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1.  An Assessment of Traditional Uighur Medicine in Current Xinjiang Region (China) 
Background
The main objectives of this study were to assess the current research and development of traditional Uighur medicine in Xinjiang (China), and to evaluate the promising pharmacological products of traditional Uighur medicine for further studies.
Materials and Methods
Traditional Uighur medicine data of medicine registry, patent, and academic publications was collected and analyzed.
Results
Data showed that, among the registered and studied traditional Uighur medicine, the main therapeutic areas of traditional Uighur medicine focused on skin disease, urogenital disease, rheumatism and digestive system disease. The representative traditional Uighur patent medicine included the following: BaixuanXiatare Tablets, Kaliziran Tincture and Vernoniaanthelmintica Injection (Psoriasis and vitiligo); Xi-payimazibiziLiquid (prostatitis); KursiKaknaq (urinary tract infection); Tongzhisurunjiang Capsules (anti-rheumatism medicine); HuganBuzure Granules (digestive system disease). Moreover, ten Uighur herbs were widely used, including: ResinaScammoniae, Folium FumicisDentati, HerbaDracocephali, Semen AmygdaliDulcis, HerbaChamomillae, FructusPimpinellaeanisi, Cortex Foeniculi, FructusVernoniae, FructusApii, and Radix AnacycliPyrethri.
Conclusion
This study concluded by indicating that traditional Uighur medicine with excellent curative effect should be screened in details for their phytochemical properties and pharmacological activity to discover new bioactive constituents.
PMCID: PMC4202637  PMID: 25435613
Traditional Uighur medicine; Traditional Uighur patent medicine; Uighur herb
2.  New strategies for prevention and treatment of splenic artery steal syndrome after liver transplantation 
World Journal of Gastroenterology : WJG  2014;20(41):15367-15373.
AIM: To explore a prophylactic procedure to prevent splenic artery steal syndrome (SASS), as well as a therapeutic intervention to correct it.
METHODS: Forty-three liver transplant patients were enrolled in a non-randomized controlled trial, with the eligible criterion that the diameter of the splenic artery is more than 5 mm and/or 1.5 times of the diameter of the hepatic artery. The procedure of splenic artery banding was performed in 28 of the 43 patients, with the other 15 patients studied as a control group. SASS and other complications were compared between these two groups. A new therapeutic intervention, temporary incomplete blockade of the splenic artery with a balloon, was performed to treat SASS in this study.
RESULTS: The incidence of SASS was decreased by banding the splenic artery (0/28 vs 5/15, P = 0.006), and the same result was observed in total complications associated with prophylactic procedures (2/28 vs 6/15, P = 0.014). Five patients in the control group developed SASS within 5 d after OLT, 2 of whom were treated by coil embolization of the splenic artery, whereas the other 3 by temporary blockade of the splenic artery. Reappeared or better hepatic arteries with improved systolic amplitude and increased diastolic flow were detected by Doppler ultrasonography in all the 5 patients. Local splenic ischemic necrosis and nonanastomotic biliary stricture were diagnosed respectively in one patient treated by coil embolization, and no collateral complication was detected in patients treated by temporary blockade of the splenic artery.
CONCLUSION: SASS should be avoided during the operation by banding the splenic artery. Temporary blockade of the splenic artery is a new safe and effective intervention for SASS.
doi:10.3748/wjg.v20.i41.15367
PMCID: PMC4223271  PMID: 25386086
Organ transplantation; Liver transplantation; Splenic artery steal syndrome; Vascular complication; Angiography
3.  Mandibular talon cusps: A Systematic review and data analysis 
Objectives: The purpose of the present study was to evaluate mandibular talon cusps distribution from the comprehensive literature search and proposal of new classification Material and Methods: The study was a review of articles published in the English language from January 1960 to December 2013. The PubMed/MEDLINE/Google Scholor databases were searched electronically using ‘talon cusp’, ‘dens evaginatus’, ‘anterior teeth’, mandible, ‘primary dentition’ and ‘ permanent dentition’ as search terms in various combinations. The citation lists from the included references were subsequently examined, and a hand search was also performed in an attempt to identify additional reports. The distribution, characteristics, common tooth type, associated dental anomaly and proposal of new classification have been included in final data analysis. Descriptive statistics were carried out using Chi square test (SPSS, version 17). Results: Overall 37 citations were retrieved from the literature where one was prevalence studies and rest were case reports among those two were duplication. Total 35 articles with 43 patients were reported on mandibular talon cusps. Males were predominantly affected than females (p<0.05). Eight cases (19%) were reported in archeological skulls 81% were clinical reports. Forty cases (93%) were reported in permanent dentition while 7% cases in primary dentition. Lingual mandibular talon are more common than facial type in permanent dentition facial talons (p<0.05). Seven cases (18%) were bilaterally involved. Double tooth (45%) was commonly associated with mandibular talons. Most of the cases reported from Asia and asia derived populations. Conclusions: Central incisor is the most common tooth type that effected by talon cusp in permanent dentition and lateral incisor is in primary dentition. Lingual talons are common in mandible. Double tooth common dental anomaly associated with mandibular talon cusp. Most of the case reported from Asia. Talon cusps should be classified as facial, lingual, and facial and lingual types.
