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1.  MiR-130b plays an oncogenic role by repressing PTEN expression in esophageal squamous cell carcinoma cells 
BMC Cancer  2015;15:29.
Esophageal carcinoma is one of the most common malignancies with high cancer-related morbidity and mortality worldwide. MicroRNAs (miRNAs) are a class of small non-coding RNAs that regulate a wide variety of cellular processes, and also play an important role in the development and progression of cancers. In a previous microarray study, we demonstrated that miR-130b was upregulated in esophageal squamous cell carcinoma (ESCC) tissues. However, the biologic functions and the molecular mechanism of miR-130b in ESCC remain to be elucidated.
qRT-PCR assays were used to quantify miR-130b expression levels in ESCC samples. Novel targets of miR-130b were identified via a bioinformatics search and confirmed using a dual-luciferase reporter system. Western blotting and qRT-PCR assays were used to quantify the expression of the target gene PTEN (phosphatase and tensin homolog) and the downstream effector, Akt. ESCC cells over- or underexpressing miR-130b were analyzed for in vitro biologic functions.
High levels of miR-130b were identified in 20 ESCC samples following comparison with adjacent non-neoplastic tissues. We confirmed that miR-130b interacted with the 3′-untranslated region of PTEN, and that an increase in the expression level of miR-130b negatively affected the protein level of PTEN. However, the dysregulation of miR-130b had no obvious impact on PTEN mRNA. As Akt is a downstream effector of PTEN, we explored if miR-130b affected Akt expression, and found that miR-130b indirectly regulated the level of phosphorylated Akt, while total Akt protein remained unchanged. Overexpression of miR-130b increased the proliferation of ESCC cells and enhanced their ability to migrate and invade. In contrast, the proliferation, migration, and invasion of ESCC cells were weakened when miR-130b expression was suppressed, which was reversed by PTEN-targeted siRNA.
The results indicate that miR-130b plays an oncogenic role in ESCC cells by repressing PTEN expression and Akt phosphorylation, which would be helpful in developing miRNA-based treatments for ESCC.
Electronic supplementary material
The online version of this article (doi:10.1186/s12885-015-1031-5) contains supplementary material, which is available to authorized users.
PMCID: PMC4318221  PMID: 25637514
Esophageal squamous cell carcinoma; miR-130b; Oncogenic; PTEN
2.  Deletion of the Cathepsin B Gene Improves Memory Deficits in a Transgenic Alzheimer’s Disease Mouse Model Expressing AβPP Containing the Wild-Type β-Secretase Site Sequence 
Therapeutic agents that improve the memory loss of Alzheimer’s disease (AD) may eventually be developed if drug targets are identified that improve memory deficits in appropriate AD animal models. One such target is β-secretase which, in most AD patients, cleaves the wild-type (WT) β-secretase site sequence of the amyloid-β protein precursor (AβPP) to produce neurotoxic amyloid-β (Aβ). Thus, an animal model representing most AD patients for evaluating β-secretase effects on memory deficits is one that expresses human AβPP containing the WT β-secretase site sequence. BACE1 and cathepsin B (CatB) proteases have β-secretase activity, but gene knockout studies have not yet validated that the absence of these proteases improves memory deficits in such an animal model. This study assessed the effects of deleting these protease genes on memory deficits in the AD mouse model expressing human AβPP containing the WT β-secretase site sequence and the London γ-secretase site (AβPPWT/Lon mice). Knockout of the CatB gene in the AβPPWT/Lon mice improved memory deficits and altered the pattern of Aβ-related biomarkers in a manner consistent with CatB having WT β-secretase activity. But deletion of the BACE1 gene had no effect on these parameters in the AβPPWT/Lon mice. These data are the first to show that knockout of a putative β-secretase gene results in improved memory in an AD animal model expressing the WT β-secretase site sequence of AβPP, present in the majority of AD patients. CatB may be an effective drug target for improving memory deficits in most AD patients.
PMCID: PMC4309289  PMID: 22337825
Amyoid-β; amyoid-β protein precursor; cathepsin B; gene knockout; protease
3.  Aberrant Hypermethylation of Aldehyde Dehydrogenase 2 Promoter Upstream Sequence in Rats with Experimental Myocardial Infarction 
BioMed Research International  2015;2015:503692.
Background. Aldehyde dehydrogenase 2 (ALDH2) plays a crucial role in myocardial protection against ischemia. Downregulation of ALDH2 was evidenced after myocardial infarction and the underlying mechanism is not fully understood. DNA methylation can regulate gene transcription in epigenetic level. We thus hypothesized that DNA methylation may affect ALDH2 expression in myocardial infarction (MI). Methods. MI was induced in Sprague-Dawley rats. MI border zone tissues were harvested at 1st week, 2nd week, and 3rd week after MI. Bisulfite sequencing PCR (BSP) was performed to detect the methylation levels of ALDH2 core promoter. Sequenom MassARRAY platform (MassARRAY) was used to examine the methylation levels of ALDH2 promoter upstream sequence. ALDH2 protein and mRNA expression were assayed by Western blot and real-time PCR, respectively. Results. Compared with Sham group, ALDH2 protein and mRNA expression of MI groups was significantly downregulated. Compared with Sham group, DNA methylation level of CpG sites in ALDH2 promoter upstream sequence was significantly higher in MI groups in a time-dependent manner (CpG1, CpG2, and CpG7, P < 0.01). DNA methylation did not affect ALDH2 core promoter sequence during the progress of MI. No significant difference was detected in DNA methylation level of ALDH2 promoter upstream sequence among MI groups. Conclusion. Aberrant hypermethylation of CpG sites in ALDH2 promoter upstream sequence is associated with myocardial ischemia injury and may partly result in ALDH2 downregulation after MI.
