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1.  TRPV4 Channel Inhibits TGF-β1-Induced Proliferation of Hepatic Stellate Cells 
PLoS ONE  2014;9(7):e101179.
TRPV4, one of the TRP channels, is implicated in diverse physiological and pathological processes including cell proliferation. However, the role of TRPV4 in liver fibrosis is largely unknown. Here, we characterized the role of TRPV4 in regulating HSC-T6 cell proliferation. TRPV4 mRNA and protein were measured by RT-PCR and Western blot in patients and rat model of liver fibrosis in vivo and TGF-β1-activated HSC-T6 cells in vitro. Both mRNA and protein of TRPV4 were dramatically increased in liver fibrotic tissues of both patients and CCl4-treated rats. Stimulation of HSC-T6 cells with TGF-β1 resulted in increase of TRPV4 mRNA and protein. However, TGF-β1-induced HSC-T6 cell proliferation was inhibited by Ruthenium Red (Ru) or synthetic siRNA targeting TRPV4, and this was accompanied by downregulation of myofibroblast markers including α-SMA and Col1α1. Moreover, our study revealed that miR-203 was downregulated in liver fibrotic tissues and TGF-β1-treated HSC-T6 cell. Bioinformatics analyses predict that TRPV4 is the potential target of miR-203. In addition, overexpression of miR-203 in TGF-β1-induced HSC significantly reduced TRPV4 expression, indicating TRPV4, which was regulated by miR-203, may function as a novel regulator to modulate TGF-β1-induced HSC-T6 proliferation.
PMCID: PMC4094468  PMID: 25013893
2.  Novel YAP1-TFE3 Fusion Defines a Distinct Subset of Epithelioid Hemangioendothelioma 
Genes, chromosomes & cancer  2013;52(8):775-784.
Conventional epithelioid hemangioendotheliomas (EHE) have a distinctive morphologic appearance and are characterized by a recurrent t(1;3) translocation, resulting in a WWTR1-CAMTA1 fusion gene. We have recently encountered a fusion-negative subset characterized by a somewhat different morphology, including focally well-formed vasoformative features, which was further investigated for recurrent genetic abnormalities. Based on a case showing strong TFE3 immunoreactivity, FISH analysis for TFE3 gene rearrangement was applied to the index case as well as to 9 additional cases, selected through negative WWTR1-CAMTA1 screening. A control group, including 18 epithelioid hemangiomas, 9 pseudomyogenic HE and 3 epithelioid angiosarcomas, was also tested. TFE3 gene rearrangement was identified in 10 patients, with equal gender distribution and a mean age of 30 years old. The lesions were located in somatic soft tissue in 6 cases, lung in 3 and one in bone. One case with available frozen tissue was tested by RNA sequencing and FusionSeq data analysis to detect novel fusions. A YAP1-TFE3 fusion was thus detected, which was further validated by FISH and RT-PCR. YAP1 gene rearrangements were then confirmed in 7 of the remaining 9 TFE3-rearranged EHEs by FISH. No TFE3 structural abnormalities were detected in any of the controls. The TFE3-rearranged EHEs showed similar morphologic features with at least focally, well-formed vascular channels, in addition to a variably solid architecture. All tumors expressed endothelial markers, as well as strong nuclear TFE3. In summary we are reporting a novel subset of EHE occurring in young adults, showing a distinct phenotype and YAP1-TFE3 fusions.
PMCID: PMC4089994  PMID: 23737213
TFE3; YAP1; epithelioid hemangioendothelioma; WWTR1
3.  Encapsulated Annealing: Enhancing the Plasmon Quality Factor in Lithographically–Defined Nanostructures 
Scientific Reports  2014;4:5537.
Lithography provides the precision to pattern large arrays of metallic nanostructures with varying geometries, enabling systematic studies and discoveries of new phenomena in plasmonics. However, surface plasmon resonances experience more damping in lithographically–defined structures than in chemically–synthesized nanoparticles of comparable geometries. Grain boundaries, surface roughness, substrate effects, and adhesion layers have been reported as causes of plasmon damping, but it is difficult to isolate these effects. Using monochromated electron energy–loss spectroscopy (EELS) and numerical analysis, we demonstrate an experimental technique that allows the study of these effects individually, to significantly reduce the plasmon damping in lithographically–defined structures. We introduce a method of encapsulated annealing that preserves the shape of polycrystalline gold nanostructures, while their grain-boundary density is reduced. We demonstrate enhanced Q–factors in lithographically–defined nanostructures, with intrinsic damping that matches the theoretical Drude damping limit.