Key words:Double tooth, permanent dentition, primary dentition, mandibular arch, Talon cusp.
doi:10.4317/jced.51476
PMCID: PMC4282910  PMID: 25593665
4.  Roles of histamine on the expression of aldehyde dehydrogenase 1 in endometrioid adenocarcinoma cell line 
Cancer Medicine  2014;3(5):1126-1135.
Cancer-initiating cells (CICs) are a limited number of cells that are essential for maintenance, recurrence, and metastasis of tumors. Aldehyde dehydrogenase 1 (ALDH1) has been recognized as a marker of CICs. We previously reported that ALDH1-high cases of uterine endometrioid adenocarcinoma showed poor prognosis, and that ALDH1 high population was more tumorigenic, invasive, and resistant to apoptosis than ALDH1 low population. Histamine plays a critical role in cancer cell proliferation, migration, and invasion. Here, we examined the effect of histamine on ALDH1 expression in endometrioid adenocarcinoma cell line. The addition of histamine increased ALDH1 high population, which was consistent with the result that histamine enhanced the invasive ability and the resistance to anticancer drug. Among 4 types of histamine receptors, histamine H1 and H2 receptor (H1R and H2R) were expressed in endometrioid adenocarcinoma cell line. The addition of H1R agonist but not H2R agonist increased ALDH1. The antagonist H1R but not H2R inhibited the effect of histamine on ALDH1 expression. These results indicated that histamine increased the expression of ALDH1 via H1R but not H2R. These findings may provide the evidence for exploring a new strategy to suppress CICs by inhibiting ALDH1 expression with histamine.
doi:10.1002/cam4.296
PMCID: PMC4302664  PMID: 25045085
Aldehyde dehydrogenase 1; cancer-initiating cells; endometrioid adenocarcinoma; histamine; histamine receptor
5.  Popularity and customer preferences for over-the-counter Chinese medicines perceived by community pharmacists in Shanghai and Guangzhou: a questionnaire survey study 
Chinese Medicine  2014;9:22.
Background
This study interviewed community pharmacists in Shanghai and Guangzhou for their perception of the popular categories of over-the-counter (OTC) Chinese medicines and the factors affecting customer preferences for OTC Chinese medicines.
Methods
A cross-sectional survey was carried out in six main administrative districts in Guangzhou and eight main administrative districts in Shanghai, China. Descriptive statistical analysis was conducted in this study.
Results
OTC Chinese medicines contributed 21–50% among all the pharmaceutical sales by the community pharmacies. The prevalent categories of OTC Chinese medicines were common cold medicines, respiratory system medicines, digestive system agents, gynecological medicines, health tonic medicines, and qing re (heat-clearing) and qu du (detoxifying) medicines. Customers were more concerned about medical factors of OTC Chinese medicines than business factors. Among the medical factors, the most important was drug safety, followed by efficacy, contraindications, indications, and side effects. Among the business factors, the most important were brand and price.
Conclusions
This study identified the top sales categories of OTC Chinese medicines in Shanghai and Guangzhou and the important factors such as drug safety, efficacy, period of validity, contraindications, and indications that are affecting the customer preferences for OTC Chinese medicines.
doi:10.1186/1749-8546-9-22
PMCID: PMC4169131  PMID: 25243017
6.  Induction of apoptosis by Cordyceps militaris fraction in human chronic myeloid leukemia K562 cells involved with mitochondrial dysfunction 
Pharmacognosy Magazine  2014;10(39):325-331.
Background:
Cordyceps militaris is widely used for various ethno medical conditions including cancer and inflammation complications in traditional Chinese medicine.
Objective:
To investigate the in vitro antitumor activity of Cordyceps militaris fraction (CMF) and the molecular mechanism underlying the apoptosis it induces in human chronic myeloid leukemia K562 cells.
Materials and Methods:
CMF was prepared according to our previous report. Cell viability was assessed by MTT assay. The rate of apoptosis, distribution of cell cycle and loss of mitochondrial membrane potential were measured by flow cytometry. Caspase activities were analyzed by Western blot and oxygen consumption rate was recorded using the Oxytherm system.
Results:
The results demonstrated that CMF triggered growth inhibition in K562 cells with only minor toxicity on a normal human cell line and inhibited the proliferation of K562 cells in a dose- and time-dependent manner with IC50 value of 34.1 ± 2.0 μg/ml after 48 h incubation. This most likely resulted from cell cycle arrest at the S phase and the induction of apoptosis. In addition, CMF induced activation of caspase-3 and subsequent cleavage of poly ADP-ribose polymerase (PARP). The caspase signals may originate from mitochondrial dysfunction, which was supported by the finding of decreased mitochondria transmembrance potential and the lower oxygen consumption rate.
Conclusion:
CMF possessed the in vitro antitumor effect on K562 cells and CMF-induced apoptosis might be involved by the mitochondrial dysfunction and valuable to research and develop as a potential antitumor agency.
doi:10.4103/0973-1296.137374
PMCID: PMC4159927  PMID: 25210321
Apoptosis; Cordyceps militaris; K562 cells; mitochondria dysfunction
7.  Enhanced dissolution and stability of Tanshinone IIA base by solid dispersion system with nano-hydroxyapatite 
Pharmacognosy Magazine  2014;10(39):332-337.