PMCID: PMC4299765  PMID: 25629048
4.  Insulin Resistance Is an Important Risk Factor for Cognitive Impairment in Elderly Patients with Primary Hypertension 
Yonsei Medical Journal  2014;56(1):89-94.
Insulin resistance plays a role in the development of dementia and hypertension. We investigated a possible relationship between cognitive impairment and insulin resistance in elderly Chinese patients with primary hypertension.
Materials and Methods
One hundred and thirty-two hypertensive elderly patients (>60 years) were enrolled in this study, and assigned into either the cognitive impairment group (n=61) or the normal cognitive group (n=71). Gender, age, education, body mass index (BMI), waist hip ratio (WHR), total cholesterol (TC), triglyceride (TG), C-reactive protein (CRP), high density lipoprotein cholesterol (HDL-C), low density lipoprotein cholesterol (LDL-C), creatinine (Cr), fasting plasma glucose (FPG), fasting insulin (FINS), homeostasis model of assessment for insulin resistance index (HOMA-IR), systolic blood pressure, diastolic blood pressure, smoking history, atherosclerosis and the proportion of uncontrolled hypertension were compared between the two groups. Multi-factorial logistic regression analysis was performed.
No significant differences were found in gender, age, TC, CRP, HDL-C, LDL-C, Cr, BP, smoking history, atherosclerosis and the proportion of uncontrolled hypertension between the two groups. The cognitive impairment group had lower education levels, and higher BMI, WHR, TG, FPG, FINS, and HOMA-IR levels than the control group. Logistic regression analysis revealed the levels of education, BMI, WHR, and HOMA-IR as independent factors that predict cognitive impairment in patients.
Our study demonstrates that poor education and increased BMI, WHR, and HOMA-IR are independent risk factors for cognitive impairment in elderly patients with hypertension. Insulin resistance plays an important role in the development of cognitive impairment in primary elderly hypertensive patients.
PMCID: PMC4276782  PMID: 25510751
Hypertension; insulin resistance; cognitive impairment; elderly; risk factor
5.  Efficacy and safety of individually tailored antiplatelet therapy in patients with acute coronary syndrome after coronary stenting: a single center, randomized, feasibility study 
Low responsiveness to clopidogrel (LRC) is associated with increased risk of ischemic events. This study was aimed to explore the feasibility of tailored antiplatelet therapy according to the responsiveness to clopidogrel.
A total of 305 clopidogrel naïve patients with acute coronary syndromes (ACS) undergoing coronary stenting were randomly assigned to receive standard (n = 151) or tailored (n = 154) antiplatelet therapy. The ADP-induced platelet aggregation tests by light transmission aggregometry were performed to identify LRC patients assigned to the tailored group. The standard antiplatelet regimen was dual antiplatelet therapy with aspirin and clopidogrel. The tailored antiplatelet therapy was standard regimen for non-LRC patients and an additional 6-month cilostazol treatment for LRC patients. The primary efficacy outcome was the composite of cardiovascular death, myocardial infarction or stroke at one year.
LCR was present in 26.6% (41/154) of patients in the tailored group. The percentage platelet aggregation for LCR patients was significantly decreased at three days after adjunctive cilostazol treatment (77.5% ± 12.1% vs. 64.5% ± 12.1%, P < 0.001). At one year follow-up, a non-significant 37% relative risk reduction of primary events were observed in the tailored group as compared to the standard group (5.8% vs. 9.3%, P = 0.257). There were no differences in the rates of stent thrombosis and hemorrhagic events between the two groups.
Tailored antiplatelet therapy for ACS patients after coronary stenting according to responsiveness to clopidogrel is feasible. However, its efficacy and safety need further confirmation by clinical trials with larger sample sizes.
PMCID: PMC4308455
Acute coronary syndrome; Antiplatelet therapy; Clopidogrel; Coronary stenting
6.  HIF-1α induces VE-cadherin expression and modulates vasculogenic mimicry in esophageal carcinoma cells 
World Journal of Gastroenterology : WJG  2014;20(47):17894-17904.
AIM: To investigate whether hypoxia inducible factor (HIF)-1α modulates vasculogenic mimicry (VM) by upregulating VE-cadherin expression in esophageal squamous cell carcinoma (ESCC).
METHODS: Esophageal squamous cancer cell lines Eca109 and TE13 were transfected with plasmids harboring small interfering RNAs targeting HIF-1α or VE-cadherin. The proliferation and invasion of esophageal carcinoma cells were detected by MTT and Transwell migration assays. The formation of tubular networks of cells was analyzed by 3D culture in vitro. BALB/c nude mice were used to observe xenograft tumor formation. The relationship between the expression of HIF-1α and VE-cadherin, ephrinA2 (EphA2) and laminin5γ2 (LN5γ2) was measured by Western blot and real-time polymerase chain reaction.
RESULTS: Knockdown of HIF-1α inhibited cell proliferation (32.3% ± 6.1% for Eca109 cells and 38.6% ± 6.8% for TE13 cells, P < 0.05). Both Eca109 and TE13 cells formed typical tubular networks. The number of tubular networks markedly decreased when HIF-1α or VE-cadherin was knocked down. Expression of VE-cadherin, EphA2 and LN5γ2 was dramatically inhibited, but the expression of matrix metalloproteinase 2 had no obvious change in HIF-1α-silenced cells. Knockdown of VE-cadherin significantly decreased expression of both EphA2 and LN5γ2 (P < 0.05), while HIF-1α expression was unchanged. The time for xenograft tumor formation was 6 ± 1.2 d for Eca109 cells and Eca109 cells transfected with HIF-1α Neo control short hairpin RNA (shRNA) vector, and 8.4 ± 2.1 d for Eca109 cells transfected with an shRNA against HIF-1α. Knockdown of HIF-1α inhibited vasculogenic mimicry (VM) and tumorigenicity in vivo.