PMCID: PMC4078311  PMID: 24986023
4.  Endovascular coil embolization of aneurysm neck for the treatment of ruptured intracranial aneurysm with bleb formation 
Ruptured intracranial aneurysm (ICA) with bleb formation (RICABF) is a special type of ruptured ICA. However, the exact role and effectiveness of endovascular coil embolization (ECE) in RICABF is unknown.
We aimed to investigate the effectiveness and safety of ECE of aneurysm neck for RICABF treatment.
We retrospectively assessed consecutive patients who were hospitalized in our endovascular intervention center between October 2004 and May 2012. Overall, 86 patients underwent ECE of aneurysm neck for 86 RICABF. Treatments outcomes included secondary rupture/bleeding rate, aneurysm neck embolization rate, residual/recurrent aneurysm, intraoperative incidents, and post-embolization complications, as well as improvements in the Glasgow outcome scale (extended) (GOS-E).
Complete occlusion was achieved in 72 aneurysms (72/86, 83.7%), while 12 aneurysms (12/86, 14.0%) had a residual neck, and 2 aneurysms (2/86, 2.3%) had a residual aneurysm. The postoperative GOS-E was 3 in 3 patients (3.5%), 4 in 10 patients (11.6%), and 5 in 73 patients (84.9%). Follow-up angiography was performed in all patients (mean 9.0 months, interquartile range of 9.0). Recurrence was found in 3 patients (3/86, 3.5%). No aneurysm rupture or bleeding was reported.
Our mid-term follow-up study showed that ECE of aneurysm neck was an effective and safe treatment modality for RICABF. The long-term effectiveness and safety of this interventional radiology technique need to be investigated in prospective and comparative studies.
PMCID: PMC4095703  PMID: 24986761
Intracranial Aneurysm; Ruptured Intracranial Aneurysm With Bleb Formation; False Aneurysm; Endovascular Embolization; Aneurysm Neck Embolization; Interventional Therapy
5.  Mesenchymal Stem Cells Induce Granulocytic Differentiation of Acute Promyelocytic Leukemic Cells via IL-6 and MEK/ERK Pathways 
Stem Cells and Development  2013;22(13):1955-1967.
All-trans retinoic acid (ATRA) induces clinical remission in most acute promyelocytic leukemia (APL) patients by inducing terminal differentiation of APL cells toward mature granulocytes. Here we report that human umbilical cord-derived mesenchymal stem cells (UC-MSCs) are capable of inducing granulocytic differentiation of the APL-derived NB4 cell line as well as primary APL cells and also cooperate with ATRA in an additive manner. Transwell coculture experiments revealed that UC-MSCs' differentiation-inducing effect was mediated through some soluble factors. Differentiation attenuation by IL-6Ra neutralization and induction by addition of exogenous IL-6 confirmed that IL-6 secreted by UC-MSCs was at least partially responsible for this differentiation induction process. Moreover, we found that UC-MSCs activated the MEK/ERK signaling pathway in promyelocytic cells and pharmacological inhibition of the MEK/ERK pathway reversed UC-MSC-induced differentiation, indicating that UC-MSCs exerted effect through activation of the MEK/ERK signaling pathway. These results demonstrate for the first time a stimulatory effect of MSCs on the differentiation of APL cells and bring a new insight into the interaction between MSCs and leukemic cells. Our data suggest that UC-MSCs/ATRA combination could be used as a novel therapeutic strategy for APL patients.
PMCID: PMC3685326  PMID: 23391335
6.  Participation of Women and Sex Analyses in Late-Phase Clinical Trials of New Molecular Entity Drugs and Biologics Approved by the FDA in 2007–2009 
Journal of Women's Health  2013;22(7):604-616.
Biological sex differences may contribute to differential treatment outcomes for therapeutic products. This study tracks women's participation in late-phase clinical trials (LPCTs), where efficacy and safety of drugs and biologics are evaluated, of new molecular entity (NME) drugs and biologics approved by the U.S. Food and Drug Administration (FDA) in 2007–2009. Furthermore, presentations of sex-based analyses were assessed from the FDA reviews.
New drug applications (NDAs) and biologics license applications (BLAs) were accessed from the U.S. FDA database and evaluated for women's participation in LPCTs. Sex-based analyses for efficacy and safety contained in FDA reviews were surveyed. Ratios for women's LPCT participation (PROPORTION OF STUDY SUBJECTS) to their proportion in the disease population were calculated for each approved therapeutic product and grouped into therapeutic categories.