Background:
Tanshinone IIA (TSIIA) exhibits a variety of cardiovascular effects; however, it has low solubility in water. The preparation of poorly soluble drugs for oral delivery is one of the greatest challenges in the field of formulation research. Among the approaches available, solid dispersion (SD) technique has proven to be one of the most commonly used these methods for improving dissolution and bioavailability of drugs, because of its relative simplicity and economy in terms of both preparation and evaluation.
Objective:
This study was aimed at investigating the dissolution behavior and physical stability of SDs of TSIIA by employing nano-hydroxyapatite (n-HAp).
Materials and Methods:
The TSIIA SDs was prepared to use a spray-drying method. First, an in vitro dissolution test was performed to assess dissolution characteristics. Next, a set of complementary techniques (differential scanning calorimetry, scanning electron microscopy, X-ray powder diffraction, and Fourier transform infrared spectroscopy) was used to monitor the physicochemical properties of the SDs. The SDs was stored at 40°C/75% relative humidity for 6 months, after which their stability was assessed.
Results:
TSIIA dissolution remarkably improved because of the formulation of the SDs with n-HAp particles. Comparisons with the corresponding physical mixtures revealed changes in the SDs and explained the formation of the amorphous phase. In the stability test, virtually no time-dependent decrease was observed in either in vitro drug dissolution or drug content.
Conclusion:
SD formulation with n-HAp may be a promising approach for enhancing the dissolution and stability of TSIIA.
doi:10.4103/0973-1296.137375
PMCID: PMC4159928  PMID: 25210322
Dissolution; nano-hydroxyapatite; solid dispersion; stability; Tanshinone IIA
8.  Combination of autoantibodies against NY-ESO-1 and viral capsid antigen immunoglobulin A for improved detection of nasopharyngeal carcinoma 
Oncology Letters  2014;8(3):1096-1102.
Nasopharyngeal carcinoma (NPC) is one of the most common malignant tumors in Southern China and Southeast Asia, and early detection remains a challenge. Autoantibodies have been found to precede the manifestations of symptomatic cancer by several months to years, making their identification of particular relevance for early detection. In the present study, the diagnostic value of serum autoantibodies against NY-ESO-1 in NPC patients was evaluated. The study included 112 patients with NPC and 138 normal controls. Serum levels of autoantibodies against NY-ESO-1 and classical Epstein-Barr virus marker, viral capsid antigen immunoglobulin A (VCA-IgA), were measured by enzyme-linked immunosorbent assay. Measurement of autoantibodies against NY-ESO-1 and VCA-IgA demonstrated a sensitivity/specificity of 42.9/94.9% [95% confidence interval (CI), 33.7–52.6/89.4–97.8%] and 55.4/95.7% (95% CI, 45.7–64.7/90.4–98.2%), respectively. The area under receiver operating characteristic curve for autoantibodies against NY-ESO-1 (0.821; 95% CI, 0.771–0.871) was marginally lower than that for VCA-IgA (0.860; 95% CI, 0.810–0.910) in NPC. The combination of autoantibodies against NY-ESO-1 and VCA-IgA yielded an enhanced sensitivity of 80.4% (95% CI, 71.6–87.0%) and a specificity of 90.6% (95% CI, 84.1–94.7%). Moreover, detection of autoantibodies against NY-ESO-1 could differentiate early-stage NPC patients from normal controls. Our results suggest that autoantibodies against NY-ESO-1 may serve as a potential biomarker, as a supplement to VCA-IgA, for the screening and diagnosis of NPC.
doi:10.3892/ol.2014.2286
PMCID: PMC4114591  PMID: 25120665
NY-ESO-1; autoantibody; nasopharyngeal carcinoma; viral capsid antigen immunoglobulin A; diagnosis
9.  Rare presentation of peripheral primitive neuroectodermal tumor in the maxilla and mandible: A report of two cases 
Oncology Letters  2014;8(2):615-619.
Peripheral primitive neuroectodermal tumor (pPNET) is a rare and highly malignant undifferentiated tumor, which presents in infants and young adults. pPNETs in the head and neck region are uncommon and have a varying incidence of occurrence. Peripheral PNETs of the maxilla and mandible are particularly rare. At present, only 16 cases of pPNET of the maxilla and 13 cases of pPNET of the mandible have been reported. The present study describes a case of pPNET of the maxilla in a 16-year-old male and a case of pPNET of the mandible in another 16-year-old male. The present study reports the radiological findings and the clinical courses of the two patients.
doi:10.3892/ol.2014.2219
PMCID: PMC4081291  PMID: 25013475
maxilla; mandible; primitive neuroectodermal tumor; diagnosis; management
10.  Coagulation and Fibrinolysis Index Profile in Patients with ANCA-Associated Vasculitis 
PLoS ONE  2014;9(5):e97843.
Background
Previous studies observed the high prevalence of venous thromboembolism in patients with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). The current study analyzed the coagulation and fibrinolysis index profile in AAV patients.