CONCLUSION: HIF-1α may modulate VM in ESCC by regulating VE-cadherin expression, which affects VM formation through EphA2 and LN5γ2.
PMCID: PMC4273139  PMID: 25548487
Esophageal squamous cell carcinoma; Hypoxia-inducible factor-1α; VE-cadherin; RNA interference; Vasculogenic mimicry
7.  Analysis of prognostic factors and comparison of prognostic index scores in patients with brain metastases after whole-brain radiotherapy 
Background and purpose: Brain metastases (BMs) are typically associated with poor patient prognosis. Radiation therapy remains the primary treatment for BMs, and patient’s prognosis is affected by many factors. The aim of this study was to identify prognostic factors and to compare prognostic index scores in patients with BMs who received whole-brain radiotherapy (WBRT). Methods: A retrospective prognostic study was conducted in 125 patients with BMs who underwent WBRT between Jan 2008 and Jul 2011. The significance of prognostic variables with regard to survival was determined using univariate and multivariate analyses. A prognostic index (PI) was established based on Cox regression analysis and subgrouping values. The recursive partitioning analysis classes (RPA), basic score for brain metastases (BS-BM), Graded Prognostic Assessment index (GPA), and PI were assessed with regard to prognosis. Results: The median survival time was 213 days (7.1 months). In the univariate analysis of the test group, survival was significantly associated with Karnofsky performance status (KPS) score, the number of BMs, the presence of extracranial metastases, primary tumor status and the number of involved extracranial organs. The multivariate analysis showed that the KPS score (P = 0.002, Wald = 9.700), presence of extracranial metastases (P = 0.018, Wald = 5.604) and primary tumor status (P = 0.001, Wald = 10.212) were significantly correlated with overall survival. RPA, BS-BM and GPA were all closely related to prognosis, as determined using a log-rank test. In predicting the 3- and 6-month survival for patients, the PI was superior to the other three modes. Conclusions: The three indexes, RPA, BS-BM and GPA, are valid prognostic index models; however, the PI model was the most powerful.
PMCID: PMC4307471  PMID: 25664024
Neoplasms; brain metastases; whole-brain radiotherapy; prognosis; prognostic index scores
8.  Prediction of protein-protein interactions from amino acid sequences using a novel multi-scale continuous and discontinuous feature set 
BMC Bioinformatics  2014;15(Suppl 15):S9.
Identifying protein-protein interactions (PPIs) is essential for elucidating protein functions and understanding the molecular mechanisms inside the cell. However, the experimental methods for detecting PPIs are both time-consuming and expensive. Therefore, computational prediction of protein interactions are becoming increasingly popular, which can provide an inexpensive way of predicting the most likely set of interactions at the entire proteome scale, and can be used to complement experimental approaches. Although much progress has already been achieved in this direction, the problem is still far from being solved and new approaches are still required to overcome the limitations of the current prediction models.
In this work, a sequence-based approach is developed by combining a novel Multi-scale Continuous and Discontinuous (MCD) feature representation and Support Vector Machine (SVM). The MCD representation gives adequate consideration to the interactions between sequentially distant but spatially close amino acid residues, thus it can sufficiently capture multiple overlapping continuous and discontinuous binding patterns within a protein sequence. An effective feature selection method mRMR was employed to construct an optimized and more discriminative feature set by excluding redundant features. Finally, a prediction model is trained and tested based on SVM algorithm to predict the interaction probability of protein pairs.
When performed on the yeast PPIs data set, the proposed approach achieved 91.36% prediction accuracy with 91.94% precision at the sensitivity of 90.67%. Extensive experiments are conducted to compare our method with the existing sequence-based method. Experimental results show that the performance of our predictor is better than several other state-of-the-art predictors, whose average prediction accuracy is 84.91%, sensitivity is 83.24%, and precision is 86.12%. Achieved results show that the proposed approach is very promising for predicting PPI, so it can be a useful supplementary tool for future proteomics studies. The source code and the datasets are freely available at for academic use.
PMCID: PMC4271571  PMID: 25474679
9.  Ancient DNA provides new insight into the maternal lineages and domestication of Chinese donkeys 
BMC Evolutionary Biology  2014;14(1):246.
The donkey (Equus asinus) is an important domestic animal that provides a reliable source of protein and method of transportation for many human populations. However, the process of domestication and the dispersal routes of the Chinese donkey are still unclear, as donkey remains are sparse in the archaeological record and often confused with horse remains. To explore the maternal origins and dispersal route of Chinese donkeys, both mitochondrial DNA D-loop and cytochrome b gene fragments of 21 suspected donkey remains from four archaeological sites in China were amplified and sequenced.
Molecular methods of species identification show that 17 specimens were donkeys and three samples had the maternal genetic signature of horses. One sample that dates to about 20,000 years before present failed to amplify. In this study, the phylogenetic analysis reveals that ancient Chinese donkeys have high mitochondrial DNA diversity and two distinct mitochondrial maternal lineages, known as the Somali and Nubian lineages. These results indicate that the maternal origin of Chinese domestic donkeys was probably related to the African wild ass, which includes the Nubian wild ass (Equus africanus africanus) and the Somali wild ass (Equus africanus somaliensis). Combined with historical records, the results of this study implied that domestic donkeys spread into west and north China before the emergence of the Han dynasty. The number of Chinese domestic donkeys had increased primarily to meet demand for the expansion of trade, and they were likely used as commodities or for shipping goods along the Silk Road during the Tang Dynasty, when the Silk Road reached its golden age.
