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2.  Intranasal Delivery of a Peptide with Antidepressant-Like Effect 
Neuropsychopharmacology  2014;39(9):2131-2141.
A critical issue in drug development is developing effective, noninvasive delivery routes to the central nervous system (CNS). Major depressive disorder (MDD) is an illness associated with significant morbidity. Even with multiple antidepressant trials, 10–15% of patients continue to experience persistent depressive symptoms. We previously developed an interfering peptide that has antidepressant-like effects in rats when injected directly into the brain. To be clinically viable, it must demonstrate efficacy via a noninvasive administration route. We report here that the interfering peptide designed to disrupt the interaction between the D1 and D2 dopamine receptors can be delivered to relevant brain areas using the Pressurized Olfactory Device (POD), a novel intranasal delivery system developed by Impel NeuroPharma. We validate this delivery method by demonstrating that, at doses ⩾1.67 nmol/g, the D1–D2 interfering peptide has a significant antidepressant-like effect comparable to that of imipramine in the forced swimming test (FST), a common test for antidepressant efficacy. The antidepressant-like effect of the interfering peptide can be detected for 2 h after intranasal administration. Furthermore, we show that the interfering peptide disrupts the D1–D2 interaction and it can be detected in the prefrontal cortex after intranasal administration. This study provides strong preclinical support for intranasal administration of the D1–D2 interfering peptide as a new treatment option for patients suffering from MDD.
doi:10.1038/npp.2014.61
PMCID: PMC4104330  PMID: 24633557
3.  The effect of socioeconomic status on health-care delay and treatment of esophageal cancer 
Background
Socioeconomic status (SES) has been focused on as a key determinant of the incidence of cancer, cancer stage at diagnosis as well as treatment choices in western countries. However, to the authors’ knowledge, little work has been done concerning the relationship of SES and esophageal cancer in China.
Methods
Patients diagnosed with primary esophageal cancer from January to December 2007 in Qilu hospital were included. Socioeconomic status was determined by a questionnaire including religion, years of schooling and high education, place of residence, occupation, annual household income, and insurance.
Results
A total of 238 cases were collected in this study. Linear-by-linear association testing revealed that health-care delay was significantly associated with SES (P = 0.009). Multivariable logistic regression analysis revealed that increased health-care delay (>2 months) was more frequently observed in patients with lower SES (OR 2.271; 95% CI 1.069–4.853). Patients diagnosed at TNM I and II were more frequently in higher SES groups (P = 0.017). The association test was statistically significant for undergoing surgical resection only (P = 0.015) and chemotherapy (P = 0.015). Multivariable logistic regression analysis revealed that surgical resection only was less performed in higher SES group compared with lower SES group (OR 0.372; 95% CI 0.188–0.734). For chemotherapy, higher SES patients had a three-fold higher likelihood compared with lower SES group (OR 3.042; 95% CI 1.335–6.928).
Conclusion
Socioeconomic status was found to be associated with health-care delay, tumor stage and treatment modalities in esophageal cancer.
Electronic supplementary material
The online version of this article (doi:10.1186/s12967-015-0579-9) contains supplementary material, which is available to authorized users.
doi:10.1186/s12967-015-0579-9
PMCID: PMC4511992  PMID: 26205792
Esophageal cancer; Socioeconomic status; Delay; Stage; Treatment
4.  Expression analysis of human adipose-derived stem cells during in vitro differentiation to an adipocyte lineage 
BMC Medical Genomics  2015;8:41.
Background
Adipose tissue-derived stromal stem cells (ASCs) represent a promising regenerative resource for soft tissue reconstruction. Although autologous grafting of whole fat has long been practiced, a major clinical limitation of this technique is inconsistent long-term graft retention. To understand the changes in cell function during the transition of ASCs into fully mature fat cells, we compared the transcriptome profiles of cultured undifferentiated human primary ASCs under conditions leading to acquisition of a mature adipocyte phenotype.
Methods
Microarray analysis was performed on total RNA extracted from separate ACS isolates of six human adult females before and after 7 days (7 days: early stage) and 21 days (21 days: late stage) of adipocyte differentiation in vitro. Differential gene expression profiles were determined using Partek Genomics Suite Version 6.4 for analysis of variance (ANOVA) based on time in culture. We also performed unsupervised hierarchical clustering to test for gene expression patterns among the three cell populations. Ingenuity Pathway Analysis was used to determine biologically significant networks and canonical pathways relevant to adipogenesis.
Results
Cells at each stage showed remarkable intra-group consistency of expression profiles while abundant differences were detected across stages and groups. More than 14,000 transcripts were significantly altered during differentiation while ~6000 transcripts were affected between 7 days and 21 days cultures. Setting a cutoff of +/-two-fold change, 1350 transcripts were elevated while 2929 genes were significantly decreased by 7 days. Comparison of early and late stage cultures revealed increased expression of 1107 transcripts while 606 genes showed significantly reduced expression. In addition to confirming differential expression of known markers of adipogenesis (e.g., FABP4, ADIPOQ, PLIN4), multiple genes and signaling pathways not previously known to be involved in regulating adipogenesis were identified (e.g. POSTN, PPP1R1A, FGF11) as potential novel mediators of adipogenesis. Quantitative RT-PCR validated the microarray results.
Conclusions
ASC maturation into an adipocyte phenotype proceeds from a gene expression program that involves thousands of genes. This is the first study to compare mRNA expression profiles during early and late stage adipogenesis using cultured human primary ASCs from multiple patients.
Electronic supplementary material
The online version of this article (doi:10.1186/s12920-015-0119-8) contains supplementary material, which is available to authorized users.
doi:10.1186/s12920-015-0119-8
PMCID: PMC4513754  PMID: 26205789
Microarray; Adipose-derived stem cells; Transcriptome; Gene expression; Stromal vascular fraction; Adipogenesis
5.  Generating optical superimposed vortex beam with tunable orbital angular momentum using integrated devices 
Scientific Reports  2015;5:10958.
An integrated device, which consists of a variable amplitude splitter and an orbital angular momentum (OAM) emitter, is proposed for the superposition of optical vortex beams. With fixed wavelength and power of incident beam, the OAM of the radiated optical superimposed vortex beam can be dynamically tuned. To verify the operating principle, the proposed device has been fabricated on the SOI substrate and experimentally measured. The experimental results confirm the tunability of superimposed vortex beams. Moreover, the ability of independently varying the OAM flux and the geometric distribution of intensity is illustrated and discussed with numerical simulation. We believe that this work would be promising in various applications.
doi:10.1038/srep10958
PMCID: PMC4507141  PMID: 26190669
6.  Identifying Orbital Angular Momentum of Vectorial Vortices with Pancharatnam Phase and Stokes Parameters 
Scientific Reports  2015;5:11982.
In this work, an explicit formula is deduced for identifying the orbital angular moment (OAM) of vectorial vortex with space-variant state of polarization (SOP). Different to scalar vortex, the OAM of vectorial vortex can be attributed to two parts: 1. the azimuthal gradient of Pancharatnam phase; 2. the product between the azimuthal gradient of orientation angle of SOP and relevant solid angle on the Poincaré sphere. With our formula, a geometrical description for OAM of light beams can be achieved under the framework of the traditional Poincaré sphere. Numerical simulations for two types of vectorial vortices have been carried on to confirm our presented formula as well as demonstrate the geometrical description of OAM. Furthermore, this work would pave the way for precise characterization of OAM charge of vectorial vortices.
doi:10.1038/srep11982
PMCID: PMC4498175  PMID: 26160007
7.  Decreased Expression of MiRNA-204-5p Contributes to Glioma Progression and Promotes Glioma Cell Growth, Migration and Invasion 
PLoS ONE  2015;10(7):e0132399.
Gliomas are the most common malignant primary brain tumors in adults and exhibit a spectrum of aberrantly aggressive phenotype. Although increasing evidence indicated that the deregulation of microRNAs (miRNAs) contributes to tumorigenesis and invasion, little is known about the roles of miR-204-5p in human gliomas. In the present study, the expression of miR-204-5p in clinical glioma tissues was measured by qRT-PCR. The effects of miR-204-5p on glioma cell growth and metastasis were examined by overexpressing or inhibiting miR-204-5p. We found that the expression level of miR-204-5p was significantly reduced in clinical glioma tissues compared with normal brain tissues. Moreover, we revealed that the introduction of miR-204-5p dramatically suppressed glioma cell growth, migration and invasion. Furthermore, mechanistic investigations revealed that RAB22A, a member of the RAS oncogene family, is a direct functional target of miR-204-5p in gliomas. In vivo, restoring miR-204-5p expression in glioma cells suppressed tumorigenesis and increased overall host survival. Our findings suggest that miR-204-5p is a cancer suppressor miRNA and overexpression of miR-204-5p is a novel glioma treatment strategy.
doi:10.1371/journal.pone.0132399
PMCID: PMC4489611  PMID: 26134825
8.  A Meta-Analysis of Acupuncture Use in the Treatment of Cognitive Impairment After Stroke 
Abstract
Objective: This meta-analysis was conducted to evaluate the efficacy of acupuncture on cognitive impairment (function) after a stroke.
Design: Randomized controlled trials (RCTs) comparing acupuncture with no acupuncture in addition to medicine or rehabilitation were identified from databases (PubMed, Cochrane Central Register of Controlled Trials, Chinese National Knowledge Infrastructure, VIP Chinese Periodical Database, Wangfang Chinese Periodical Database, Chinese Bio-medicine Database, Cochrane Library, and Chinese medical literature databases) and two relevant journals (Chinese Acupuncture and Moxibustion and the Journal of Shanghai Acupuncture and Moxibustion). Meta-analyses were conducted for the eligible RCTs.