Methods
The current study recruited 321 AAV patients in active stage and 78 AAV patients in quiescent stage. Coagulation and fibrinolysis index profiles in these AAV patients were analysed, and their associations with various clinical and pathological parameters were further investigated.
Results
The circulating levels of D-dimer, fibrin degradation products and platelet count were significantly higher in AAV patients in active stage compared with those in remission [0.8 (0.4, 1.5) mg/L vs. 0.28 (0.2, 0.55) mg/L, P<0.05; 5.6 (5.0, 10.0) mg/L vs. 1.9 (1.2, 2.8) mg/L, P<0.05; 269±127×109/L vs. 227±80×109/L, P<0.05, respectively]. Among the 321 AAV patients in active stage, compared with patients with normal levels of D-dimer, patients with elevated D-dimer levels had significantly higher levels of initial serum creatinine, erythrocyte sedimentation rate, C reactive protein and the Birmingham Vasculitis Activity Scores (P = 0.014, P<0.001, P<0.001, P = 0.002, respectively). Moreover, correlation analysis showed that the levels of D-dimer correlated with erythrocyte sedimentation rate and C reactive protein levels (r = 0.384, P<0.001; r = 0.380, P<0.001, respectively).
Conclusion
Patients with active AAV are in hypercoagulable states, and circulating levels of D-dimer are associated with disease activity of AAV.
doi:10.1371/journal.pone.0097843
PMCID: PMC4026389  PMID: 24842719
11.  Mutation Analysis of JAK2V617F, FLT3-ITD, NPM1, and DNMT3A in Chinese Patients with Myeloproliferative Neoplasms 
BioMed Research International  2014;2014:485645.
Since the discovery of JAK2V617F tyrosine kinase-activating mutation, several genes have been found mutated in myeloproliferative neoplasms (MPNs). FLT3-ITD, NPM1, and DNMT3A mutations frequently occurred in AML patients and have been found conferred with myeloproliferative neoplasms in mouse model. Therefore, we sought to search for mutations in JAK2V617F, FLT3-ITD, NPM1, and DNMT3A in 129 cases including 120 classic MPN cases and 9 MDS/MPN cases. JAK2V617F mutation was found in 60% of the 120 classic MPNs. However, none of the patients displayed FLT3-ITD and NPM1 mutations; only 2 patients harbored DNMT3A R882 mutation. Further studies including whole-genome sequence will be conducted to investigate the possible involvement of these genes in MPN.
doi:10.1155/2014/485645
PMCID: PMC4034537  PMID: 24895580
12.  Treatment of Mild Traumatic Brain Injury with an Erythropoietin-Mimetic Peptide 
Journal of Neurotrauma  2013;30(9):765-774.
Abstract
Mild traumatic brain injury (mTBI) results in an estimated 75–90% of the 1.7 million TBI-related emergency room visits each year. Post-concussion symptoms, which can include impaired memory problems, may persist for prolonged periods of time in a fraction of these cases. The purpose of this study was to determine if an erythropoietin-mimetic peptide, pyroglutamate helix B surface peptide (pHBSP), would improve neurological outcomes following mTBI. Sixty-four rats were randomly assigned to pHBSP or control (inactive peptide) 30 μg/kg IP every 12 h for 3 days, starting at either 1 hour (early treatment) or 24 h (delayed treatment), after mTBI (cortical impact injury 3 m/sec, 2.5 mm deformation). Treatment with pHBSP resulted in significantly improved performance on the Morris water maze task. Rats that received pHBSP required 22.3±1.3 sec to find the platform, compared to 26.3±1.3 sec in control rats (p=0.022). The rats that received pHBSP also traveled a significantly shorter distance to get to the platform, 5.0±0.3 meters, compared to 6.1±0.3 meters in control rats (p=0.019). Motor tasks were only transiently impaired in this mTBI model, and no treatment effect on motor performance was observed with pHBSP. Despite the minimal tissue injury with this mTBI model, there was significant activation of inflammatory cells identified by labeling with CD68, which was reduced in the pHBSP-treated animals. The results suggest that pHBSP may improve cognitive function following mTBI.
doi:10.1089/neu.2012.2431
PMCID: PMC3653382  PMID: 22827443
adult brain injury; traumatic brain injury; treatment strategies for traumatic brain injury
13.  Acute Coronary Syndrome Remodels the Protein Cargo and Functions of High-Density Lipoprotein Subfractions 
PLoS ONE  2014;9(4):e94264.
Objectives
This study examined alterations in the functions and proteome of high-density lipoprotein (HDL) subfractions (HDL2 and HDL3) isolated from patients with acute coronary syndrome (ACS) compared with control subjects.
Methods
We measured HDL subfraction cholesterol efflux capacity, inflammatory index (HII), paraoxonase-1 (PON1) activity, and lipid hydroperoxide (LOOH) levels in both male age-matched controls and the ACS group (n = 40/group). Additionally, proteomic analysis was used to monitor changes in the HDL subfraction proteome between controls and ACS subjects.
Results
Both HDL2 and HDL3 from ACS patients had greater HII and LOOH levels compared with controls (P<0.001); PON1 activity and cholesterol efflux capacity in both HDL2 and HDL3 from the ACS group were significantly less than those of controls (P<0.001). Using proteomic analysis, we demonstrated that, compared with the control group, nine proteins were selectively enriched in HDL3 from subjects with ACS, and ras-related protein Rab-7b was decreased in HDL3. Additionally, in the ACS subjects, 12 proteins were decreased in HDL2 and 4 proteins were increased in HDL2.
Conclusions
Functional HDL subfractions shifted to dysfunctional HDL subfractions during ACS, and the functional impairment was linked to remodeled protein cargo in HDL subfractions from ACS patients.
doi:10.1371/journal.pone.0094264
PMCID: PMC3988065  PMID: 24736723
14.  Cytoplasmic Retention of a Nucleocytoplasmic Protein TBC1D3 by Microtubule Network Is Required for Enhanced EGFR Signaling 
PLoS ONE  2014;9(4):e94134.
The hominoid oncogene TBC1D3 enhances epidermal growth factor receptor (EGFR) signaling and induces cell transformation. However, little is known regarding its spatio-temporal regulation and mechanism of tumorigenesis. In the current study, we identified the microtubule subunit β-tubulin as a potential interaction partner for TBC1D3 using affinity purification combined with mass spectrometry analysis. The interaction between TBC1D3 and β-tubulin was confirmed by co-immunoprecipitation. Using the same method, we also revealed that TBC1D3 co-precipitated with endogenous α-tubulin, another subunit of the microtubule. In agreement with these results, microtubule cosedimentation assays showed that TBC1D3 associated with the microtubule network. The β-tubulin-interacting site of TBC1D3 was mapped to amino acids 286∼353 near the C-terminus of the TBC domain. Deletion mutation within these amino acids was shown to abolish the interaction of TBC1D3 with β-tubulin. Interestingly, the deletion mutation caused a complete loss of TBC1D3 from the cytoplasmic filamentous and punctate structures, and TBC1D3 instead appeared in the nucleus. Consistent with this, wild-type TBC1D3 exhibited the same nucleocytoplasmic distribution in cells treated with the microtubule depolymerizing agent nocodazole, suggesting that the microtubule network associates with and retains TBC1D3 in the cytoplasm. We further found that deficiency in β-tubulin-interacting resulted in TBC1D3's inability to inhibit c-Cbl recruitment and EGFR ubiquitination, ultimately leading to dysregulation of EGFR degradation and signaling. Taken together, these studies indicate a novel model by which the microtubule network regulates EGFR stability and signaling through tubulin dimer/oligomer interaction with the nucleocytoplasmic protein TBC1D3.
doi:10.1371/journal.pone.0094134
PMCID: PMC3979746  PMID: 24714105
15.  Polymorphisms of CLEC16A Region and Autoimmune Thyroid Diseases 
G3: Genes|Genomes|Genetics  2014;4(6):973-977.
To investigate the association of CLEC16A gene polymorphisms and autoimmune thyroid diseases (AITDs). Six hundred sixty seven Han Chinese patients with AITDs were selected as study subjects, including 417 patients with Graves’ disease (GD), 250 patients with Hashimoto’s thyroiditis (HT) and 301 healthy control patients. Polymerase chain reaction-restriction fragment length polymorphism (RFLP) and the mass spectrometry technique were used to genotype five CLEC16A single-nucleotide polymorphisms (SNPs) (rs12708716, rs12917716, rs12931878, rs2903692, and rs6498169). Higher frequency of G allele of rs6498169 CLEC16A gene in AITDs patients [P = 0.029, odds ratio (OR) 1.29 and 95% confidence interval 1.022−1.505] was observed. In addition an association between rs6498169 and HT was observed with statistical significance (P = 0.018, OR 1.335, 95% confidence interval 1.051−1.696). Furthermore, the GG haplotype containing the major allele of (rs12708716 and rs6498169) was associated with an increased risk of HT (P = 0.0148, OR 1.344). When patients with HT and controls were compared, results from the dominant and recessive models showed that the genotype frequency of rs6498169 were at borderline levels (P = 0.054 and P = 0.05), and the other four SNPs of CLEC16A gene showed no significant association with AITDs. Our results suggest that polymorphisms rs6498169 of CLEC16A gene confers susceptibility to AITDs. We therefore disclose for the first time the association of rs6498169 SNP with AITDs.
doi:10.1534/g3.114.010926
PMCID: PMC4065265  PMID: 24646814
CLEC16A; single-nucleotide polymorphisms (SNPs); autoimmune thyroid diseases (AITDs); Graves’ disease (GD); Hashimoto’s thyroiditis (HT); innate immunity; complex genetics; tolerance; complex immunity; infection; resistance
16.  Active Calcium/Calmodulin-Dependent Protein Kinase II (CaMKII) Regulates NMDA Receptor Mediated Postischemic Long-Term Potentiation (i-LTP) by Promoting the Interaction between CaMKII and NMDA Receptors in Ischemia 
Neural Plasticity  2014;2014:827161.