This study is the first to provide valuable ancient animal DNA evidence for early trade between African and Asian populations. The ancient DNA analysis of Chinese donkeys also sheds light on the dynamic process of the maternal origin, domestication, and dispersal route of ancient Chinese donkeys.
PMCID: PMC4263014  PMID: 25433485
Chinese domestic donkeys; Ancient DNA; Mitochondrial DNA; D-loop; Cytochrome b gene; Maternal lineage; The Silk Road
10.  Draft Genome Sequence of the Algicidal Bacterium Mangrovimonas yunxiaonensis Strain LY01 
Genome Announcements  2014;2(6):e01234-14.
Mangrovimonas yunxiaonensis LY01, a novel bacterium isolated from mangrove sediment, showed high algicidal effects on harmful algal blooms of Alexandrium tamarense. Here, we present the first draft genome sequence of this strain to further understanding of the functional genes related to algicidal activity.
PMCID: PMC4246170  PMID: 25428978
11.  Post-splenectomy intrapancreatic accessory spleen mimicking endocrine tumor of the pancreas 
•The first case of IPAS arising after splenectomy.•The IPAS has similar features of pancreatic neuroendocrine tumor on images.•Typical pathologic data and characteristics of IPAS were presented and described.•A brief review of IPAS was included.
Intrapancreatic accessory spleen is an uncommon congenital abnormality of the spleen with no indication for surgical intervention. Among the few cases reported, IPAS coexisted with a normal spleen. We here report the first case of IPAS arising a couple years after splenectomy with the appearance of an endocrine tumor of the pancreas.
A 62-year-old female presented with a one-week history of left upper quadrant discomfort. She had splenectomy for the treatment of hypersplenism caused by cirrhotic portal hypertension two years before this admission. Her physical examination was unremarkable and laboratory data was within the normal range. Both the ultrasonography and magnetic resonance image revealed a small oval-shaped mass in the tail of her pancreas with the diameter 2 cm or less. A distal pancreatectomy was performed for the suspection of malignant neuroendocrine tumor of the pancreas. An intrapancreatic accessory spleen was confirmed by the pathologic examination.
Intrapancreatic accessory spleen is one kind of congenital ectopic spleen without indication for operative intervention. We present the case to support that intrapancreatic accessory spleen may enlarge through a compensatory mechanism, and raise the awareness of this intrapacreatic entity to avoid unnecessary surgical operation.
IPAS should be highly considered as a differential diagnosis while the lesion is no more than 2.5 cm in diameter and/or other accessory spleens show around the splenic hilum.
PMCID: PMC4275968  PMID: 25437661
Intrapancreatic accessory spleen; Pancreatic neuroendocrine tumor; Splenectomy; Pancreas
12.  Minimal invasive trans-eyelid approach to anterior and middle skull base meningioma: a preliminary study of Shanghai Huashan hospital 
Transpalpebral or trans-eyelid approach is a modified trans-orbital access to lesions of anterior cranial fossa and sellar region. But whether this approach is also suitable for tumors extending laterally to the temporal lobe or middle cranial fossa is not clarified. We would like to share our experiences from the cadaveric anatomy study to clinical operations. We used 5 cadavers to study trans-eyelid approaches in a step-by-step fashion. And then assisted by an experienced ophthalmologist for incisions, we treated 3 female patients via this approach: One with spheno-orbital meningioma, one with sellar tuberculum meningioma, and the other with medial sphenoidal wing meningioma. After studying the cadavers, we made several revisions to the previously reported approach: 1) move the incision close to the edge of the eyelid, which resembled the double-eyelid incision. 2) A vascularized periosteum flap was dissected for repairing the opened frontal sinus and reconstruction of the skull base. 3) The dura was sutured up with a slice of temporalis muscle. Then we treated 3 patients by this approach. All tumors were totally resected as Simpson Grade I. Complications included orbital apex syndrome and transient oculomotor paralysis because of tumor invasion into orbit and cavernous sinus. No cerebrospinal fluid leakage. We find that trans-eyelid approach is suitable for lesions not only at anterior cranial base or sellar region, but also extending to middle cranial base, especially around sphenoidal wings within 2 cm range or spheno-orbital region. Thus, we propose whether it appropriate to nominate this approach as ‘trans-eyelid pterional approach’, since it may treat some anterior and middle cranial fossa lesions with a mini-craniotomy around pterion.
PMCID: PMC4276163  PMID: 25550905
Transeyelid; skull base; meningioma; minimal invasive neurosurgery
13.  Age-Related Cataract, Cataract Surgery and Subsequent Mortality: A Systematic Review and Meta-Analysis 
PLoS ONE  2014;9(11):e112054.
Changes in lens may reflect the status of systemic health of human beings but the supporting evidences are not well summarized yet. We aimed to determine the relationship of age-related cataract, cataract surgery and long-term mortality by pooling the results of published population-based studies.
We searched PubMed and Embase from their inception till March, 2014 for population-based studies reporting the associations of any subtypes of age-related cataract, cataract surgery with all-cause mortality. We pooled the effect estimates (hazards ratios [HRs]) under a random effects model.