Results: Twenty-one trials with a total of 1421 patients met inclusion criteria. Pooled random-effects estimates of the change in the Mini-Mental State Examination were calculated for the comparison of acupuncture with no acupuncture in addition to medicine or rehabilitation. Following 4 weeks and 8 weeks of intervention with acupuncture, the merged mean difference was 3.14 (95% confidence interval [CI], 2.06–4.21; p<.00001) and 2.03 (95% CI, 0.26–3.80; p=0.02), respectively. For the comparison of 3–4 weeks of acupuncture with no acupuncture in addition to medicine or rehabilitation groups, the merged MD in Neurobehavioral Cognitive State Examination total scores was 5.63 (95% CI, 3.95–7.31; p<.00001). For the comparison of 8–12 weeks of acupuncture with no acupuncture in addition to medicine or rehabilitation groups, the P300 latency merged MD was −12.80 (95% CI, −21.08 to −4.51; p<.00001), while the P300 amplitude merged MD was 1.38 (95% CI, 0.93–1.82; p<.00001). Overall, the study quality was rated as moderate on the basis of the Cochrane Handbook for Systematic Reviews of Interventions (part 2: 8.5).
Conclusions: This meta-analysis suggests that acupuncture had positive effects on cognitive function after stroke and supports the need for additional research on the potential benefits of this therapeutic approach.
doi:10.1089/acm.2013.0364
PMCID: PMC4086349  PMID: 24915606
9.  GENETIC AND PHARMACOLOGICAL EVIDENCE FOR SCHIZOPHRENIA-RELATED DISC1 INTERACTION WITH GSK-3 
Synapse (New York, N.Y.)  2011;65(3):234-248.
Recent studies have identified Disrupted-In-Schizophrenia-1 (DISC1) as a strong genetic risk factor associated with schizophrenia. Previously, we have reported that a mutation in the second exon of the DISC1 gene (leucine (L) to proline (P) at amino acid position 100, L100P) leads to the development of schizophrenia-related behaviors in mice. Glycogen synthase kinase-3 (GSK-3) is a serine/threonine protein kinase that interacts with the N-terminal region of DISC1 (aa 1-220) and has been implicated as an important downstream component in the etiology of schizophrenia.
Here, for the first time, we show that pharmacological and genetic inactivation of GSK-3 reverses Pre-Pulse Inhibition (PPI) and Latent Inhibition (LI) deficits as well as normalizing the hyperactivity of Disc1-L100P mutants. In parallel to these observations, interaction between DISC1 and GSK-3α and β is reduced in Disc1-L100P mutants. Our data provide genetic, biochemical and behavioral evidence for a molecular link between DISC1 and GSK-3 in relation to psychopathology and highlights the value of missense mutations in dissecting the underlying and complex molecular mechanisms of neurological disorders.
doi:10.1002/syn.20839
PMCID: PMC4485461  PMID: 20687111 CAMSID: cams1566
DISC1; GSK-3; TDZD-8; genetic mouse model; Schizophrenia
10.  Gender-Specific Effect of -102G>A Polymorphism in Insulin Induced Gene 2 on Obesity in Chinese Children 
Background. Insulin induced gene 2 (INSIG2) encodes a protein that has a biological effect on regulation of adipocyte metabolism and body weight. This study aimed to investigate the association of INSIG2 gene -102G>A polymorphism with obesity related phenotypes in Chinese children and test gender-specific effects. Methods. The 2,030 independent individuals aged from 7 to 18 years, including 705 obese cases and 1,325 nonobese controls, were recruited from local schools. We measured the obesity-related phenotypes and detected the serum lipids. We genotype -102G>A polymorphism by using the matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS). Results. In all individuals, we found that the GG/GA genotype of INSIG2 -102G>A polymorphism was associated with risk of severe obesity (OR = 1.62, 95% CI: 1.11–2.36, and P = 0.012) under the dominant model. The association with severe obesity existed only in boys (OR = 1.91, 95% CI: 1.15–3.17, P = 0.012). The GG/GA genotype of -102G>A polymorphism was also associated with higher waist circumference (β = 2.61 cm, P = 0.031) in boys. No similar association was found in girls. The polymorphism was not associated with other obesity-related phenotypes, neither in all individuals nor in gender-specific population. Conclusions. This study identified a gender-specific effect of INSIG2 -102G>A polymorphism on risk of severe obesity and waist circumference in Chinese boys.
doi:10.1155/2015/872506
PMCID: PMC4487926  PMID: 26161092
11.  Octreotide Protects the Mouse Retina against Ischemic Reperfusion Injury through Regulation of Antioxidation and Activation of NF-κB 
Somatostatin (SST), an endogenous peptide, may exert anti-inflammatory and neuroprotective effects on retinal injury induced by ischemia. Retinal ischemic reperfusion (I/R) injury always produces many reactive oxygen species (ROS), which can aggravate the tissue damage. The effects of octreotide (OCT), a SST analogue, on retinal I/R injury and ROS formation, are not very clear. In this study, we observed the effects of OCT on morphological changes, oxidative stress, and cell death, induced by retinal I/R injury. The activation of nuclear factor κB (NF-κB) and intercellular adhesion molecule-1 (ICAM-1) were further evaluated in I/R retina treated with or without OCT. The retinal layer thickness was increased at 1 day after I/R and decreased at 7 days after I/R (P < 0.05). This effect was associated with increase in MDA and ROS levels (P < 0.05). The Tunel-positive cells increased and the number of ganglion cell layer (GCL) neurons decreased significantly after I/R injury. The expression of p-p65 and ICAM-1 increased significantly in I/R retinas (P < 0.05). Each effect was markedly attenuated by application of OCT. These data indicate that OCT protects the retina against retinal I/R damage, which could be through inhibition of oxidative stress and downregulation of NF-κB and ICAM-1 expression.
doi:10.1155/2015/970156
PMCID: PMC4484568  PMID: 26175842
12.  Acidic Fibroblast Growth Factor Promotes Endothelial Progenitor Cells Function via Akt/FOXO3a Pathway 
PLoS ONE  2015;10(6):e0129665.
Acidic fibroblast growth factor (FGF1) has been suggested to enhance the functional activities of endothelial progenitor cells (EPCs). The Forkhead homeobox type O transcription factors (FOXOs), a key substrate of the survival kinase Akt, play important roles in regulation of various cellular processes. We previously have shown that FOXO3a is the main subtype of FOXOs expressed in EPCs. Here, we aim to determine whether FGF1 promotes EPC function through Akt/FOXO3a pathway. Human peripheral blood derived EPCs were transduced with adenoviral vectors either expressing a non-phosphorylable, constitutively active triple mutant of FOXO3a (Ad-TM-FOXO3a) or a GFP control (Ad-GFP). FGF1 treatment improved functional activities of Ad-GFP transduced EPCs, including cell viability, proliferation, antiapoptosis, migration and tube formation, whereas these beneficial effects disappeared by Akt inhibitor pretreatment. Moreover, EPC function was declined by Ad-TM-FOXO3a transduction and failed to be attenuated even with FGF1 treatment. FGF1 upregulated phosphorylation levels of Akt and FOXO3a in Ad-GFP transduced EPCs, which were repressed by Akt inhibitor pretreatment. However, FGF1 failed to recover Ad-TM-FOXO3a transduced EPCs from dysfunction. These data indicate that FGF1 promoting EPC function is at least in part mediated through Akt/FOXO3a pathway. Our study may provide novel ideas for enhancing EPC angiogenic ability and optimizing EPC transplantation therapy in the future.
doi:10.1371/journal.pone.0129665
PMCID: PMC4463857  PMID: 26061278
13.  Developing an animal model of Dupuytren’s disease by orthotopic transplantation of human fibroblasts into athymic rat 
Background
Dupuytren’s disease (DD) is a slow, progressive fibroproliferative disorder affecting the palms of the hands. The disease is characterized by the formation of collagen rich- cords which gradually shorten by the action of myofibroblasts resulting in finger contractures. It is a disease that is confined to humans, and a major limiting factor in investigating this disorder has been the lack of a faithful animal model that can recapitulate its distinct biology. The aim of this study was to develop such a model by determining if Dupuytren’s disease (DD)- and control carpal tunnel (CT)-derived fibroblasts could survive in the forepaw of the nude rats and continue to exhibit the distinct characteristics they display in in vitro cultures.
Methods
1x107 fluorescently labeled DD- and CT-derived fibroblasts were transplanted into the left and right forepaws of nude rats respectively. Cells were tracked at regular intervals for a period of two months by quantifying emitted fluorescent signal using an IVIS imaging system. After a period of 62 days rat forepaw connective tissues were harvested for histology and total RNA was isolated. Human-specific probes were used to perform real time RT-PCR assays to examine the expression patterns of gene products associated with fibrosis in DD. Rat forepaw skin was also harvested to serve as an internal control.
Results
Both CT- and DD-derived fibroblasts survived for a period of 62 days, but DD-derived cells showed a significantly greater level of persistent fluorescent signal at the end of this time than did CT-derived cells. mRNA expression levels of α-smooth muscle actin (α-SMA), type I- and type III- collagens were all significantly elevated in the forepaw receiving DD cord-derived fibroblasts in comparison to CT-derived fibroblasts. Masson’s trichrome stain confirmed increased collagen deposition in the forepaw that was injected with DD cord-derived fibroblasts.