Active calcium/calmodulin-dependent protein kinase II (CaMKII) has been reported to take a critical role in the induction of long-term potentiation (LTP). Changes in CaMKII activity were detected in various ischemia models. It is tempting to know whether and how CaMKII takes a role in NMDA receptor (NMDAR)-mediated postischemic long-term potentiation (NMDA i-LTP). Here, we monitored changes in NMDAR-mediated field excitatory postsynaptic potentials (NMDA fEPSPs) at different time points following ischemia onset in vitro oxygen and glucose deprivation (OGD) ischemia model. We found that 10 min OGD treatment induced significant i-LTP in NMDA fEPSPs, whereas shorter (3 min) or longer (25 min) OGD treatment failed to induce prominent NMDA i-LTP. CaMKII activity or CaMKII autophosphorylation displays a similar bifurcated trend at different time points following onset of ischemia both in vitro OGD or in vivo photothrombotic lesion (PT) models, suggesting a correlation of increased CaMKII activity or CaMKII autophosphorylation with NMDA i-LTP. Disturbing the association between CaMKII and GluN2B subunit of NMDARs with short cell-permeable peptides Tat-GluN2B reversed NMDA i-LTP induced by OGD treatment. The results provide support to a notion that increased interaction between NMDAR and CaMKII following ischemia-induced increased CaMKII activity and autophosphorylation is essential for induction of NMDA i-LTP.
doi:10.1155/2014/827161
PMCID: PMC3964903  PMID: 24734203
17.  Promise and Challenge: The Lens Model as a Biomarker for Early Diagnosis of Alzheimer's Disease 
Disease Markers  2014;2014:826503.
Alzheimer's disease (AD) is the most common form of dementia pathologically characterized by cerebral amyloid-beta (Aβ) deposition. Early and accurate diagnosis of the disease still remains a big challenge. There is evidence that Aβ aggregation starts to occur years before symptoms arise. Noninvasive monitoring of Aβ plaques is critical for both the early diagnosis and prognosis of AD. Presently, there is a major effort on looking for a reasonably priced technology capable of diagnosing AD by detecting the presence of Aβ. Studies suggest that AD is systemic rather than brain-limited focus diseases and the aggregation of the disease-causing proteins also takes place in lens except the brain. There is a possible relationship between AD and a specific subtype of age-related cataract (supranuclear cataract). If similar abnormal protein deposits are present in the lens, it would facilitate non-invasive diagnosis and monitoring of disease progression. However, there are controversies on the issues related to performance and validation of Aβ deposition in lens as biomarkers for early detection of AD. Here we review the recent findings concerning Aβ deposition in the lenses of AD patients and evaluate if the ocular lens can provide a biomarker for AD.
doi:10.1155/2014/826503
PMCID: PMC3945026  PMID: 24688166
18.  Alleviation of Lead Toxicity by 5-Aminolevulinic Acid Is Related to Elevated Growth, Photosynthesis, and Suppressed Ultrastructural Damages in Oilseed Rape 
BioMed Research International  2014;2014:530642.
Lead (Pb) is a widely spread pollutant and leads to diverse morphological and structural changes in the plants. In this study, alleviating role of 5-aminolevulinic acid (ALA) in oilseed rape (Brassica napus L.) was investigated with or without foliar application of ALA (25 mg L−1) in hydroponic environment under different Pb levels (0, 100, and 400 µM). Outcomes stated that plant morphology and photosynthetic attributes were reduced under the application of Pb alone. However, ALA application significantly increased the plant growth and photosynthetic parameters under Pb toxicity. Moreover, ALA also lowered the Pb concentration in shoots and roots under Pb toxicity. The microscopic studies depicted that exogenously applied ALA ameliorated the Pb stress and significantly improved the cell ultrastructures. After application of ALA under Pb stress, mesophyll cell had well-developed nucleus and chloroplast having a number of starch granules. Moreover, micrographs illustrated that root tip cell contained well-developed nucleus, a number of mitochondria, and golgi bodies. These results proposed that under 15-day Pb-induced stress, ALA improved the plant growth, chlorophyll content, photosynthetic parameters, and ultrastructural modifications in leaf mesophyll and root tip cells of the B. napus plants.
doi:10.1155/2014/530642
PMCID: PMC3934662  PMID: 24683549
19.  Elevated Th22 Cells Correlated with Th17 Cells in Peripheral Blood of Patients with Acute Myeloid Leukemia 
Acute myeloid leukemia (AML) is a hematological tumor in which progress T helper (Th) subsets including Th22, Th17, and Th1 cells play a pivotal role. However, the role of T helper (Th) subsets in the immune pathogenesis of AML remains unclear. Here, we investigated frequencies of Th22, Th17, pure Th17, and Th1 cells in the peripheral blood (PB) of AML patients. We demonstrated that Th22, Th17, and pure Th17 in newly-diagnosed (ND) and non-complete remission (Non-CR) AML patients and plasma IL-22 in ND AML patients were significantly increased. Retinoid-related orphan receptor C (RORC) expression was significantly elevated in CR and Non-CR AML patients. However, Th1 in ND AML patients and IL-17 in ND, Non-CR or CR AML patients was significantly decreased compared with controls. Moreover, Th22 and IL-22 showed positive correlation with pure Th17, but Th22 showed negative correlation with Th1 in ND AML patients. RORC showed positive correlation with Th22 and approximately positive correlation with pure Th17 in Non-CR patients. PB blast cell showed positive correlation with Th22 and negative correlation with Th1 in ND AML patients. Our results indicate that Th22 and pure Th17 cells conjointly contribute to the pathogenesis of AML and might be promising novel clinical index for AML.