Totally, we identified 10 unique population-based studies including 39,659 individuals at baseline reporting the associations of any subtypes of cataract with all-cause mortality from 6 countries. The presence of any cataract including cataract surgery was significantly associated with a higher risk of death (pooled HR: 1.43, 95% CI, 1.21, 2.02; P<0.001; I2 = 64.2%). In the meta-analysis of 9 study findings, adults with nuclear cataract were at higher risks of mortality (pooled HR: 1.55, 95% CI, 1.17, 2.05; P = 0.002; I2 = 89.2%). In the meta-analysis of 8 study findings, cortical cataract was associated with higher risks of mortality (pooled HR: 1.26, 95% CI, 1.12, 1.42; P<0.001, I2 = 29.7%). In the meta-analysis of 6 study findings, PSC cataract was associated with higher risks of mortality (pooled HR: 1.37, 95% CI, 1.04, 1.80; P = 0.03; I2 = 67.3%). The association between cataract surgery and mortality was marginally non-significant by pooling 8 study findings (pooled HR: 1.27, 95% CI, 0.97, 1.66; P = 0.08; I2 = 76.6%).
All subtypes of age-related cataract were associated with an increased mortality with nuclear cataract having the strongest association among the 3 cataract subtypes. However, cataract surgery was not significantly related to mortality. These findings indicated that changes in lens may serve as markers for ageing and systemic health in general population.
PMCID: PMC4219834  PMID: 25369040
14.  The performance of transrectal ultrasound in the diagnosis of seminal vesicle defects: a comparison with magnetic resonance imaging 
Asian Journal of Andrology  2014;16(6):907-911.
Obstructive azoospermia (OA) is one of the most common causes of male infertility. Transrectal ultrasound (TRUS) has been used to diagnose OA for many years. From 2009 to 2013, we evaluated a prospective cohort of 1249 patients with suspected OA using TRUS. It was found that dilation of the ejaculatory duct (ED) (29.9%, 374/1249) was the most common cause of OA, followed by seminal vesicle (SV) abnormalities (28.5%, 356/1249). A total of 237 patients were diagnosed with congenital defects (agenesis and/or hypoplasia) of the SV, constituting more than half of the cases of SV disease in OA (19.0%, 237/1249). In contrast to ED, congenital defects of the SV could not be corrected with surgical treatment. Therefore, it is meaningful to compare TRUS and magnetic resonance imaging (MRI) for accurate diagnosis of SV defects. Among our patients, 30 with agenesis or/and hypoplasia of the SV on TRUS were further evaluated using pelvic MRI within 2 years, with the objective of verifying the TRUS results. The concordance rate for diagnosing congenital defects of the SV was 73.3% (22/30). We concluded that TRUS is a reliable and convenient method for diagnosing agenesis or hypoplasia of the SV in OA patients with a high concordance with MRI while MRI is useful in patients with inconclusive TRUS findings.
PMCID: PMC4236338  PMID: 25337847
defects; magnetic resonance imaging; obstructive azoospermia; seminal vesicle; transrectal ultrasound
15.  Activation of the AT1R/HIF-1α/ACE Axis Mediates Angiotensin II-Induced VEGF Synthesis in Mesenchymal Stem Cells 
BioMed Research International  2014;2014:627380.
A local renin-angiotensin system (RAS) is expressed in mesenchymal stem cells (MSCs) and regulates stem cell function. The local RAS influences the survival and tissue repairing ability of transplanted stem cells. We have previously reported that angiotensin II (Ang II) pretreatment can significantly increase vascular endothelial growth factor (VEGF) synthesis in MSCs through the ERK1/2 and Akt pathways via the Ang II receptor type 1 (AT1R). However, the role of angiotensin-converting enzyme (ACE) has not been clarified. Furthermore, whether Ang II pretreatment activates hypoxia-inducible factor-1α (HIF-1α) in MSCs has not been elucidated. Our data show that both ACE and HIF-1α are involved in promoting VEGF expression in MSCs, and that both are upregulated by Ang II stimulation. The upregulation of ACE appeared after the rapid degradation of exogenous Ang II, and led to the formation of endogenous Ang II. On the other hand, the ACE inhibitor, captopril, attenuated Ang II-enhanced HIF-1α upregulation, while HIF-1α suppression markedly attenuated ACE expression. This interesting finding suggests an interaction between ACE and HIF-1α. We conclude that Ang II pretreatment, as a trigger, activated the AT1R/HIF-1α/ACE axis that then mediated Ang II-induced VEGF synthesis in MSCs.
PMCID: PMC4221905  PMID: 25401104
16.  Comparative Study on “Long-Dan”, “Qin-Jiao” and Their Adulterants by HPLC Analysis 
“Long-Dan” and “Qin-Jiao” are two important TCM herbs since ancient times in China. In the Chinese Pharmacopoeia, the dried roots and rhizomes of four species from the genus Gentiana, e.g. Gentiana manshurica, G. scabra, G. triflora and G. rigescens, are recorded under the name of Gentianae Radix et Rhizoma (“Long-Dan” in Chinese), while the other four species from the same genus including G. macrophylla, G. crassicaulis, G. straminea and G. duhurica are recorded and used as the raw materials of Gentianae Macrophyllae Radix (“Qin-Jiao” in Chinese). On the basis of the establishment of a validated HPLC–UV method for quantifying simultaneously, five iridoid glycosides, e.g. loganic acid (1), swertiamarinin (2), gentiopicroside (3), sweroside (4) and 2′-(o,m-dihydroxybenzyl)sweroside (5) have been used successfully as chemical markers for the comparison of the species used as “Long-Dan”, “Qin-Jiao” and their adulterants in the present study. The results suggested that four iridoid glycosides 1–4 commonly existed in both “Long-Dan” and “Qin-Jiao”, while 2′-(o,m-dihydroxybenzyl)sweroside (5) also existed as one of the major components in “Dian-Long-Dan” species. Moreover, the contents of compounds 1–5 were various in different “Long-Dan” and “Qin-Jiao” species. Herein, we profiled and compared three “Long-Dan” species, four “Qin-Jiao” species and five adulterants by applying multivariate statistical techniques to their HPLC data sets to establish the differences and/or similarities.