Conclusions
For the first time we describe an animal model for Dupuytren’s disease at the orthotopic anatomical location. We further show that gene expression differences between control (CT) and diseased (DD) derived fibroblasts persist when these cells are transplanted to the forepaw of the nude rat. These preliminary findings indicate that, with further refinements, this animal model holds promise as a baseline for investigating novel therapeutic regimens to determine an effective strategy in treating DD.
doi:10.1186/s12891-015-0597-z
PMCID: PMC4458343  PMID: 26049932
Dupuytren’s contracture; Palmar fascia fibrosis; Carpal tunnel syndrome; Fibroblasts; Collagen; Alpha-SMA
14.  Calpain-1 contributes to IgE-mediated mast cell activation 
Mast cells play a central role in allergy through secretion of both preformed and newly synthesized mediators. Mast cell mediator secretion is controlled by a complex network of signaling events. Despite intensive studies, signaling pathways in the regulation of mast cell mediator secretion remain incompletely defined. Here, we examined the role of calpain in IgE-dependent mast cell activation. IgE-mediated activation of mouse bone marrow-derived mast cells (BMMCs) enhanced calpain activity. Inhibition of calpain activity by a number of calpain inhibitors reduced IgE-mediated mast cell degranulation both in vitro and in vivo. Calpain inhibitors blocked IgE-mediated TNF and IL-6 production in vitro and reduced late-phase allergic response in vivo. Importantly, mouse calpain-1 null BMMCs showed reduced IgE-mediated mast cell degranulation in vitro and in vivo, diminished cytokine and chemokine production in vitro, and impaired late-phase allergic response in vivo. Further studies revealed that calpain-1-deficiency led to specific attenuation of IκB-NF-κB pathway and IKK-SNAP23 pathway, while calcium flux, MAP kinases, Akt, and NFAT pathway proceed normally in IgE-activated calpain-1 null mast cells. Thus, calpain-1 is identified as a novel regulator in IgE-mediated mast cell activation and could serve as a potential therapeutic target for the management of allergic inflammation.
doi:10.4049/jimmunol.1301677
PMCID: PMC4038093  PMID: 24760147
15.  Discovering chemistry with an ab initio nanoreactor 
Nature chemistry  2014;6(12):1044-1048.
Chemical understanding is driven by the experimental discovery of new compounds and reactivity, and is supported by theory and computation that provides detailed physical insight. While theoretical and computational studies have generally focused on specific processes or mechanistic hypotheses, recent methodological and computational advances harken the advent of their principal role in discovery. Here we report the development and application of the ab initio nanoreactor – a highly accelerated, first-principles molecular dynamics simulation of chemical reactions that discovers new molecules and mechanisms without preordained reaction coordinates or elementary steps. Using the nanoreactor we show new pathways for glycine synthesis from primitive compounds proposed to exist on the early Earth, providing new insight into the classic Urey-Miller experiment. These results highlight the emergence of theoretical and computational chemistry as a tool for discovery in addition to its traditional role of interpreting experimental findings.
doi:10.1038/nchem.2099
PMCID: PMC4239668  PMID: 25411881
16.  Inhibition of the Transition of Ductal Carcinoma In Situ to Invasive Ductal Carcinoma by a Gemini Vitamin D Analog 
Ductal carcinoma in situ (DCIS) is a non-malignant lesion of the breast with the potential to progress to invasive ductal carcinoma (IDC). The disappearance and breakdown of the myoepithelial cell layer and basement membrane in DCIS have been identified as major events in the development of breast cancer. The MCF10DCIS.com cell line is a well-established model which recapitulates the progression of breast cancer from DCIS to IDC. We have previously reported that a novel Gemini vitamin D analog, 1α,25-dihydroxy-20R-21(3-hydroxy-3-deuteromethyl-4,4,4-trideuterobutyl)-23-yne-26,27-hexafluoro-cholecalciferol (BXL0124) is a potent inhibitor of the growth of MCF10DCIS.com xenografted tumors without hypercalcemic toxicity. In the present study, we utilized the MCF10DCIS.com in vivo model to assess the effects of BXL0124 on breast cancer progression from weeks 1 to 4. Upon DCIS progression to IDC from weeks 3 to 4, tumors lost the myoepithelial cell layer and basement membrane as shown by immunofluorescence staining with smooth muscle actin (SMA) and laminin 5, respectively. Administration of BXL0124 maintained the critical myoepithelial cell layer as well as basement membrane, and animals treated with BXL0124 showed a 43% reduction in tumor volume by week 4. BXL0124 treatment decreased cell proliferation and maintained vitamin D receptor (VDR) levels in tumors. In addition, the BXL0124 treatment reduced the mRNA levels of matrix metalloproteinases (MMPs) starting at week 3, contributing to the inhibition of invasive transition. Our results suggest that the maintenance of DCIS plays a significant role in the cancer preventive action of the Gemini vitamin D BXL0124 during the progression of breast lesions.
doi:10.1158/1940-6207.CAPR-13-0362
PMCID: PMC4047145  PMID: 24691501
Vitamin D analog; Vitamin D receptor; Ductal Carcinoma in Situ; Invasive Ductal Carcinoma; Matrix Metalloproteinases
17.  A Novel Application of Multiscale Entropy in Electroencephalography to Predict the Efficacy of Acetylcholinesterase Inhibitor in Alzheimer's Disease 
Alzheimer's disease (AD) is the most common form of dementia. According to one hypothesis, AD is caused by the reduced synthesis of the neurotransmitter acetylcholine. Therefore, acetylcholinesterase (AChE) inhibitors are considered to be an effective therapy. For clinicians, however, AChE inhibitors are not a predictable treatment for individual patients. We aimed to disclose the difference by biosignal processing. In this study, we used multiscale entropy (MSE) analysis, which can disclose the embedded information in different time scales, in electroencephalography (EEG), in an attempt to predict the efficacy of AChE inhibitors. Seventeen newly diagnosed AD patients were enrolled, with an initial minimental state examination (MMSE) score of 18.8 ± 4.5. After 12 months of AChE inhibitor therapy, 7 patients were responsive and 10 patients were nonresponsive. The major difference between these two groups is Slope 2 (MSE6 to 20). The area below the receiver operating characteristic (ROC) curve of Slope 2 is 0.871 (95% CI = 0.69–1). The sensitivity is 85.7% and the specificity is 60%, whereas the cut-off value of Slope 2 is −0.024. Therefore, MSE analysis of EEG signals, especially Slope 2, provides a potential tool for predicting the efficacy of AChE inhibitors prior to therapy.
doi:10.1155/2015/953868
PMCID: PMC4450304  PMID: 26120358
18.  TMEM16A overexpression contributes to tumor invasion and poor prognosis of human gastric cancer through TGF-β signaling 
Oncotarget  2015;6(13):11585-11599.
TMEM16A is a newly identified calcium activated chloride channel, and has been reported to be overexpressed by various solid malignant cancers to promote proliferation and invasion, yet little is known about its role in gastric cancer(GC). Therefore, we investigated the role of TMEM16A in GC and its clinical significance by a retrospective analysis of 367 GC patients, and in vitro study was performed for validation and underlying molecular mechanism.
TMEM16A was significantly upregulated and amplified in GC tissues, and its overexpression was positively correlated with disease stage, negatively with patient survival and identified as an independent prognostic factor for patient outcome. A negative correlation between TMEM16A and E-cadherin was found in 367 GC specimens. TMEM16A silencing significantly decreased calcium activated chloride currents, impaired TGF-β secretion, reduced E-cadherin expression, and inhibited the migration and invasion without affecting proliferation of GC cells (AGS and BGC-823). Supplement of TGF-β reverted the effects of TMEM16A silencing on E-cadherin expression, cell migration and invasion.
In conclusion, TMEM16A promotes invasion and metastasis in GC, and might be a novel prognostic biomarker and potential therapeutic target in the treatment of GC.
PMCID: PMC4484478  PMID: 25839162
TMEM16A; invasion; prognosis; gastric cancer; TGF-β
19.  Building on Cram’s Legacy: Stimulated Gating in Hemicarcerands 
Accounts of Chemical Research  2014;47(7):2168-2176.
Conspectus
Donald Cram’s pioneering Nobel Prize-winning work on host–guest molecules led eventually to his creation of the field of container molecules. Cram defined two types of container molecules: carcerands and hemicarcerands. Host–guest complexes of carcerands, called carceplexes, are formed during their synthesis; once a carceplex is formed, the trapped guest cannot exit without breaking covalent bonds. Cram defined a quantity called constrictive binding, arising from the mechanical force that prevents guest escape. The constrictive binding in carceplexes is high. In contrast, hemicarcerands have low constrictive binding and are able to release the incarcerated guests at elevated temperatures without breaking covalent bonds. We have designed molecules that can switch from carcerand to hemicarcerand through a change in structure that we call gating.
The original discovery of gating in container molecules involved our computational studies of a Cram hemicarceplex that was observed to release a guest upon heating. We found that the side portals of this hemicarceplex have multiple thermally accessible conformations. An eight-membered ring that is part of a portal changes from a “chair” to a “boat” structure, leading to the enlargement of the side portal and the release of the guest. This type of gating is analogous to phenomena often observed with peptide loops in enzymes. We refer to this phenomenon as thermally controlled gating.
We have also designed and synthesized redox and photochemically controlled gated hemicarceplexes. Gates are built onto host molecules so that the opening or closing of such gates is stimulated by reducing or oxidizing conditions, or by ultraviolet irradiation. In both cases, the appropriate stimuli can produce a carceplex (closed gates) or hemicarceplex (open gates). A hemicarceplex with closed gates behaves like a carceplex, due to its very high constrictive binding energy. When the gates are opened, constrictive binding is dramatically lowered, and guest entrance and exit become facile. This stimulated switching between open and closed states controls access of the guest to the binding site. The experimental and computational investigations of gated hemicarcerands and several potential applications of gated hemicarceplexes are described in this Account.
doi:10.1021/ar5001296
PMCID: PMC4215849  PMID: 24802979
20.  Identification and validation of a two-gene expression index for subtype classification and prognosis in Diffuse Large B-Cell Lymphoma 
Scientific Reports  2015;5:10006.