Sex-specific (n=5) and pediatric (n=3) drug applications were excluded. Women's participation in LPCTs was 39%, 48%, and 42% in NDAs (n=50) and 49%, 62%, and 58% in BLAs (n=11) for 2007, 2008, and 2009, respectively. Sixty-four percent of NDAs and 91% of BLAs had participation to proportion ratios of ≥0.80. Seventy-four percent of NDA reviews and 64% of BLA reviews included safety and efficacy sex analysis. Ninety-six percent of NDA reviews and 100% of BLA reviews included efficacy sex analysis.
Women's participation in LPCTs averaged 43% for NDAs and 57% for BLAs in 2007–2009 and varied widely by indication. As a comparison, the 2001 U.S. Government Accountability Office (GAO) reported 52% of women's participation for drug clinical trials in1998–2000 and an FDA study reported 45% for BLAs approved from 1995 to 1999. This study showed that sex-analysis of both safety and efficacy in NDA has increased to 74% since the GAO report of 72%, while those for BLAs increased to 64% from 37% reported for therapeutic biologics approved in 1995–1999. Knowledge of disease prevalence and participation in clinical trials provides an understanding of recruitment and retention patterns of patients in these trials.
PMCID: PMC3704049  PMID: 23768021
7.  Therapeutic Protein Drug–Drug Interactions: Navigating the Knowledge Gaps–Highlights from the 2012 AAPS NBC Roundtable and IQ Consortium/FDA Workshop 
The AAPS Journal  2013;15(4):933-940.
The investigation of therapeutic protein drug–drug interactions has proven to be challenging. In May 2012, a roundtable was held at the American Association of Pharmaceutical Scientists National Biotechnology Conference to discuss the challenges of preclinical assessment and in vitro to in vivo extrapolation of these interactions. Several weeks later, a 2-day workshop co-sponsored by the U.S. Food and Drug Administration and the International Consortium for Innovation and Quality in Pharmaceutical Development was held to facilitate better understanding of the current science, investigative approaches and knowledge gaps in this field. Both meetings focused primarily on drug interactions involving therapeutic proteins that are pro-inflammatory cytokines or cytokine modulators. In this meeting synopsis, we provide highlights from both meetings and summarize observations and recommendations that were developed to reflect the current state of the art thinking, including a four-step risk assessment that could be used to determine the need (or not) for a dedicated clinical pharmacokinetic interaction study.
PMCID: PMC3787234  PMID: 23794076
cytochrome P450s; drug–drug interactions; pro-inflammatory cytokines; small molecule; therapeutic protein
8.  Novel ZC3H7B-BCOR, MEAF6-PHF1 and EPC1-PHF1 Fusions in Ossifying Fibromyxoid Tumors – Molecular Characterization Shows Genetic Overlap with Endometrial Stromal Sarcoma 
Genes, chromosomes & cancer  2013;53(2):183-193.
PHF1 gene rearrangements have been recently described in around 50% of ossifying fibromyxoid tumors (OFMT) including benign and malignant cases, with a small subset showing EP400-PHF1 fusions. In the remaining cases no alternative gene fusions have been identified. PHF1-negative OFTs, especially if lacking S100 protein staining or peripheral ossification, are difficult to diagnose and distinguish from other soft tissue mimics. In seeking more comprehensive molecular characterization, we investigated a large cohort of 39 OFMT of various anatomic sites, immunoprofiles and grades of malignancy. Tumors were screened for PHF1 and EP400 rearrangements by FISH. RNA sequencing was performed in two index cases (OFMT1, OFMT3), negative for EP400-PHF1 fusions, followed by FusionSeq data analysis, a modular computational tool developed to discover gene fusions from paired-end RNA-seq data. Two novel fusions were identified ZC3H7B-BCOR in OFMT1 and MEAF6-PHF1 in OFMT3. After being validated by FISH and RT-PCR, these abnormalities were screened on the remaining cases. With these additional gene fusions, 33/39 (85%) of OFMTs demonstrated recurrent gene rearrangements, which can be used as molecular markers in challenging cases. The most common abnormality is PHF1 gene rearrangement (80%), being present in benign, atypical and malignant lesions, with fusion to EP400 in 44% of cases. ZC3H7B-BCOR and MEAF6-PHF1 fusions occurred predominantly in S100 protein-negative and malignant OFMT. As similar gene fusions were reported in endometrial stromal sarcomas, we screened for potential gene abnormalities in JAZF1 and EPC1 by FISH and found two additional cases with EPC1-PHF1 fusions.
PMCID: PMC4053209  PMID: 24285434
Ossifying fibromyxoid tumor; PHF1; EP400; BCOR; MEAF6
9.  Bushen-Yizhi formula ameliorates cognition deficits and attenuates oxidative stress-related neuronal apoptosis in scopolamine-induced senescence in mice 
Bushen-Yizhi formula (BSYZ), a traditional Chinese medicine formula consisting of six herbs has been reported to possess a neuroprotective effect. The present study aimed to investigate the effects of BSYZ on learning and memory abilities, as well as oxidative stress and neuronal apoptosis in the hippocampus of scopolamine (SCOP)-induced senescence in mice, in order to reveal whether BSYZ is a potential therapeutic agent for Alzheimer’s disease (AD). A high-performance liquid chromatography (HPLC) fingerprint was applied to provide a chemical profile of BSYZ. Extracts of BSYZ were orally administered to mice with SCOP-induced memory impairment for two weeks. The learning and memory abilities were determined by the Morris water maze test. The oxidant stress-related indices, such as activity of superoxide dismutase (SOD) and levels of glutathione (GSH) and malondialdehyde (MDA) were examined in hippocampus of SCOP-treated mice. The cell death ratio was assessed by TUNEL staining, while apoptotic-related proteins including Bcl-2 and Bax were determined by immunofluorescent staining and western blot analysis. Caspase-3 was determined by western blot analysis. Consequently, a chromatographic condition, which was conducted at 35°C with a flow rate of 0.8 ml/min on the Gemini C18 column with mobile phase of acetonitrile and water-phosphoric acid (100:0.1, v/v), was established to yield common fingerprint chromatography under 203 nm with a similarity index of 0.986 within 10 batches of BSYZ samples. BSYZ at a dose of 2.92 g/kg significantly improved the cognitive ability, restored the abnormal activity of SOD and increased the levels of MDA and GSH induced by SCOP. Moreover, the neural apoptosis in the hippocampus of SCOP-treated mice was reversed by BSYZ by regulating the expression of Bcl-2, Bax and caspase-3. The results demonstrated that BSYZ had neuroprotective effects in SCOP-induced senescence in mice by ameliorating oxidative stress and neuronal apoptosis in the brain, supporting its potential in AD treatment.
PMCID: PMC4094586  PMID: 24919922
Alzheimer’s disease; scopolamine; Bushen-Yizhi formula; antioxidant; antiapoptosis; neuroprotection
10.  Genome-Wide Mapping of Virulence in Brown Planthopper Identifies Loci That Break Down Host Plant Resistance 
PLoS ONE  2014;9(6):e98911.
Insects and plants have coexisted for over 350 million years and their interactions have affected ecosystems and agricultural practices worldwide. Variation in herbivorous insects' virulence to circumvent host resistance has been extensively documented. However, despite decades of investigation, the genetic foundations of virulence are currently unknown. The brown planthopper (Nilaparvata lugens) is the most destructive rice (Oryza sativa) pest in the world. The identification of the resistance gene Bph1 and its introduction in commercial rice varieties prompted the emergence of a new virulent brown planthopper biotype that was able to break the resistance conferred by Bph1. In this study, we aimed to construct a high density linkage map for the brown planthopper and identify the loci responsible for its virulence in order to determine their genetic architecture. Based on genotyping data for hundreds of molecular markers in three mapping populations, we constructed the most comprehensive linkage map available for this species, covering 96.6% of its genome. Fifteen chromosomes were anchored with 124 gene-specific markers. Using genome-wide scanning and interval mapping, the Qhp7 locus that governs preference for Bph1 plants was mapped to a 0.1 cM region of chromosome 7. In addition, two major QTLs that govern the rate of insect growth on resistant rice plants were identified on chromosomes 5 (Qgr5) and 14 (Qgr14). This is the first study to successfully locate virulence in the genome of this important agricultural insect by marker-based genetic mapping. Our results show that the virulence which overcomes the resistance conferred by Bph1 is controlled by a few major genes and that the components of virulence originate from independent genetic characters. The isolation of these loci will enable the elucidation of the molecular mechanisms underpinning the rice-brown planthopper interaction and facilitate the development of durable approaches for controlling this most destructive agricultural insect.
PMCID: PMC4049697  PMID: 24911169
11.  Expression Pattern of Long Non-Coding RNAs in Renal Cell Carcinoma Revealed by Microarray 
PLoS ONE  2014;9(6):e99372.
Recent large-scale transcriptome analyses have found large numbers of transcripts, including that of long non-coding RNAs (lncRNAs), which are aberrant in various diseases, especially cancers. However, it is not clear whether lncRNAs are involved specifically in renal cell carcinoma (RCC). We investigated the expression patterns of lncRNAs in five RCC tumor samples (T) relative to those of matched adjacent non-tumor tissues (N) via microarray.
A microarray with 33,045 lncRNA probes and 30,215 mRNA probes was used to identify deregulated lncRNAs in five RCC patients. Furthermore, we confirmed the relative expression levels of AK096725 and ENST00000453068 in 70 paired samples by quantitative reverse transcription polymerase chain reaction (qRT-PCR).
The lncRNA microarray revealed 27,279 lncRNAs in RCC samples, of which 480 were significantly upregulated (P<0.05; T/N>1.5) and 417 were significantly downregulated (P<0.05; N/T>1.5) compared with the matched non-tumor samples. In addition, 19,995 mRNAs were detected, of which 458 were significantly upregulated (P<0.05; T/N>1.5) and 413 were significantly downregulated (P<0.05; N/T>1.5). The expression level changes of AK096725 (P = 0.043) and ENST00000453068 (P<0.001) in 70 paired samples were in accord with the microarray data.
The study uncovered expression patterns of lncRNAs in 5 RCC patients, as well as a number of aberrant lncRNAs and mRNAs in tumor samples compared with the non-tumor tissues. The revelation of an association between AK096725 expression and RCC is especially noteworthy. These findings may help to find new biomarkers in RCC.
PMCID: PMC4048223  PMID: 24905231
12.  Frequent PLAG1 Gene Rearrangements in Skin and Soft Tissue Myoepithelioma with Ductal Differentiation 
Genes, chromosomes & cancer  2013;52(7):675-682.
A subset of cutaneous and superficial soft tissue myoepithelial (ME) tumors displays a distinct ductal component and closely resembles mixed tumors/pleomorphic adenomas of salivary gland. As PLAG1 and HMGA2 rearrangements are the most common genetic events in pleomorphic adenomas, we sought to investigate if these abnormalities are also present in the skin/soft tissue ME lesions. In contrast, half of the deep-seated soft tissue ME tumors lacking ductal differentiation are known to be genetically unrelated, showing EWSR1 rearrangements. FISH analysis to detect PLAG1 and HMGA2 abnormalities was performed in 35 ME tumors, nine skin and 26 soft tissue, lacking EWSR1 and FUS rearrangements. For the PLAG1-rearranged tumors, FISH and RACE were performed to identify potential fusion partners, including CTNNB1 (beta-catenin) on 3p21 and LIFR (leukemia inhibitory factor receptor) on 5p13. Recurrent PLAG1 rearrangement by FISH was detected in 13 (37%) lesions, including three (33%) in the skin and 10 (38%) in the soft tissue. All were classified as benign and all except one showed abundant tubulo-ductal differentiation (comprising 12/24 [50%] of all tumors with ductal structures). A LIFR-PLAG1 fusion was detected by RACE and then confirmed by FISH in one soft tissue ME tumor with tubular formation. No CTNNB1 or LIFR abnormalities were detected in any of the remaining PLAG1-rearranged tumors. No structural HMGA2 abnormalities were detected in any of the 22 ME lesions tested. A subset of cutaneous and soft tissue ME tumors appears genetically linked to their salivary gland counterparts, displaying frequent PLAG1 gene rearrangements and occasionally LIFR-PLAG1 fusion.
PMCID: PMC4041540  PMID: 23630011
13.  Recurrent NCOA2 gene rearrangements in congenital/infantile spindle cell rhabdomyosarcoma 
Genes, chromosomes & cancer  2013;52(6):10.1002/gcc.22050.
Spindle cell rhabdomyosarcoma (RMS) is a rare form of RMS with different clinical characteristics and behavior between children and adult patients. Its genetic hallmark remains unknown and it remains debatable if there is pathogenetic relationship between the spindle cell and the so-called sclerosing RMS. We studied two pediatric and one adult spindle cell RMS by next generation RNA sequencing and used FusionSeq for data analysis to detect novel fusions. An SRF-NCOA2 gene fusion was detected in a spindle cell RMS from the posterior neck in a 7 month-old child. The fusion matched the tumor karyotype and was further confirmed by fluorescence in situ hybridization (FISH) and by RT-PCR, which showed fusion of SRF exon 6 to NCOA2 exon 12. Additional 14 spindle cell (from 8 children and 6 adults) and 4 sclerosing (from 2 children and 2 adults) RMS were tested by FISH for the presence of abnormalities in NCOA2, SRF, as well as for PAX3 and NCOA1, identifying NCOA2 rearrangements in two additional spindle cell RMS from a 3 month-old and a 4 week-old child, both arising in the chest wall. In the latter tumor, TEAD1 was identified by rapid amplification of cDNA ends (RACE) to be the NCOA2 gene fusion partner. None of the adult tumors were positive for NCOA2 rearrangement. Despite similar histomorphology in adults and young children, these results suggest that spindle cell RMS is a heterogeneous disease genetically as well as clinically. Our findings also support a relationship between NCOA2-rearranged spindle cell RMS occurring in young childhood and the so-called congenital RMS, which often displays rearrangements at 8q13 locus (NCOA2).
PMCID: PMC3734530  PMID: 23463663
rhabdomyosarcoma; spindle cell; NCOA2; SRF; TEAD1; translocation; infantile
14.  Video-assisted mediastinoscopic resection compared with video-assisted thoracoscopic surgery in patients with esophageal cancer 
Journal of Thoracic Disease  2014;6(6):663-667.
The purpose of this study was to explore the indications of radical vedio-assisted mediastinoscopic resection for esophageal cancer.
The data of 109 patients with T1 esophageal cancer who underwent video-assisted mediastinoscopic resection (VAMS group) in Third Affiliated Hospital of Soochow University Hospital from December 2005 to December 2011 were collected in the study for comparison with the 58 patients with T1 esophageal cancer who underwent video-assisted thoracoscopic surgery (VATS group) in Zhongshan Hospital, Fudan University. The perioperative safety and survival were compared between the two groups.
All operations were successful in both groups. One perioperative death was noted in the VATS group. The incidences of post-operative complications were not significantly different between these two groups, whereas the VAMS group was favorable in terms of operative time (P<0.001) and blood loss (P<0.001), and a significantly larger number of chest lymph nodes were dissected in the VATS group compared with the VAMS group (P<0.001). Long-term follow-up showed that the overall survival was not significantly different between these two groups (P=0.876).
T1N0M0 esophageal cancer can be as the indication of VAMS radical resection. VAMS radical resection can be considered as the preferred option for patients with poor pulmonary and cardiac function or a history of pleural disease.
PMCID: PMC4073377  PMID: 24976988
Esophageal cancer; mediastinoscopy; video-assisted thoracoscopic surgery (VATS)
15.  Activation of mGluR5 Attenuates NMDA-Induced Neurotoxicity through Disruption of the NMDAR-PSD-95 Complex and Preservation of Mitochondrial Function in Differentiated PC12 Cells 
Glutamate-mediated toxicity is implicated in various neuropathologic conditions, and activation of ionotropic and metabotropic glutamate receptors is considered to be the most important mechanism. It has been reported that pharmacological saturation of metabotropic glutamate receptors (mGluRs) can facilitate N-methyl-d-aspartate receptor (NMDAR) related signaling cascades, but the mechanism leading to mGluR-NMDAR interactions in excitotoxic neuronal injury has remained unidentified. In the present study, we investigated the role of mGluR5 in the regulation of N-methyl-d-aspartate (NMDA)-induced excitotoxicity in differentiated PC12 cells. We found that activation of mGluR5 with the specific agonist R,S-2-chloro-5-hydroxyphenylglycine (CHPG) increased cell viability and inhibited lactate dehydrogenase (LDH) release in a dose-dependent manner. CHPG also inhibited an increase in the Bax/Bcl-2 ratio, attenuated cleavage of caspase-9 and caspase-3, and reduced apoptotic cell death after NMDA treatment. The NMDA-induced mitochondrial dysfunction, as indicated by mitochondrial reactive oxygen species (ROS) generation, collapse of mitochondrial membrane potential (MMP), and cytochrome c release, was also partly prevented by CHPG treatment. Furthermore, CHPG blocked the NMDA-induced interaction of NMDAR with postsynaptic density protein-95 (PSD-95), but had no effects on intracellular calcium concentrations. All these results indicated that activation of mGluR5 protects differentiated PC12 cells from NMDA-induced neuronal excitotoxicity by disrupting NMDAR-PSD-95 interaction, which might be an ideal target for investigating therapeutic strategies in various neurological diseases where excitotoxicity may contribute to their pathology.
PMCID: PMC4100187  PMID: 24941251
glutamate; mGlu receptor; NMDAR (N-methyl-d-aspartate receptor) receptor; post-synaptic density protein 95; mitochondrial dysfunction
16.  A description of the hepatitis B virus genomic background in a high-prevalence area in China 
Virology Journal  2014;11:101.
Hepatitis B (HB) is an important disease worldwide. Almost 350 million people are positive for Hepatitis B virus surface antigen (HBsAg), and one-third of them live in China. According to a nation-wide serosurvey in China in 2006, the prevalence of HBsAg was higher in Northwest China than in other areas. However, the epidemic HBV strains in this area are poorly studied.
In this study, 242 complete hepatitis B virus (HBV) genome sequences were obtained from HBV asymptomatic carriers in major cities of Northwest China. The 242 HBV sequences clustered into genotypes B, C and D. Through comparison of the genotype consensus sequences, 158 genotype-dependent positions were observed in P, S and X ORFs. Clinically relevant mutation screening in this study revealed that no HBV antiviral drug resistance mutations were observed and the vaccination failure mutations were heavily underrepresented.
The role of genotype D strains in HBV prevalence should not be ignored in Northwest China. Due to low prevalence of vaccination failure mutations, it can be inferred that the genotype B, C and D strains in Northwest China may have less likelihood of vaccine escape.
PMCID: PMC4074864  PMID: 24884702
Hepatitis B virus; Consensus sequences; Clinically relevant mutations
17.  Natural killer/T-cell lymphoma-associated hemophagocytic syndrome: A case report 
Oncology Letters  2014;8(2):886-890.
Natural killer (NK)/T-cell lymphoma-associated hemophagocytic syndrome (HPS) is a rare and fatal disease with no optimal treatment. The present study reports the clinical features, diagnosis and treatment process of three patients with relapsed NK/T-cell lymphoma-associated HPS. All of the patients were classified as Ann Arbor stage IV and presented with a poor performance status. Two patients were successfully treated with a pegaspargase-containing combination regimen and one patient succumbed due to serious complications. These cases indicate that for patients with a history of lymphoma, the diagnosis of HPS should be considered when patients present with progressive high fever, pancytopenia and liver dysfunction. Early identification and effective treatments, including pegaspargase-based regimens are essential for an enhanced prognosis.
PMCID: PMC4081409  PMID: 25013513
natural killer/T-cell lymphoma; hemophagocytic syndrome; clinical features; pegaspargase
18.  Genome-wide approaches for identifying genetic risk factors for osteoporosis 
Genome Medicine  2013;5(5):44.
Osteoporosis, the most common type of bone disease worldwide, is clinically characterized by low bone mineral density (BMD) and increased susceptibility to fracture. Multiple genetic and environmental factors and gene-environment interactions have been implicated in its pathogenesis. Osteoporosis has strong genetic determination, with the heritability of BMD estimated to be as high as 60%. More than 80 genes or genetic variants have been implicated in risk of osteoporosis by hypothesis-free genome-wide studies. However, these genes or genetic variants can only explain a small portion of BMD variation, suggesting that many other genes or genetic variants underlying osteoporosis risk await discovery. Here, we review recent progress in genome-wide studies of osteoporosis and discuss their implications for medicine and the major challenges in the field.
PMCID: PMC3706967  PMID: 23731620
19.  Exposure to 1800 MHz radiofrequency radiation impairs neurite outgrowth of embryonic neural stem cells 
Scientific Reports  2014;4:5103.
A radiofrequency electromagnetic field (RF-EMF) of 1800 MHz is widely used in mobile communications. However, the effects of RF-EMFs on cell biology are unclear. Embryonic neural stem cells (eNSCs) play a critical role in brain development. Thus, detecting the effects of RF-EMF on eNSCs is important for exploring the effects of RF-EMF on brain development. Here, we exposed eNSCs to 1800 MHz RF-EMF at specific absorption rate (SAR) values of 1, 2, and 4 W/kg for 1, 2, and 3 days. We found that 1800 MHz RF-EMF exposure did not influence eNSC apoptosis, proliferation, cell cycle or the mRNA expressions of related genes. RF-EMF exposure also did not alter the ratio of eNSC differentiated neurons and astrocytes. However, neurite outgrowth of eNSC differentiated neurons was inhibited after 4 W/kg RF-EMF exposure for 3 days. Additionally, the mRNA and protein expression of the proneural genes Ngn1 and NeuroD, which are crucial for neurite outgrowth, were decreased after RF-EMF exposure. The expression of their inhibitor Hes1 was upregulated by RF-EMF exposure. These results together suggested that 1800 MHz RF-EMF exposure impairs neurite outgrowth of eNSCs. More attention should be given to the potential adverse effects of RF-EMF exposure on brain development.
PMCID: PMC4037711  PMID: 24869783
20.  Circulating Levels of Soluble MICB in Infants with Symptomatic Primary Dengue Virus Infections 
PLoS ONE  2014;9(5):e98509.
Dengue is the most prevalent arthropod-borne viral illness in humans. A MHC class I polypeptide-related sequence B (MICB) single nucleotide polymorphism (SNP) was previously associated with symptomatic dengue compared to non-dengue causes of acute febrile illnesses in infants. We measured circulating levels of soluble (s)MICB in the sera of infants with symptomatic primary dengue virus infections. We found that serum levels of sMICB increased between pre-infection and acute illness among infants with symptomatic primary dengue virus infections. The likelihood of being hospitalized with an acute primary DENV infection during infancy also tended to be higher with increasing acute illness sMICB levels. The elevation of sMICB during acute primary DENV infections in infants likely represents an immune evasion strategy and contributes to the severity of the acute illness.
PMCID: PMC4037195  PMID: 24869966
21.  Depletion of canonical Wnt signaling components has a neuroprotective effect on midbrain dopaminergic neurons in an MPTP-induced mouse model of Parkinson’s disease 
The canonical Wnt signaling pathway is critical for the development of midbrain dopaminergic (DA) neurons, and recent studies have suggested that disruption of this signaling cascade may underlie the pathogenesis of Parkinson’s disease (PD). However, the exact role of the canonical Wnt signaling pathway, including low-density lipoprotein receptor-related protein 5 and 6 (LRP5/6) and β-catenin components, in a mouse model of PD remains unclear. In the present study, the tyrosine hydroxylase (TH)-Cre transgenic mouse line was used to generate mice with the specific knockout of LRP5, LRP6 or β-catenin in DA neurons. Following inactivation of LRP5, LRP6 or β-catenin, TH-immunohistochemical staining was performed. The results indicated that β-catenin is required for the development or maintenance of these neurons; however, LRP5 and LRP6 were found to be dispensable. In 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated mice, the depletion of LRP5, LRP6 or β-catenin was found to be protective for the midbrain DA neurons to a certain extent. These in vivo results provide a novel perspective for the function of the canonical Wnt signaling pathway in a mouse model of PD.
PMCID: PMC4079420  PMID: 25009587
LRP5; LRP6; β-catenin; MPTP; dopaminergic neuron; Parkinson’s disease
22.  Atrophin–Rpd3 complex represses Hedgehog signaling by acting as a corepressor of CiR 
The Journal of Cell Biology  2013;203(4):575-583.
Atrophin suppresses Hedgehog signaling by interacting with the transcriptional effector CiR and recruiting the histone deacetylase Rpd3 to the dpp locus to repress its transcription.
The evolutionarily conserved Hedgehog (Hh) signaling pathway is transduced by the Cubitus interruptus (Ci)/Gli family of transcription factors that exist in two distinct repressor (CiR/GliR) and activator (CiA/GliA) forms. Aberrant activation of Hh signaling is associated with various human cancers, but the mechanism through which CiR/GliR properly represses target gene expression is poorly understood. Here, we used Drosophila melanogaster and zebrafish models to define a repressor function of Atrophin (Atro) in Hh signaling. Atro directly bound to Ci through its C terminus. The N terminus of Atro interacted with a histone deacetylase, Rpd3, to recruit it to a Ci-binding site at the decapentaplegic (dpp) locus and reduce dpp transcription through histone acetylation regulation. The repressor function of Atro in Hh signaling was dependent on Ci. Furthermore, Rerea, a homologue of Atro in zebrafish, repressed the expression of Hh-responsive genes. We propose that the Atro–Rpd3 complex plays a conserved role to function as a CiR corepressor.
PMCID: PMC3840934  PMID: 24385484
23.  Traditional Formula, