, the results of a pharmacokinetic study in rats showed that the relative bioavailabilities of PPD-cubosome [area under concentration–time curve (AUC)0–∞] and PPD-cubosome containing piperine (AUC0–∞) compared to that of raw PPD (AUC0–∞) were 166% and 248%, respectively.
Conclusion
The increased bioavailability of PPD-cubosome loaded with piperine is due to an increase in absorption and inhibition of metabolism of PPD by cubic nanoparticles containing piperine rather than because of improved release of PPD. The cubic nanoparticles containing piperine may be a promising oral carrier for anticancer drugs with poor oral absorption and that undergo extensive metabolism by cytochrome P450.
doi:10.2147/IJN.S38203
PMCID: PMC3576041  PMID: 23426652
20(S)-protopanaxadiol; cubosome; piperine; Caco-2 cell monolayer; bioavailability; metabolites
2.  Preparation of a nanoscale baohuoside I-phospholipid complex and determination of its absorption: in vivo and in vitro evaluations 
Background
Baohuoside I is a potential anticancer drug for a variety of malignancies and has been approved for in vitro use. However, baohuoside I has very poor oral absorption.
Methods
In the present study, we prepared baohuoside I-phospholipid complexes of different diameters and determined their physicochemical properties using transmission electron microscopy, ultraviolet spectroscopy, and differential scanning calorimetry. The in vitro absorption of baohuoside I and baohuoside I-phospholipid complexes of different sizes were compared using the Caco-2 cell culture model, and subsequently, the bioavailability of baohuosidel and its complexes were estimated in vivo.
Results
Compared with the large-sized phospholipid complexes, a nanoscale phospholipid complex improved the oral bioavailability of baohuoside I. In addition, our results suggest that the smaller the particle size, the faster the complexes crossed the Caco-2 monolayer and the faster they were resorbed after oral administration in rats. The relative oral bioavailability of a nanoscale size 81 ± 10 nm baohuoside I-phospholipid complex (area under the concentration-time curve [AUC]0–∞) was 342%, while that of baohuoside I and a 227.3 ± 65.2 μm baohuoside I-phospholipid complex was 165%.
Conclusion
We enhanced the oral bioavailability of baohuoside I by reducing the particle size of the phospholipid complex to the nanometer range, thereby improving its potential for clinical application.
doi:10.2147/IJN.S35965
PMCID: PMC3446837  PMID: 23028219
nanoscale phospholipid complex; Caco-2 cell monolayer; bioavailability; oral absorption
3.  Postsynaptic potentiation of corticospinal projecting neurons in the anterior cingulate cortex after nerve injury 
Molecular Pain  2014;10:33.
Long-term potentiation (LTP) is the key cellular mechanism for physiological learning and pathological chronic pain. In the anterior cingulate cortex (ACC), postsynaptic recruitment or modification of AMPA receptor (AMPAR) GluA1 contribute to the expression of LTP. Here we report that pyramidal cells in the deep layers of the ACC send direct descending projecting terminals to the dorsal horn of the spinal cord (lamina I-III). After peripheral nerve injury, these projection cells are activated, and postsynaptic excitatory responses of these descending projecting neurons were significantly enhanced. Newly recruited AMPARs contribute to the potentiated synaptic transmission of cingulate neurons. PKA-dependent phosphorylation of GluA1 is important, since enhanced synaptic transmission was abolished in GluA1 phosphorylation site serine-845 mutant mice. Our findings provide strong evidence that peripheral nerve injury induce long-term enhancement of cortical-spinal projecting cells in the ACC. Direct top-down projection system provides rapid and profound modulation of spinal sensory transmission, including painful information. Inhibiting cortical top-down descending facilitation may serve as a novel target for treating neuropathic pain.
doi:10.1186/1744-8069-10-33
PMCID: PMC4060852  PMID: 24890933
4.  Comparison of long non-coding RNAs, microRNAs and messenger RNAs involved in initiation and progression of esophageal squamous cell carcinoma 
Molecular Medicine Reports  2014;10(2):652-662.
Traditionally, cancer research has focused on protein-coding genes, which are considered the principal effectors and regulators of tumorigenesis. Non-coding RNAs, in particular microRNAs (miRNAs) and long non-coding RNAs (lncRNAs), have been widely reported to be important in the regulation of tumorigenesis and cancer development. However, to the best of our knowledge, investigation of the expression profiles of lncRNAs and a comparison of the involvement of lncRNAs, miRNAs and messenger RNAs (mRNAs) in esophageal tumorigenesis and development have not previously been performed. In the current study, intrinsic associations among the expression profiles of lncRNAs, miRNAs and mRNAs from normal esophageal tissues and those from cancer tissues were investigated. Oligonucleotide microarrays were used to detect the expression profiles of the three types of RNA in the canceration processes of human esophageal squamous cell carcinoma (ESCC) tissues. It was demonstrated that the different RNAs exhibit associated patterns of expression among normal esophageal epithelium, low-grade intraepithelial neoplasia (LGIN), high-grade intraepithelial neoplasia (HGIN), and carcinoma tissues, particularly in the critical period of canceration (HGIN to ESCC). Furthermore, the results indicated a high level of similarity in the potential function of lncRNAs, miRNAs and mRNAs in the processes of ESCC development. In the current study, a first generation atlas of lncRNA profiling and its association with miRNAs and mRNAs in the canceration processes of ESCC were presented.
doi:10.3892/mmr.2014.2287
PMCID: PMC4094766  PMID: 24888564
long non-coding RNA; microRNA; messenger RNA; esophageal squamous cell carcinoma; canceration processes; bioinformatic analysis
5.  The Significance of Removing Ruptured Intervertebral Discs for Interbody Fusion in Treating Thoracic or Lumbar Type B and C Spinal Injuries through a One-Stage Posterior Approach 
PLoS ONE  2014;9(5):e97275.
Objectives
To identify the negative effect on treatment results of reserving damaged intervertebral discs when treating type B and type C spinal fracture-dislocations through a one-stage posterior approach.
Methods
This is a retrospective review of 53 consecutive patients who were treated in our spine surgery center from January 2005 to May 2012 due to severe thoracolumbar spinal fracture-dislocation. The patients in Group A (24 patients) underwent long-segment instrumentation laminectomy with pedicle screw-rod fixators for neural decompression. In Group B (29 patients), the patients underwent long-segment instrumentation laminectomy with pedicle screw-rod fixators for neural decompression evacuating of the ruptured disc and inserting of a bone graft into the evacuated disc space for interbody fusion. The mean time between injury and operation was 4.1 days (range 2–15 days). The clinical, radiologic and complication outcomes were analyzed retrospectively.
Results
Periodic follow-ups were carried out until an affirmative union or treatment failure took place. A progressive kyphosis angle larger than 10°, loss of disc height, pseudoarthrosis, recurrence of dislocation or subluxation, or instrument failure before fusion were considered treatment failures. Treatment failures were detected in 13 cases in Group A (failure rate was 54.2%). In Group B, there were 28 cases in which definitive bone fusion was demonstrated on CT scans, and CT scans of the other cases demonstrated undefined pseudoarthrosis without hardware failure. There were statistically significant differences between the two groups (p<0.001 chi-square test). The neurologic recoveries, assessed by the ASIA scoring system, were not satisfactory for the neural deficit patients in either group, indicating there was no significant difference with regard to neurologic recovery between the two groups (p>0.05 Fisher's exact test).
Conclusion
Intervertebral disc damage is a common characteristic in type B and C spinal fracture-dislocation injuries. The damaged intervertebral disc should be removed and substituted with a bone graft because reserving the damaged disc in situ increases the risk of treatment failure.
doi:10.1371/journal.pone.0097275
PMCID: PMC4020822  PMID: 24827733
6.  Enhanced bioavailability of apigenin via preparation of a carbon nanopowder solid dispersion 
In this study, a novel carbon nanopowder (CNP) drug carrier was developed to improve the oral bioavailability of apigenin (AP). Solid dispersions (SDs) of AP with CNP were prepared, and their in vitro drug release and in vivo performance were evaluated. The physicochemical properties of the formulations were examined by differential scanning calorimetry, X-ray diffraction, and scanning electron microscopy. Drug release profiles showed that AP dissolution from the CNP-AP system (weight ratio, 6:1) after 60 minutes improved by 275% compared with that of pure AP. Moreover, the pharmacokinetic analysis of SD formulations in rats showed that the AP area under the curve0–t value was 1.83 times higher for the CNP-AP system than for pure AP, indicating that its bioavailability was significantly improved. In addition, compared with pure AP, SDs had a significantly higher peak and shorter time to peak. Preliminary intestinal toxicity tests indicated that there was no significant difference in the tissues of the rats treated with the CNP-AP system, rats treated with the CNP alone, and controls. In conclusion, CNP-based SDs could be used for enhancing the bioavailability of poorly water-soluble drugs while also improving drug safety.
doi:10.2147/IJN.S60938
PMCID: PMC4026550  PMID: 24872695
apigenin; carbon nanopowder; solid dispersions; dissolution; oral bioavailability
7.  Functional promoter -765 G > C variant in COX-2 gene is associated with the susceptibility of breast cancer in Chinese Han women 
Background
Cyclooxygenase (COX) is a rate-limiting enzyme in prostaglandins synthesis which exists in two isoforms, COX-1 and COX-2. Over-expression of COX-2 was considered to increase the proliferation and enhance the invasiveness of breast cancer cells. It was suggested that genetic variations in COX-2 could influence its expression. Herein, the present study was aimed to investigate the associations between two mostly studied functional polymorphisms (-765 G > C and 8473 C > T) in COX-2 and breast cancer risk in Chinese Han women.
Methods
In the hospital-based case-control study, 465 breast cancer patients and 799 cancer-free controls were genotyped for the COX-2 -765 G > C and 8473 C > T polymorphisms using TaqMan assay. We estimated odds ratios (ORs) and 95% confidence intervals (95% CIs) using the logistic regression.
Results
Compared with the wild genotype of -765 G > C, we found a statistically significant increased risk of breast cancer associated with the variant genotypes [GC/CC vs. GG: OR = 1.56, 95% CI = 1.11–2.21]. In the stratified analysis, the increased risk was more predominant among the subgroups of younger subjects (OR = 1.61, 95% CI = 1.00–2.61). Furthermore, the variant genotypes were associated with large tumor size (OR = 3.01, 95% CI = 1.47–6.12). No significant association was observed for the 8473 C > T polymorphism.