The division of diffuse large B-cell lymphoma (DLBCL) into germinal center B-cell-like (GCB) and activated B-cell-like (ABC) subtypes based on gene expression profiling has proved to be a landmark in understanding the pathogenesis of the disease. This study aims to identify a novel biomarker to facilitate the translation of research into clinical practice. Using a training set of 350 patients, we identified a two-gene expression signature, “LIMD1-MYBL1 Index”, which is significantly associated with cell-of-origin subtypes and clinical outcome. This two-gene index was further validated in two additional dataset. Tested against the gold standard method, the LIMD1-MYBL1 Index achieved 81% sensitivity, 89% specificity for ABC group and 81% sensitivity, 87% specificity for GCB group. The ABC group had significantly worse overall survival than the GCB group (hazard ratio = 3.5, P = 0.01). Furthermore, the performance of LIMD1-MYBL1 Index was satisfactory compared with common immunohistochemical algorithms. Thus, the LIMD1-MYBL1 Index had considerable clinical value for DLBCL subtype classification and prognosis. Our results might prompt the further development of this two-gene index to a simple assay amenable to routine clinical practice.
doi:10.1038/srep10006
PMCID: PMC4419520  PMID: 25940947
21.  Hydrogen Sulfide Improves Wound Healing via Restoration of Endothelial Progenitor Cell Functions and Activation of Angiopoietin-1 in Type 2 Diabetes 
Diabetes  2014;63(5):1763-1778.
Impaired angiogenesis and its induced refractory wound lesions are common complications of diabetes. Hydrogen sulfide (H2S) has been reported to have proangiogenic effects. We hypothesize that H2S improves diabetic wound healing by restoring endothelial progenitor cell (EPC) function in type 2 diabetes. db/db Mice were treated with sodium hydrosulfide (NaHS), 4-hydro-xythiobenzamide group (HTB), or saline for 18 days. db/+ Mice were treated with dl-propargylglycine (PAG) or saline for 18 days. Plasma H2S levels were significantly decreased in db/db mice and restored in the NaHS and HTB mice compared with the diabetic control group. Wound-closure rates were significantly faster in the NaHS and HTB groups than in the db/db group, in which the PAG group had slower wound-closure rates. Wound skin capillary densities were enhanced in the NaHS and HTB groups. EPC functions were significantly preserved in the NaHS and HTB groups but were decreased in the PAG group. Meanwhile, EPC functions of the db/+ mice were significantly reduced after in vitro PAG treatment or cystathionine-γ-lyase (CSE) silencing; EPC functions of db/db mice were significantly improved after in vitro NaHS treatment. The expressions of Ang-1 in wound skin tissue and in EPCs were upregulated in the NaHS and HTB groups compared with db/db controls, but were downregulated by in vivo PAG and in vitro siCSE treatment compared with normal controls. Diabetic EPC tube formation capacity was significantly inhibited by Ang-1 small interfering RNA before NaHS treatment compared with db/db EPCs treated with NaHS only. Taken together, these results show that H2S improves wound healing by restoration of EPC functions and activation of Ang-1 in type 2 diabetic mice.
doi:10.2337/db13-0483
PMCID: PMC3994958  PMID: 24487028
22.  Modification of HSP proteins and Ca2+ are responsible for the NO-derived peroxynitrite mediated neurological damage in PC12 cell 
Peroxynitrite as one crucial metabolite of NO-derived agents has been well multi-investigated to inspect its potential role and sought to define its concrete mechanism underlying the memory loss and impaired cognition involved in pathological processes. In this investigation, the cell viability was assessed by the MTT assay. The neurotoxicity of peroxynitrite was analyzed by using immunohistochemical measurements in cultured PC12 cells to explore the underlying mechanisms. The generation of ROS was evaluated by a fluorometry assay by a fluorometry assay. Apoptosis was assayed by annexin V-FITC and PI staining with flow cytometry. [Ca2+]i was examined by using the microspectrofluorometer. Hsp70 was detected by western blot assay. The results revealed that PC12 cells were inhibited by peroxynitrite both in a dose-dependent and time-dependent manner. The level of ROS in PC12 cells exposed to SIN-1 was increased in a dose-dependent manner. The result indicated that the SIN-1 induced apoptosis of PC12 cells in a dose-dependent manner. Quercetin inhibited the viability of PC12 cells in a concentration-dependent manner. [Ca2+]i was increased gradually when cells treated with quercetin alone and also increased with treatment of dantrolene-containing. Hsp70 was significantly decreased in SIN-1-treated group compared with that of control group (P<0.01). In conclusion, Ca2+ homeostasis and chaperone Hsp70 were critically involved in peroxynitrite induced nitrosative stress as protective. Peroxynitrite acts as the pathological agent in learning and memory defects in CNS disorders associated with challenge.
PMCID: PMC4503011  PMID: 26191139
Peroxynitrite; neurotoxicity; Ca2+; Hsp70; cognition
23.  Reductions of the components of the calreticulin/calnexin quality-control system by proteasome inhibitors and their relevance in a rodent model of Parkinson’s disease 
Journal of neuroscience research  2014;92(10):1319-1329.