doi:10.3390/ijms15021927
PMCID: PMC3958830  PMID: 24473142
acute myeloid leukemia; T helper 22; T helper 17; T helper 1; interleukin-22; interleukin-17
20.  Targeting Six1 by lentivirus-mediated RNA interference inhibits colorectal cancer cell growth and invasion 
The Six1 homeodomain protein is a developmental transcription factor that has been implicated in tumor onset and progression. Recently, it’s reported that overexpression of Six1 is sufficient to induce epithelial-to-mesenchymal transition (EMT) and metastasis of colorectal cancer. Moreover, its expression is significantly associated with poorer overall survival probability in advanced-stage colorectal cancer. To address whether Six1 could serve as a therapeutic target for human colorectal cancer, we used a lentivirus-mediated short hairpin RNA (shRNA) gene knockdown method to suppress the expression of Six1 in colorectal cancer cells. We showed that lentivirusmediated shRNA targeted to Six1 gene efficiently reduced its expression in colorectal cancer cells at both mRNA and protein levels. In vitro functional assays revealed that knockdown of Six1 significantly suppressed cell proliferation, and inhibited cell migration and invasion of colorectal cancer cells. Furthermore, tumor xenograft model demonstrated that downregulation of Six1 dramatically inhibited colorectal cancer growth in vivo. In conclusion, these findings suggest that lentivirus-mediated Six1 inhibition may represent a novel therapeutic approach for treatment of colorectal cancer.
PMCID: PMC3925907  PMID: 24551283
Six1; colorectal cancer; cell growth; invasion
21.  Surface assembly and nanofabrication of 1,1,1-tris(mercaptomethyl)heptadecane on Au(111) studied with time-lapse atomic force microscopy 
Summary
The solution self-assembly of multidentate organothiols onto Au(111) was studied in situ using scanning probe nanolithography and time-lapse atomic force microscopy (AFM). Self-assembled monolayers (SAMs) prepared from dilute solutions of multidentate thiols were found to assemble slowly, requiring more than six hours to generate films. A clean gold substrate was first imaged in ethanolic media using liquid AFM. Next, a 0.01 mM solution of multidentate thiol was injected into the liquid cell. As time progressed, molecular-level details of the surface changes at different time intervals were captured by successive AFM images. Scanning probe based nanofabrication was accomplished using protocols of nanografting and nanoshaving with n-alkanethiols and a tridentate molecule, 1,1,1-tris(mercaptomethyl)heptadecane (TMMH). Nanografted patterns of TMMH could be inscribed within n-alkanethiol SAMs; however, the molecular packing of the nanopatterns was less homogeneous compared to nanopatterns produced with monothiolates. The multidentate molecules have a more complex assembly pathway than monothiol counterparts, mediated by sequential steps of forming S–Au bonds to the substrate.
doi:10.3762/bjnano.5.3
PMCID: PMC3896263  PMID: 24455459
liquid AFM; multidentate; nanografting; nanolithography; self-assembly
22.  MiR-194 Deregulation Contributes To Colorectal Carcinogenesis via Targeting AKT2 Pathway 
Theranostics  2014;4(12):1193-1208.
Abstract: Recent studies have increasingly linked microRNAs to colorectal cancer (CRC). MiR-194 has been reported deregulated in different tumor types, whereas the function of miR-194 in CRC largely remains unexplored. Here we investigated the biological effects, mechanisms and clinical significance of miR-194. Functional assay revealed that overexpression of miR-194 inhibited CRC cell viability and invasion in vitro and suppressed CRC xenograft tumor growth in vivo. Conversely, block of miR-194 in APCMin/+ mice promoted tumor growth. Furthermore, miR-194 reduced the expression of AKT2 both in vitro and in vivo. Clinically, the expression of miR-194 gradually decreased from 20 normal colorectal mucosa (N-N) cases through 40 colorectal adenomas (CRA) cases and then to 40 CRC cases, and was negatively correlated with AKT2 and pAKT2 expression. Furthermore, expression of miR-194 in stool samples was gradually decreased from 20 healthy cases, 20 CRA cases, then to 28 CRC cases. Low expression of miR-194 in CRC tissues was associated with large tumor size (P=0.006), lymph node metastasis (P=0.012) and shorter survival (HR =2.349, 95% CI = 1.242 to 4.442; P=0.009). In conclusion, our data indicated that miR-194 acted as a tumor suppressor in the colorectal carcinogenesis via targeting PDK1/AKT2/XIAP pathway, and could be a significant diagnostic and prognostic biomarker for CRC.
doi:10.7150/thno.8712
PMCID: PMC4183997  PMID: 25285168
colorectal cancer; miR-194; AKT2 pathway; biomarker; carcinogenesis.