Conclusions
Our results suggest that the functional -765 G > C polymorphism in the promoter of COX-2 may influence the susceptibility and progression of breast cancer in the Chinese Han population.
doi:10.1186/1475-2867-14-38
PMCID: PMC4018614  PMID: 24826080
Cyclooxygenase; COX-2; Polymorphism; Breast cancer; Susceptibility
8.  Diabetic Retinopathy and Estimated Cerebrospinal Fluid Pressure. The Beijing Eye Study 2011 
PLoS ONE  2014;9(5):e96273.
Purpose
The cerebrospinal fluid pressure (CSFP) is a major determinant of central retinal vein pressure and thus of retinal capillary pressure. We tested the hypothesis whether prevalence and severity of diabetic retinopathy are associated with CSFP.
Methods
The population-based Beijing Eye Study 2011 included 3468 individuals with a mean age of 64.6±9.8 years. A detailed ophthalmic examination was performed including fundus photography for the assessment of diabetic retinopathy according. Based on a previous study with lumbar cerebrospinal fluid pressure (CSFP) measurements, CSFP was calculated as CSFP[mmHg] = 0.44xBody Mass Index[kg/m2]+0.16 Diastolic Blood Pressure[mmHg]–0.18xAge[Years]−1.91.
Results
In binary regression analysis, presence of diabetic retinopathy was significantly associated with higher levels of HbA1c (P<0.001; regression coefficient B:0.25; odds ratio (OR):1.28; 95% confidence interval (CI):1.15,1.43), higher blood concentration of glucose (P<0.001; B:0.40;OR:1.49;95%CI:1.36,1.63), longer known duration of diabetes mellitus (P<0.001; B:0.14;OR:1.15; 95%CI:1.11,1.19), higher systolic blood pressure (P<0.001; B:0.03;OR:1.03;95%CI:1.02,1.04), lower diastolic blood pressure (P<0.001; B:−0.06;OR:0.94;95%CI:0.91,0.97), and higher CSFP (P = 0.002; B:0.13;OR:1.14;95%CI:1.05,1.24). Severity of diabetic retinopathy was significantly associated with higher HbA1c value (P<0.001; standardized coefficient beta: 0.19; correlation coefficient B: 0.07;95%CI:0.05,0.08), higher blood concentration of glucose (P<0.001; beta:0.18;B:0.04;95%CI:0.04,0.05), longer known duration of diabetes mellitus (P<0.001; beta:0.20;B:0.03;95%CI:0.02,0.03), lower level of education (P = 0.001; beta:−0.05;B:−0.02;95%CI:−0.03,−0.01), lower diastolic blood pressure (P = 0.002; beta:−0.08;B:−0.001;95%CI:−0.004,−0.001), higher systolic blood pressure (P = 0.006; beta:0.06;B:0.001;95%CI:0.000,0.001), and higher CSFP (P = 0.006; beta:0.06;B:0.006;95%CI:0.002,0.010).
Conclusions
Higher prevalence and severity of diabetic retinopathy were associated with higher estimated CSFP after adjusting for systemic parameters. Higher CSFP through a higher retinal vein pressure may lead to more marked retinal venous congestion and vascular leakage in diabetic retinae.
doi:10.1371/journal.pone.0096273
PMCID: PMC4006875  PMID: 24789334
9.  Chronic stress impairs GABAergic control of amygdala through suppressing the tonic GABAA receptor currents 
Molecular Brain  2014;7:32.
Background
Chronic stress is generally known to exacerbate the development of numerous neuropsychiatric diseases such as fear and anxiety disorders, which is at least partially due to the disinhibition of amygdala subsequent to the prolonged stress exposure. GABA receptor A (GABAAR) mediates the primary component of inhibition in brain and its activation produces two forms of inhibition: the phasic and tonic inhibition. While both of them are critically engaged in limiting the activity of amygdala, their roles in the amygdala disinhibition subsequent to chronic stress exposure are largely unknown.
Results
We investigated the possible alterations of phasic and tonic GABAAR currents and their roles in the amygdala disinhibition subsequent to chronic stress. We found that both chronic immobilization and unpredictable stress led to long lasting loss of tonic GABAAR currents in the projection neurons of lateral amygdala. By contrast, the phasic GABAAR currents, as measured by the spontaneous inhibitory postsynaptic currents, were virtually unaltered. The loss of tonic inhibition varied with the duration of daily stress and the total days of stress exposure. It was prevented by pretreatment with metyrapone to block corticosterone synthesis or RU 38486, a glucocorticoid receptor antagonist, suggesting the critical involvement of glucocorticoid receptor activation. Moreover, chronic treatment with corticosterone mimicked the effect of chronic stress and reduced the tonic inhibition in lateral amygdala of control mice. The loss of tonic inhibition resulted in the impaired GABAergic gating on neuronal excitability in amygdala, which was prevented by metyrapone pretreatment.
Conclusions
Our study suggests that enduring loss of tonic but not phasic GABAAR currents critically contributes to the prolonged amygdala disinhibition subsequent to chronic stress. We propose that the preferential loss of tonic inhibition may account for the development of stress-related neuropsychiatric diseases.
doi:10.1186/1756-6606-7-32
PMCID: PMC4012764  PMID: 24758222
Amygdala; Chronic stress; GABA; Electrophysiology; Tonic inhibition; Corticosterone; Glucocorticoid receptor; Neuronal excitability
10.  Clinical evaluation of cetuximab combined with an S-1 and oxaliplatin regimen for Chinese patients with advanced gastric cancer 
Background
The prognosis of patients with advanced gastric cancer is poor. The goal of this study was to evaluate the efficacy and safety of combination therapy of cetuximab and S-1 combined with oxaliplatin (SOX) in Chinese patients with advanced gastric cancer.
Methods
For patients in the experimental group (cetuximab in combination with SOX (Ce-SOX), 30 patients), once-weekly cetuximab (400 mg/m2 at the first infusion then 250 mg/m2 every week) was administered. For patients in both the control (SOX alone, 26 patients) and experimental groups, oxaliplatin (100 mg/m2) was administered intravenously on day 1, while S-1 (80 mg/m2/day) was given orally twice daily for 14 days. The endpoints of this study included progression-free survival, response rate, and disease-control rate.
Results
There was no statistically significant difference in response rate between the Ce-SOX and SOX groups (54.8% versus 44%, P = 0.225). The difference in disease-control rate was also statistically insignificant between the two groups (87.1% versus 76%, P = 0.162). Median progression-free survival in the Ce-SOX group was significantly higher than that in the SOX group (12.8 versus 10.1 months, P = 0.007). The median overall survival of the Ce-SOX group and SOX group was 14.0 and 12.2 months, respectively (P = 0.043). The one-year survival rate for the Ce-SOX group was 57% compared to 40% in the SOX group. There was no statistical difference in the grade 3 or 4 adverse effects between the two groups.
Conclusions
These findings suggest that the cetuximab combined with SOX regimen is feasible and shows promising efficacy with tolerable adverse effects in Chinese patients with advanced gastric cancer.
doi:10.1186/1477-7819-12-115
PMCID: PMC4020605  PMID: 24758484
11.  An attempt to stabilize tanshinone IIA solid dispersion by the use of ternary systems with nano-CaCO3 and poloxamer 188 
Pharmacognosy Magazine  2014;10(Suppl 2):S311-S317.
Background:
Tanshinone IIA (TSIIA) on solid dispersions (SDs) has thermodynamical instability of amorphous drug. Ternary solid dispersions (tSDs) can extend the stability of the amorphous form of drug. Poloxamer 188 was used as a SD carrier. Nano-CaCO3 played an important role in adsorption of biomolecules and is being developed for a host of biotechnological applications.
Objective:
The aim of the present study was to investigate the dissolution behavior and accelerated stability of TSIIA on solid dispersions (SDs) by the use of ternary systems with nano-CaCO3 and poloxamer 188.
Materials and Methods:
The TSIIA tSDs were prepared by a spray-drying method. First, the effect of combination of poloxamer 188 and nano-CaCO3 on TSIIA dissolution was studied. Subsequently, a set of complementary techniques (DSC, XRPD, SEM and FTIR) was used to monitor the physical changes of TSIIA in the SDs. Finally, stability test was carried out under the conditions 40°C/75% RH for 6 months.
Results:
The characterization of tSDs by differential scanning calorimetry analysis (DSC) and X-ray powder diffraction (XRPD) showed that TSIIA was present in its amorphous form. Fourier transforms infrared spectroscopy (FTIR) suggested the presence of interactions between TSIIA and carriers in tSDs. Improvement in the dissolution rate was observed for all SDs. The stability study conducted on SDs with nano-CaCO3 showed stable drug content and dissolution behavior, over the period of 6 months as compared with freshly prepared SDs.
Conclusion:
SDs preparation with nano-CaCO3 and poloxamer 188 may be a promising approach to enhance the dissolution and stability of TSIIA.
doi:10.4103/0973-1296.133286
PMCID: PMC4078353  PMID: 24991109
Combination carriers; in vitro dissolution; stability; ternary solid dispersions
12.  Synthesis of PPAR-γ Activators Inspired by the Marine Natural Product, Paecilocin A 
Marine Drugs  2014;12(2):926-939.
A series of N-substituted phthalimide derivatives were synthesized based on a pharmacophore study of paecilocin A (a natural PPAR-γ agonist) and synthetic leads. The introduction of hydrophilic and hydrophobic groups to the phthalimide skeleton yielded compounds 3–14. Compound 7 showed significant PPAR-γ activation in a luciferase assay using rat liver Ac2F cells. Docking simulations showed that a free hydroxyl group on the phthalimide head and a suitable hydrophilic tail, including a phenyl linker, were beneficial for PPAR-γ activation. Compound 7 and rosiglitazone concentration-dependently activated PPAR-γ with EC50 values of 0.67 μM and 0.028 μM, respectively. These phthalimide derivatives could be further investigated as a new class of PPAR-γ ligands.
doi:10.3390/md12020926
PMCID: PMC3944523  PMID: 24531188
PPAR-γ; diabetes; phthalimide; luciferase assay; docking simulation; cell proliferation
13.  Distal pancreatectomy with en bloc celiac axis resection for pancreatic body-tail cancer: Is it justified? 
Background
The aim of this study was to evaluate the safety and efficacy of distal pancreatectomy with en bloc celiac axis resection (DP-CAR) for pancreatic body-tail cancer.
Material/Methods
The medical records of 12 patients who underwent DP-CAR for pancreatic body-tail cancer were retrospectively studied, together with a literature review of studies including at least 3 cases of DP-CAR.
Results
There were no deaths among our 12 cases. Postoperative morbidity developed in 9 cases and was successfully managed by non-surgical treatment. No patients developed ischemic complications. Median overall survival was 10 months. A total of 19 studies involving 203 patients who underwent DP-CAR were included in the literature review. The overall morbidity and mortality rates were 50.2% and 3.0%, respectively. The overall median survival after surgery ranged from 9.3 to 26 months.
Conclusions
DP-CAR is a safe and effective treatment for patients with locally advanced pancreatic body-tail cancer.
doi:10.12659/MSM.889847
PMCID: PMC3890411  PMID: 24382572
cancer of the pancreas; distal pancreatectomy; celiac axis resection; Appleby operation
14.  Association between APE1 Single Nucleotide Polymorphism (rs1760944) and Cancer Risk: a Meta-Analysis Based on 6,419 Cancer Cases and 6,781 Case-free Controls 
Journal of Cancer  2014;5(3):253-259.
Apurinic/apyrimidinic endonuclease 1 (APE1) is an essential enzyme in the base excision repair pathway. Epidemiological studies have suggested associations between APE1 rs1760944 polymorphism and cancer risk. This study was aimed to evaluate the relationship between APE1 rs1760944 polymorphism and cancer risk. We searched Pubmed, ISI Web of Knowledge, Embase, Chinese National Knowledge Infrastructure (CNKI) databases until September 2013 to identify eligible studies. Odds ratios (ORs) and 95 % confidence intervals (CIs) were used to estimate the strength of the associations. 12 studies from 11 articles on APE1 rs1760944 genotypes and cancer risk were identified, including a total of 6,419 cancer cases and 6,781 case-free controls. Overall, APE1 rs1760944 polymorphism was significantly associated with the decreased risk of cancer in any genetic models (G vs. T: OR = 0.86, 95% CI = 0.82-0.90; homozygote comparison: OR = 0.74, 95% CI = 0.67-0.82; heterozygote comparison: OR =0.88, 95%CI = 0.81-0.95; dominant model TG+GG vs. TT: OR = 0.82, 95% CI = 0.76-0.89; recessive model GG vs. TT+TG: OR = 0.81, 95%CI = 0.75-0.88). In the stratified analysis by populations, the effect was remain in studies of Asian population (homozygote comparison: OR = 0.71, 95%CI = 0.63-0.79; heterozygote comparison: OR = 0.86, 95 %CI = 0.79- 0.94; dominant model: OR = 0.80, 95% CI = 0.74 -0.87 and recessive model: OR = 0.78, 95%CI = 0.71-0.86). Moreover, a significantly decreased risk was found in lung cancer studies (homozygote comparison: OR = 0.68, 95% CI = 0.59-0.79; heterozygote comparison: OR = 0.86, 95%CI = 0.77- 0.98; dominant model: OR = 0.80, 95%CI = 0.72-0.90 and recessive model: OR= 0.77, 95% CI= 0.68-0.87). These findings support that APE1 rs1760944 polymorphism has a possible protective effect on cancer susceptibility particularly among Asians. Further studies based on different ethnicity and various cancer types are warranted to verify our findings.
doi:10.7150/jca.8085
PMCID: PMC3963083  PMID: 24665350
APE1; single nucleotide polymorphism; cancer susceptibility; meta-analysis.
15.  Terson syndrome with no cerebral hemorrhage: A case report 
The present study reports the case of a 33-year-old male who presented with Terson syndrome with no cerebral hemorrhage secondary to traumatic brain injury (TBI). A computed tomography scan of the patient, who had sustained an impact injury to the right occipital region, showed no cerebral lesion. Ophthalmoscopy clearly demonstrated vitreous hemorrhage in both eye globes. Vitreous hemorrhage, which results from an abrupt increase in intracranial pressure (ICP), is associated with TBI. In this case, the visual disturbance was attributed to Terson syndrome secondary to TBI. Therefore, close ophthalmological and radiological evaluation is required in patients with TBI, in order to enable the diagnosis of Terson syndrome and an early vitrectomy.
doi:10.3892/etm.2013.1400
PMCID: PMC3861496  PMID: 24348800
cerebral hemorrhage; intracranial pressure; traumatic brain injury; Terson syndrome; vitreous hemorrhage
16.  Endoplasmic reticulum stress in diethylnitrosamine-induced rat liver cancer 
Oncology Letters  2013;7(1):23-27.
To analyze the significance of endoplasmic reticulum stress (ERS) in the development of diethylnitrosamine (DEN)-induced liver cancer in rats, critical regulatory factors in ERS signaling pathways were investigated in the present study. The results showed that the expression of ERS-related proteins gradually increased in the early and mid-term stages of carcinogenesis, while in the later stages, the expression of these proteins did not change significantly after reaching a peak. ERS is involved in DEN-induced rat liver injury, the proliferation of liver cells and the occurrence and development of liver cirrhosis. However, ERS did not affect hepatoma cell growth following the formation of rat liver cancer in the current study.
doi:10.3892/ol.2013.1651
PMCID: PMC3861556  PMID: 24348814
endoplasmic reticulum stress; diethylnitrosamine; rats; liver cancer
17.  β-cyclodextrin assistant flavonoid glycosides enzymatic hydrolysis 
Pharmacognosy Magazine  2013;9(Suppl 1):S11-S18.
Background:
The content of icaritin and genistein in herba is very low, preparation with relatively large quantities is an important issue for extensive pharmacological studies.
Objective:
This study focuses on preparing and enzymic hydrolysis of flavonoid glycosides /β-cyclodextrin inclusion complex to increase the hydrolysis rate.
Materials and Methods:
The physical property of newly prepared inclusion complex was tested by differential scanning calorimetry (DSC). The conditions of enzymatic hydrolysis were optimized for the bioconversion of flavonoid glycosides /β-cyclodextrin inclusion complex by mono-factor experimental design. The experiments are using the icariin and genistein as the model drugs.
Results:
The solubility of icariin and genistein were increased almost 17 times from 29.2 μg/ml to 513.5 μg/ml at 60°C and 28 times from 7.78 μg/ml to 221.46 μg/ml at 50°C, respectively, demonstrating that the inclusion complex could significantly increase the solubility of flavonoid glycosides. Under the optimal conditions, the reaction time of icariin and genistin decreased by 68% and 145%, when compared with that without β-CD inclusion. By using this enzymatic condition, 473 mg icaritin (with the purity of 99.34%) and 567 mg genistein(with the purity of 99.46%), which was finally determined by melt point, ESI-MS, UV, IR, 1H NMR and 13C NMR, was obtained eventually by transforming the inclusion complex(contains 1.0 g substrates).
Conclusion:
This study can clearly indicate a new attempt to improve the speed of enzyme-hydrolysis of poorly water-soluble flavonoid glycosides and find a more superior condition which is used to prepare icaritin and genistein.
doi:10.4103/0973-1296.117851
PMCID: PMC3798134  PMID: 24143039
Cellulase; enzymatic hydrolysis; flavonoid glycosides; snailase; β-CD inclusion complex
18.  Tracheobronchopathia osteochondroplastica: a case report and literature review 
Journal of Thoracic Disease  2013;5(5):E182-E184.
Tracheobronchopathia osteochondroplastica (TO) was diagnosed in a 52-year-old male with prolonged dry cough. Computerized tomography (CT) demonstrated that there were multiple calcified nodules in the anterolateral wall of trachea, sparing the posterior tracheal membrane. Fiberoptic bronchoscopy (FOB) showed that submucosal nodules protruded into the airway lumen. Histopathological exam found ossification and cartilage in the submucosa. TO is a scarce benign disorder, characterized by submucosal bony and cartilaginous nodules. The clinical manifestation is undistinguished and treatment is symptomatically dependent. FOB is a definitive diagnostic procedure. The characteristics of FOB finding are described as beaded, spiculate, rock garden, or cobble-stoned like nodules, which projected into the tracheobronchus lumen, sparing the posterior wall. Histopathological exam might re-confirm the diagnosis, finding ossification and cartilage in the submucosa of airway. Awareness of TO is significantly important, especially in chronic cough patients with special CT image, and FOB should be performed to confirm the diagnosis.
doi:10.3978/j.issn.2072-1439.2013.08.64
PMCID: PMC3815732  PMID: 24255788
Tracheobronchopathia osteochondroplastica (TO); cough; fiberoptic bronchoscopy (FOB)
19.  Combined general and regional anesthesia and effects on immune function in patients with benign ovarian tumors treated by laparoscopic therapy 
Objective: Anesthesia has been shown to suppress immune function, which can negatively affect the treatment of patients with various tumors. Here, we assessed two different anesthesia methods, general versus combined regional/general, in treatment of benign ovarian tumor by laparoscopic therapy. Methods: Out of 160 patients with benign ovarian tumors treated by laparoscopic therapy, 80 received general anesthesia combined with thoracic epidural anesthesia during surgery, and 80 received general anesthesia only. Venous blood samples were obtained at the following time points: before induction of anesthesia (T0), 2 hours after anesthesia, during operation, 3 days (d) after operation, 5 d after operation, and 7 d after operation. Percentages of CD3+, CD4+, and CD4+/CD8+ T lymphocytes were determined at these time points by flow cytometry to assess immune function. Results: For both groups, percentages of CD3+, CD4+, and CD4+/CD8+ T cells decreased significantly from T0 to 2 hr after anesthesia (P < 0.05). These percentages decreased again during surgery. However, T cell percentages in patients receiving combined anesthesia returned to normal levels 5 d after surgery, and those receiving only intravenous anesthesia returned to normal by 7 d after surgery. There were no significant differences in CD3+, CD4+, or CD4+/CD8+ T cell percentages between the two anesthesia groups at T0 and 7 d. However, significant differences in these percentages were observed between the two groups at all other time points. Interestingly, the decrease observed within the combined group were less dramatic than those observed within the intravenous-only group (P < 0.05). Conclusions: These findings indicate that, while any anesthesia may suppress immune function of patients treated by laparoscopic therapy, the effect of general anesthesia combined with thoracic epidural anesthesia on immune function was less than that produced by general anesthesia alone.
PMCID: PMC3762630  PMID: 24040483
Epidural anesthesia; general anesthesia; ovarian tumor; laparoscopy; immune function
20.  Analysis of the genetic diversity of the nematode parasite Baylisascaris schroederi from wild giant pandas in different mountain ranges in China 
Parasites & Vectors  2013;6:233.
Background
Baylisascaris schroederi is one of the most common nematodes of the giant panda, and can cause severe baylisascarosis in both wild and captive giant pandas. Previous studies of the giant pandas indicated that this population is genetically distinct, implying the presence of a new subspecies. Based on the co-evolution between the parasite and the host, the aim of this study was to investigate the genetic differentiation in the B. schroederi population collected from giant pandas inhabiting different mountain ranges, and further to identify whether the evolution of this parasite correlates with the evolution of giant pandas.
Methods
In this study, 48 B. schroederi were collected from 28 wild giant pandas inhabiting the Qinling, Minshan and Qionglai mountain ranges in China. The complete sequence of the mitochondrial cytochrome b (mtCytb) gene was amplified by PCR, and the corresponding population genetic diversity of the three mountain populations was determined. In addition, we discussed the evolutionary relationship between B. schroederi and its host giant panda.
Results
For the DNA dataset, insignificant Fst values and a significant, high level of gene flow were detected among the three mountain populations of B. schroederi, and high genetic variation within populations and a low genetic distance were observed. Both phylogenetic analyses and network mapping of the 16 haplotypes revealed a dispersed pattern and an absence of branches strictly corresponding to the three mountain range sampling sites. Neutrality tests and mismatch analysis indicated that B. schroederi experienced a population expansion in the past.
Conclusions
Taken together, the dispersed haplotype map, extremely high gene flow among the three populations of B. schroederi, low genetic structure and rapid evolutionary rate suggest that the B. schroederi populations did not follow a pattern of isolation by distance, indicating the existence of physical connections before these populations became geographically separated.
doi:10.1186/1756-3305-6-233
PMCID: PMC3750503  PMID: 23924705
Giant panda; Baylisascaris schroederi; Mountain ranges; Genetic diversity; Genetic structure; Phylogeography
21.  Preparation, characterization, and in vivo evaluation of tanshinone IIA solid dispersions with silica nanoparticles 
We prepared solid dispersions (SDs) of tanshinone IIA (TSIIA) with silica nanoparticles, which function as dispersing carriers, using a spray-drying method and evaluated their in vitro dissolution and in vivo performance. The extent of TSIIA dissolution in the silica nanoparticles/TSIIA system (weight ratio, 5:1) was approximately 92% higher than that of the pure drug after 60 minutes. However, increasing the content of silica nanoparticles from 5:1 to 7:1 in this system did not significantly increase the rate or extent of TSIIA dissolution. The physicochemical properties of SDs were investigated using scanning electron microscopy, differential scanning calorimetry, X-ray powder diffraction, and Fourier transforms infrared spectroscopy. Studying the stability of the SDs of TSIIA revealed that the drug content of the formulation and dissolution behavior was unchanged under the applied storage conditions. In vivo tests showed that SDs of the silica nanoparticles/TSIIA had a significantly larger area under the concentration-time curve, which was 1.27 times more than that of TSIIA (P < 0.01). Additionally, the values of maximum plasma concentration and the time to reach maximum plasma concentration of the SDs were higher than those of TSIIA and the physical mixing system. Based on these results, we conclude that the silica nanoparticle based SDs achieved complete dissolution, increased absorption rate, maintained drug stability, and showed improved oral bioavailability compared to TSIIA alone.
doi:10.2147/IJN.S40374
PMCID: PMC3699171  PMID: 23836971
tanshinone IIA; solid dispersions; silica nanoparticles; in vitro dissolution; stability; oral bioavailability
22.  Correction: Stuttering Interneurons Generate Fast and Robust Inhibition onto Projection Neurons with Low Capacity of Short Term Modulation in Mouse Lateral Amygdala 
PLoS ONE  2013;8(6):10.1371/annotation/3bc30ead-f84a-434a-8314-4aa1c9fcdcc0.
doi:10.1371/annotation/3bc30ead-f84a-434a-8314-4aa1c9fcdcc0
PMCID: PMC3731384
23.  Long Noncoding RNA HOTAIR Is a Prognostic Marker for Esophageal Squamous Cell Carcinoma Progression and Survival 
PLoS ONE  2013;8(5):e63516.
Background
It is currently unclear whether the expression of HOX transcript antisense RNA (HOTAIR) correlates with the progression of esophageal cancer. The aim of this study was to examine HOTAIR expression in patients with esophageal squamous cell cancer (ESCC) and explore its clinical significance.
Methods
Differences in the expression of HOTAIR were examined via in situ hybridization (ISH) and quantitative reverse transcriptase PCR (qRT-PCR). The prognostic significance was evaluated using Kaplan–Meier and Cox regression analyses. Proliferation, colony formation and migration assays were performed in ESCC cell lines to determine the function of HOTAIR in the progression of ESCC in vitro.
Results
A notably higher level of HOTAIR expression was found in ESCC tissues. High expression levels of HOTAIR in ESCC patients correlated positively with clinical stage, TNM classification, histological differentiation and vital status. HOTAIR expression was found to be an independent prognostic factor in ESCC patients. ESCC patients who expressed high levels of HOTAIR had substantially lower overall 5-year survival rates than HOTAIR-negative patients. In vitro assays of ESCC cell lines demonstrated that HOTAIR mediated the proliferation, colony formation and migratory capacity of ESCC cells.
Conclusion
HOTAIR is a potential biomarker for ESCC prognosis, and the dysregulation of HOTAIR may play an important role in ESCC progression.
doi:10.1371/journal.pone.0063516
PMCID: PMC3662674  PMID: 23717443
24.  Analysis of PTEN Methylation Patterns in Soft Tissue Sarcomas by MassARRAY Spectrometry 
PLoS ONE  2013;8(5):e62971.
Soft tissue sarcomas (STSs) are a rare and fascinating group of diseases that can be subdivided into specific reciprocal translocations in STSs (SRTSs) and nonspecific reciprocal translocations in STSs (NRTSs). PTEN mutations are rare in STSs, suggesting that PTEN expression may be lost by alternative mechanisms such as methylation. In order to reveal whether aberrant PTEN methylation occurs in STSs, MassARRAY Spectrometry was carried to detect methylation patterns of PTEN in STSs. We evaluated methylation levels in 41 CpG sites from −2,515 to −2,186 bp (amplicon A) and −1,786 to −1,416 bp (amplicon B) relative to the translation initiation site in 110 different cases (46 cases of SRTSs, 40 cases of NRTSs, and 24 cases of normal controls). In addition, immunohistochemistry (IHC) was used to detect the loss of PTEN to determine whether PTEN alterations were responsible for decreased PTEN expression. Our data showed that expression of PTEN was diminished in 49 (57%) STSs, whereas the remaining cases (43%) were classified as high expression. Our previous results found that only 2 of 86 cases (2.3%) had a PTEN mutation suggesting that PTEN may be mainly downregulated in STSs by methylation, but not by mutation of PTEN itself. We observed that amplicon A was hypermethylated in STSs with low PTEN expression, whereas normal controls had low methylation levels (P<0.0001), which was not present in amplicon B (P>0.05), nor were there significant differences in the methylation levels in PTEN between SRTS and NRTS cases. The majority of individual CpG units within two amplicons was demonstrated to be hypermethylated. These findings indicate that PTEN hypermethylation is a common event in STSs suggesting that the inactivation of PTEN may be due to hypermethylation in the promoter of PTEN. The aberrant methylation of the CpG sites within PTEN promoter may serve as a potential candidate biomarker for STSs.
doi:10.1371/journal.pone.0062971
PMCID: PMC3656904  PMID: 23690972
25.  The effect of RHIZOMA COPTIDIS and COPTIS CHINENSIS aqueous extract on radiation-induced skin injury in a rat model 
Background
Radiation-induced skin injury is a common complication of radiotherapy. The RHIZOMA COPTIDIS and COPTIS CHINENSIS aqueous extract (RCE) can ameliorate radiation-induced skin injury in our clinical observation. But, the protective mechanism of RHIZOMA COPTIDIS and COPTIS CHINENSIS in radiation-induced skin injury remains unclear.
Methods
In this experiment, we developed a radiation-induced skin injury rat model to study the mechanism. The animals were randomly divided into control group, treatment group, radiation group, and treatment and radiation group. 5 rats in each group were separately executed on 2 d and 49 d post-radiation. The semi-quantitative skin injury score was used to measure skin reactions by unblinded observers, and hematoxylin and eosin staining was used to evaluate the damage areas by irradiation. The MDA content, SOD activity of skin and serum were measured to detect the oxidative stress.
Results
Acute skin reactions were caused by a single dose of 45 Gy of β-ray irradiation, and the skin injury could be found in all rats receiving irradiation based on the observation of HE staining of skin at different time-points, while RCE could significantly ameliorate those changes. The MDA content in serum and skin of control rats was 4.13 ± 0.12 mmol/ml and 4.95 ± 0.35 mmol/mgprot on 2 d post-radiation. The rats receiving radiation showed an increased content of MDA (5.54 ± 0.21 mmol/ml and 7.10 ± 0.32 mmol/mgprot), while it was 4.57 ± 0.21 mmol/ml and 5.95 ± 0.24 mmol/mgprot after treated with RCE (p < 0.05). Similar changes of the MDA content could be seen on 49 d post-radiation. However, the SOD activity of rats receiving radiation decreased compared with control group on both time-points, which was inhibited by RCE (p < 0.05). Meanwhile, no valuable changes could be found between control group and treatment group on 2 d and 49 d.
Conclusions
Our study provides evidences for the radioprotective role of RCE against radiation-induced skin damage in rats by modulating oxidative stress in skin, which may be a useful therapy for radiation-induced skin injury.
doi:10.1186/1472-6882-13-105
PMCID: PMC3694038  PMID: 23675786
RHIZOMA COPTIDIS; COPTIS CHINENSIS; Radiation; Skin injury

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