Evidence indicates that the ubiquitin-proteasome system and the endoplasmic retculum (ER) quality-control system work in concert to ensure that proteins are correctly folded in the ER and that misfolded proteins are retrotransported to the cytosol for degradation by proteasomes. Dysfunction of either system results in developmental abnormalities and even death in animals. This study investigates whether and how proteasome inhibition impacts the components of the calreticulin (CRT)/calnexin (CNX) glycoprotein folding machinery, a typical ER protein quality-control system, in the context of early neuronal injury. Here we report that proteasome inhibitor treatments, at nonlethal levels, reduced protein levels of CRT and ERp57 but not of CNX. These treatments increased protein levels of CRT in culture media, an effect blocked by brefeldin A, an inhibitor of protein trafficking; by contrast, ERp57 was not detected in culture media. Knockdown of CRT levels alone increased the vulnerability of SH-SY5Y, a neuronal cell line, to 6-hydroxydopamine (6-OHDA) toxicity. In a rat model of Parkinson’s disease, intrastriatal 6-OHDA lesions resulted in decreased levels of CRT and ERp57 in the midbrain. These findings suggest that reduction of the components of CRT/CNX glycoprotein quality-control system may play a role in neuronal injury in Parkinson’s disease and other neurodegenerative disorders associated with dysfunction of the ubiquitin-proteasome system.
doi:10.1002/jnr.23413
PMCID: PMC4412743  PMID: 24860980
24.  The Effects of Decorin and HGF-Primed Vocal Fold Fibroblasts In Vitro and Ex Vivo in a Porcine Model of Vocal Fold Scarring 
The Laryngoscope  2010;120(11):2247-2257.
Objectives
Vocal fold injury can be irreversible, leading to vocal fold scarring, with permanent functional effects and no optimal treatment. A porcine model of vocal fold scarring was used to test effects of decorin and primed vocal fold fibroblasts in vitro using a cell migration assay and immunoblotting, and by using functional measurements of porcine larynges and excised porcine vocal folds.
Methods
In vitro: primary pig vocal fold fibroblasts (PVFFs) were subjected to cell migration assays (scratch) and treated with decorin 20 μg/mL, hepatocyte growth factor (HGF) 200 ng/mL, epidermal growth factor (EGF) 1 nM, or transforming growth factor-β1 10 ng/mL. Cells also underwent decorin dose response testing. Scratch assays were analyzed in MetaMorph® Imaging; cell lysates were processed for MMP-8 and type I collagen content. Eleven pigs underwent unilateral vocal fold stripping procedures. At day 3 postoperatively, subjects underwent superficial injection into the affected vocal fold either with decorin 20 μg/mL or 1 × 106 HGF-primed fibroblasts. Larynges were harvested and either used for ex vivo laryngeal testing or for rheological testing.
Results
Scratch assay indicated significantly reduced cell migration in PVFFs treated with decorin or HGF. MMP-8 production was increased (P <0.01) and collagen was decreased in cells treated with decorin at increasing doses. Viscoelastic measurements suggested somewhat increased stiffness for decorin treated samples. Ex vivo aerodynamic testing suggested improved vocal efficiency scores in decorin-treated larynges.
Conclusions
Decorin has a noticeable effect on PVFF migration in vitro and appears to increase vocal fold stiffness but either does not change or slightly increases vocal efficiency.
Level of evidence: 5
doi:10.1002/lary.21087
PMCID: PMC4404152  PMID: 20830759
Molecular biology; laryngology
25.  The effects of sodium tanshinone IIa sulfonate pretreatment on high glucose-induced expression of fractalkine and apoptosis in human umbilical vein endothelial cells 
The development of diabetes mellitus (DM) and its complications is a chronic inflammatory response process, chemokines and their receptors play an important role in this course of events. The aim of this study is to observe the effects of sodium tanshinone IIa sulfonate (STS) on high glucose-induced fractalkine (FKN) level, and investigate possible mechanisms of STS works. HUVECs cells were employed to explore the effects of STS on FKN protein. TUNEL assay was used to detect the apoptosis rate of HUVECs. Immunohistochemistry was utilized to detect the β-actin and P-GSK-3β (Ser9) protein expression. Immunofluorescence was employed to detect FKN protein expression. Real-time RT-PCR was used to examine β-actin, GSK3β and FKN mRNA expression. The results indicated that the STS treatment could significantly decrease the apoptosis rate caused by high-glucose (P < 0.05). STS improves β-catenin and p-GSK-3β (Ser9) expression, and inhibits FKN levels induced by high glucose. STS inhibited GSK-3β and FKN mRNA induced by high glucose. In conclusion, STS may play the role of anti- inflammatory by regulate canonical Wnt pathway to inhibit the expression of FKN induced by high glucose.
PMCID: PMC4483885  PMID: 26131102
Diabetes mellitus; fractalkine; sodium tanshinone IIa sulfonate; apoptosis

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