Electronic supplementary material
The online version of this article (doi:10.1007/s13659-014-0039-x) contains supplementary material, which is available to authorized users.
PMCID: PMC4199948  PMID: 25280952
“Long-Dan”; “Qin-Jiao”; Gentiana; HPLC analysis; Iridoid glycosides
17.  Comparative Study on “Long-Dan”, “Qin-Jiao” and Their Adulterants by HPLC Analysis 
“Long-Dan” and “Qin-Jiao” are two important TCM herbs since ancient times in China. In the Chinese Pharmacopoeia, the dried roots and rhizomes of four species from the genus Gentiana, e.g. Gentiana manshurica, G. scabra, G. triflora and G. rigescens, are recorded under the name of Gentianae Radix et Rhizoma (“Long-Dan” in Chinese), while the other four species from the same genus including G. macrophylla, G. crassicaulis, G. straminea and G. duhurica are recorded and used as the raw materials of Gentianae Macrophyllae Radix (“Qin-Jiao” in Chinese). On the basis of the establishment of a validated HPLC–UV method for quantifying simultaneously, five iridoid glycosides, e.g. loganic acid (1), swertiamarinin (2), gentiopicroside (3), sweroside (4) and 2′-(o,m-dihydroxybenzyl)sweroside (5) have been used successfully as chemical markers for the comparison of the species used as “Long-Dan”, “Qin-Jiao” and their adulterants in the present study. The results suggested that four iridoid glycosides 1–4 commonly existed in both “Long-Dan” and “Qin-Jiao”, while 2′-(o,m-dihydroxybenzyl)sweroside (5) also existed as one of the major components in “Dian-Long-Dan” species. Moreover, the contents of compounds 1–5 were various in different “Long-Dan” and “Qin-Jiao” species. Herein, we profiled and compared three “Long-Dan” species, four “Qin-Jiao” species and five adulterants by applying multivariate statistical techniques to their HPLC data sets to establish the differences and/or similarities.
Electronic supplementary material
The online version of this article (doi:10.1007/s13659-014-0039-x) contains supplementary material, which is available to authorized users.
PMCID: PMC4199948  PMID: 25280952
“Long-Dan”; “Qin-Jiao”; Gentiana; HPLC analysis; Iridoid glycosides
18.  Genistein inhibits TNF-α-induced endothelial inflammation through the protein kinase pathway A and improves vascular inflammation in C57BL/6 mice 
International journal of cardiology  2013;168(3):2637-2645.
Genistein, a soy isoflavone, has received wide attention for its potential to improve vascular function, but the mechanism of this effect is unclear. Here, we report that genistein at physiological concentrations (0.1 µM–5 µM) significantly inhibited TNF-α-induced adhesion of monocytes to human umbilical vein endothelial cells (HUVECs), a key event in the pathogenesis of atherosclerosis. Genistein also significantly suppressed TNF-α-induced production of adhesion molecules and chemokines such as sICAM-1, sVCAM-1,sE-selectin, MCP-1 and IL-8, which play key role in the firm adhesion of monocytes to activated endothelial cells (ECs). Genistein at physiologically relevant concentrations didn’t significantly induce antioxidant enzyme activities or scavenge free radicals. Further, blocking the estrogen receptors (ERs) in ECs didn’t alter the preventive effect of genistein on endothelial inflammation. However, inhibition of protein kinase A (PKA) significantly attenuated the inhibitory effects of genistein on TNF-α-induced monocyte adhesion to ECs as well as the production of MCP-1 and IL-8. In animal study, dietary genistein (0.1% genistein in the diet) significantly suppressed TNF-α-induced increase in circulating chemokines and adhesion molecules in C57BL/6 mice. Genistein treatment also reduced VCAM-1 and monocytes-derived F4/80-positive macrophages in the aorta of TNF-α treated mice. In conclusion, genistein protects against TNF-α induced vascular endothelial inflammation both in vitro and in vivo models. This anti-inflammatory effect of genistein is independent of the ER-mediated signaling machinery or antioxidant activity, but mediated via the PKA signaling pathway.
PMCID: PMC3758913  PMID: 23587398
genistein; vascular inflammation; TNF-α; protein kinase A; endothelial cells
19.  Synchronous bilateral non-Hodgkin’s diffuse large B-cell lymphoma of the breast and left breast invasive ductal carcinoma: a case report and review of literature 
Lymphoma of the breast is unusual, and synchronous bilateral lymphoma and carcinoma of the breast is extremely rare. We present the case of a 51-year-old woman who found a mass in her left breast. Ultrasound scan findings revealed nodules at the 2 o’clock position in her left breast and focal dilation of the duct at the 8-9 o’clock and 10 o’clock position in her right and left breasts, respectively. A left breast ultrasound-guided core needle biopsy and right breast segmental excisional biopsy were performed. Pathological and immunohistochemical examination revealed left breast invasive ductal carcinoma and right breast diffuse large B-cell lymphoma of the non-germinal center type. Pathological examination of the left breast modified radical mastectomy specimen revealed synchronous invasive ductal carcinoma (grade III) and diffuse large B-cell lymphoma. The patient received chemotherapy and bone marrow transplantation in another hospital. Based on a review of the relevant literature, we discuss the diagnosis, clinical features, treatment, and prognosis of synchronous breast lymphoma and invasive ductal carcinoma.
PMCID: PMC4230149  PMID: 25400793
Breast lymphoma; invasive ductal carcinoma; diffuse large B-cell lymphoma; synchronous tumor
20.  Associations of Cigarette Smoking and Alcohol Consumption With Metabolic Syndrome in a Male Chinese Population: A Cross-Sectional Study 
Journal of Epidemiology  2014;24(5):361-369.
Whether cigarette smoking and alcohol consumption are associated with the risk of metabolic syndrome (MetS) remains controversial. This study investigated the associations of cigarette smoking and alcohol consumption with MetS in a male population in China.
We conducted a cross-sectional study. A questionnaire was used to collect data on cigarette smoking, alcohol consumption, MetS status, and other related information from 8169 men aged 19–97 years. Logistic regression was used to estimate the odds ratios (ORs) and 95% confidence intervals (CIs) for the associations between smoking and alcohol consumption and the risk of MetS.
The prevalence of MetS was 15.2% in the study population. Proportions of current smokers and drinkers were 48.2% and 46.5%, respectively. Adjusted OR of MetS was 1.34 (95% CI, 1.01–1.79) among smokers who smoked ≥40 cigarettes/day compared with nonsmokers and 1.22 (95% CI 1.03–1.46) for those who consumed 0.1–99 grams of alcohol/day compared with nondrinkers. Adjusted OR was 2.32 (95% CI 1.45–3.73) among ex-drinkers who never smoked, 1.98 (95% CI 1.35–2.91) among ex-drinkers who were current smokers, and 1.34 (95% CI 1.08–1.68) among current drinkers who never smoked compared with those who neither smoked nor drank. There was a significant interaction between smoking and drinking alcohol on MetS (P for interaction is 0.001).
Our study indicated that smoking and drinking is associated with higher prevalence of MetS. Interactions between smoking and drinking on the risk of MetS in men in China may also exist. Our findings need to be confirmed in future case-control or cohort studies.
PMCID: PMC4150006  PMID: 24910131
cigarette smoking; alcohol consumption; metabolic syndrome; Chinese man; interaction
21.  Interferon-stimulated Gene 15 (ISG15) is a trigger for tumorigenesis and metastasis of hepatocellular carcinoma 
Oncotarget  2014;5(18):8429-8441.
Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide with poor prognosis. IFN-stimulated genes 15 (ISG15) is an ubiquitin-like molecule that is strongly upregulated by type I interferons as a primary response to diverse microbial and cellular stress stimuli. However, the role of ISG15 in HCC remains unclear. In this study, we investigated the function of ISG15 during HCC progression and related mechanism using clinicopathological data, cell line and xenograft model. Our results indicated that ISG15 is highly expressed in HCC tissues and multiple HCC cell lines. ISG15 expression is significantly associated with the differentiation grade, metastatic of tumor and survival of HCC patients. However, the expression of ISG15 is not affected by HBV infection. ISG15 promotes the proliferation and migration of hepatocarcinoma cells through maintaining Survivin protein stabilization via sequestering XIAP from interacting with Survivin. Knowing down ISG15 with SiRNA inhibited the xenografted tumor growth and prolonged the lifespan of tumor-bearing mice. All these results support that ISG15 high expression is an intrinsic feature for HCC and a trigger for tumorigenesis and metastasis. ISG15 may be a prognostic biomarker and the inhibition of ISG15 could provide a therapeutic advantage for HCC patients over-expressing ISG15.
PMCID: PMC4226694  PMID: 25238261
ISG15; HCC; Metastasis; Tumorigenesis
22.  Utility of the combination of serum highly-sensitive C-reactive protein level at discharge and a risk index in predicting readmission for acute exacerbation of COPD*,**  
Jornal Brasileiro de Pneumologia  2014;40(5):495-503.
Frequent readmissions for acute exacerbations of COPD (AECOPD) are an independent risk factor for increased mortality and use of health-care resources. Disease severity and C-reactive protein (CRP) level are validated predictors of long-term prognosis in such patients. This study investigated the utility of combining serum CRP level with the Global Initiative for Chronic Obstructive Lung Disease (GOLD) exacerbation risk classification for predicting readmission for AECOPD.
This was a prospective observational study of consecutive patients hospitalized for AECOPD at Peking University Third Hospital, in Beijing, China. We assessed patient age; gender; smoking status and history (pack-years); lung function; AECOPD frequency during the last year; quality of life; GOLD risk category (A-D; D indicating the greatest risk); and serum level of high-sensitivity CRP at discharge (hsCRP-D).
The final sample comprised 135 patients. Of those, 71 (52.6%) were readmitted at least once during the 12-month follow-up period. The median (interquartile) time to readmission was 78 days (42-178 days). Multivariate analysis revealed that serum hsCRP-D ≥ 3 mg/L and GOLD category D were independent predictors of readmission (hazard ratio = 3.486; 95% CI: 1.968-6.175; p < 0.001 and hazard ratio = 2.201; 95% CI: 1.342-3.610; p = 0.002, respectively). The ordering of the factor combinations by cumulative readmission risk, from highest to lowest, was as follows: hsCRP-D ≥ 3 mg/L and GOLD category D; hsCRP-D ≥ 3 mg/L and GOLD categories A-C; hsCRP-D < 3 mg/L and GOLD category D; hsCRP-D < 3 mg/L and GOLD categories A-C.
Serum hsCRP-D and GOLD classification are independent predictors of readmission for AECOPD, and their predictive value increases when they are used in combination.
PMCID: PMC4263330  PMID: 25410837
Pulmonary disease; chronic obstructive/epidemiology; Acute disease; Acute-phase proteins; Hospitalization; Patient readmission; Inflammation
23.  Large-Scale Protein-Protein Interactions Detection by Integrating Big Biosensing Data with Computational Model 
BioMed Research International  2014;2014:598129.
Protein-protein interactions are the basis of biological functions, and studying these interactions on a molecular level is of crucial importance for understanding the functionality of a living cell. During the past decade, biosensors have emerged as an important tool for the high-throughput identification of proteins and their interactions. However, the high-throughput experimental methods for identifying PPIs are both time-consuming and expensive. On the other hand, high-throughput PPI data are often associated with high false-positive and high false-negative rates. Targeting at these problems, we propose a method for PPI detection by integrating biosensor-based PPI data with a novel computational model. This method was developed based on the algorithm of extreme learning machine combined with a novel representation of protein sequence descriptor. When performed on the large-scale human protein interaction dataset, the proposed method achieved 84.8% prediction accuracy with 84.08% sensitivity at the specificity of 85.53%. We conducted more extensive experiments to compare the proposed method with the state-of-the-art techniques, support vector machine. The achieved results demonstrate that our approach is very promising for detecting new PPIs, and it can be a helpful supplement for biosensor-based PPI data detection.
PMCID: PMC4151593  PMID: 25215285
24.  Solitary fibrous tumors of the pleura with Doege-Potter syndrome: a case report and three-decade review of the literature 
BMC Research Notes  2014;7(1):515.
No case of solitary fibrous tumor of the pleura with Doege-Potter syndrome has been reported in China. This study was to report a rare repeatedly recurrent case of solitary fibrous tumor of the pleura with Doege-Potter syndrome diagnosed in China and a three-decade literature review of solitary fibrous tumor of the pleura with Doege-Potter syndrome worldwide.
Case presentation
A rare case of solitary fibrous tumor of the pleura with Doege-Potter syndrome was diagnosed in 2005 with follow-up to 2011. All medical records were collected and literature of solitary fibrous tumor of the pleura with Doege-Potter syndrome from 1979 to 2011 was obtained through Medline. This typical case, diagnosed and confirmed by histopathologic results, was a 72-year-old Chinese woman who had a complaint of night sweat for a month. A localized mass 12 cm × 11 cm × 8 cm in size was found associated with pleural effusion in her left low chest cavity, and blood tests showed severe hypoglycemia. Removal of the mass solved the hypoglycemia. The case was repeatedly recurrent in April, 2010 and March, 2011 and had no signs of recurrence up to the end of 2011 after surgery. A review of 45 cases of solitary fibrous tumor of the pleura with Doege-Potter syndrome compared and summarized clinical characteristics, treatments, and outcomes by benign and malignant tumor nature.
Incidence of solitary fibrous tumor of the pleura with Doege-Potter syndrome is similar between genders. There are no significant differences in clinical characteristics between benign and malignant cases. Surgery is the first effective treatment for solitary fibrous tumor of the pleura with Doege-Potter syndrome and the completeness of the initial resection is the key to preventing recurrence. Routine follow-up examinations are recommended for early detection of recurrence.
PMCID: PMC4267432  PMID: 25113505
Solitary fibrous tumors of pleura; Doege-Potter syndrome; Surgery; Case report review
25.  18F-fluorodeoxyglucose positron emission tomography/computed tomography findings of gastric lymphoma: Comparisons with gastric cancer 
Oncology Letters  2014;8(4):1757-1764.
The role of 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) in numerous malignant tumors, including gastric lymphoma, is well-established. However, there have been few studies with regard to the 18F-FDG PET/CT features of gastric lymphoma. The aim of the present study was to characterize the 18F-FDG PET/CT features of gastric lymphoma, which were compared with those of gastric cancer. Prior to treatment, 18F-FDG PET/CT was performed on 24 patients with gastric lymphoma and 43 patients with gastric cancer. The 18F-FDG PET/CT pattern of gastric wall lesions was classified as one of three types: Type I, diffuse thickening of the gastric wall with increased FDG uptake infiltrating more than one-third of the total stomach; type II, segmental thickening of the gastric wall with elevated FDG uptake involving less than one-third of the total stomach; and type III, local thickening of the gastric wall with focal FDG uptake. The incidence of the involvement of more than one region of the stomach was higher in the patients with gastric lymphoma than in those with gastric cancer. Gastric FDG uptake was demonstrated in 23 of the 24 patients (95.8%) with gastric lymphoma and in 40 of the 43 patients (93.0%) with gastric cancer. Gastric lymphoma predominantly presented with type I and II lesions, whereas gastric cancer mainly presented with type II and III lesions. The maximal thickness was larger and the maximal standard uptake value (SUVmax) was higher in the patients with gastric lymphoma compared with those with gastric cancer. A positive correlation between the maximal thickness and SUVmax was confirmed for the gastric cancer lesions, but not for the gastric lymphoma lesions. There was no difference in the maximal thickness and SUVmax of the gastric wall lesions between the patients without and with extragastric involvement, for gastric lymphoma and gastric cancer. Overall, certain differences exist in the findings between gastric lymphoma and gastric cancer patients on 18F-FDG PET/CT images, which may contribute to the identification of gastric lymphoma.
PMCID: PMC4156241  PMID: 25202405
positron emission tomography; computed tomography; gastric lymphoma; gastric cancer

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