23.  Use of Granulocyte Colony-Stimulating Factor for the Treatment of Thin Endometrium in Experimental Rats 
PLoS ONE  2013;8(12):e82375.
Granulocyte colony-stimulating factor (G-CSF) induces stem cells to mobilize to the injury site, which have beneficial effect on tissue repair. The aim of this study was to investigate the effect of G-CSF on the thin endometrium in rat models. In the present study, rats with thin endometrium were divided into 4 groups (experimental group I: administrated with G-CSF (40 µg/kg/d) 4–6 hours post-modeling; control group I: administrated with saline 4–6 hours post-modeling; experimental group II: administrated with G-CSF (40 µg/kg/d) 12 days post-modeling; control group II: administrated with saline 12 days post-modeling. The agentia was given once daily and last for 5 days. Endometrial morphology was analyzed by Hematoxylin-Eosin staining, and the regeneration of endometrial cells was evaluated by immunohistochemistry and western-blot with cytokeratin and vimentin. We found that endometrial thickness and morphology presented a significant difference between experimental groups and control groups. No matter when we start with G-CSF, there was a significantly thicker endometrium and stronger expression of cytokeratin/vimintin in the experimental groups compared with the control groups (P<0.01). There were significant thicker endometrial lining and stronger expression of cytokeratin/vimintin in experimental group I than that of experimental group II (P<0.05), but there was no difference in the endometrial lining and the expression of cytokeratin/vimintin between the two control groups (P>0.05). In conclusion, G-CSF can promote the regeneration of endometrial cells in animal research, especially when the G-CSF was administrated earlier.
doi:10.1371/journal.pone.0082375
PMCID: PMC3871160  PMID: 24376532
24.  Beclin 1 Deficiency Correlated with Lymph Node Metastasis, Predicts a Distinct Outcome in Intrahepatic and Extrahepatic Cholangiocarcinoma 
PLoS ONE  2013;8(11):e80317.
Autophagy can be tumor suppressive as well as promotive in regulation of tumorigenesis and disease progression. Accordingly, the prognostic significance of autophagy key regulator Beclin 1 was varied among different tumors. Here, we detected the clinicopathological and prognostic effect of Beclin 1 in the subtypes of intrahepatic cholangiocarcinoma (ICC) and extrahepatic cholangiocarcinoma (ECC). Beclin 1 expression level was detected by immunohistochemistry staining in 106 ICC and 74 ECC patients. We found that Beclin 1 was lowly expressed in 126 (70%) cholangiocarcinoma patients, consist of 72 ICC and 54 ECC. Moreover, the cholangiocarcinoma patients with lymph node metastasis (N1) had a lower Beclin 1 level than that of N0 subgroup (P=0.012). However, we did not detect any correlations between Beclin 1 and other clinicopathological features, including tumor subtypes, vascular invasion, HBV infection, liver cirrhosis, cholecystolithiasis and TNM stage. Survival analysis showed that, compared with the high expression subset, Beclin 1 low expression was correlated with a poorer 3-year progression-free survival (PFS, 69.1% VS 46.8%, P=041) for cholangiocarcinoma. Importantly, our stratified univariate and multivariate analysis confirmed that Beclin 1 lowly expressed ICC had an inferior PFS as well as overall survival than ECC, particularly than that of Beclin 1 highly expressed ECC patients. Thus, our study demonstrated that Beclin 1low expression, correlated with lymph node metastasis, and might be a negative prognostic biomarker for cholangiocarcinoma. Combined Beclin 1 level with the anatomical location might lead to refined prognosis for the subtypes of ICC and ECC.
doi:10.1371/journal.pone.0080317
PMCID: PMC3841169  PMID: 24303007
25.  A Novel Antibody Humanization Method Based on Epitopes Scanning and Molecular Dynamics Simulation 
PLoS ONE  2013;8(11):e80636.
1-17-2 is a rat anti-human DEC-205 monoclonal antibody that induces internalization and delivers antigen to dendritic cells (DCs). The potentially clinical application of this antibody is limited by its murine origin. Traditional humanization method such as complementarity determining regions (CDRs) graft often leads to a decreased or even lost affinity. Here we have developed a novel antibody humanization method based on computer modeling and bioinformatics analysis. First, we used homology modeling technology to build the precise model of Fab. A novel epitope scanning algorithm was designed to identify antigenic residues in the framework regions (FRs) that need to be mutated to human counterpart in the humanization process. Then virtual mutation and molecular dynamics (MD) simulation were used to assess the conformational impact imposed by all the mutations. By comparing the root-mean-square deviations (RMSDs) of CDRs, we found five key residues whose mutations would destroy the original conformation of CDRs. These residues need to be back-mutated to rescue the antibody binding affinity. Finally we constructed the antibodies in vitro and compared their binding affinity by flow cytometry and surface plasmon resonance (SPR) assay. The binding affinity of the refined humanized antibody was similar to that of the original rat antibody. Our results have established a novel method based on epitopes scanning and MD simulation for antibody humanization.
doi:10.1371/journal.pone.0080636
PMCID: PMC3836750  PMID: 24278299

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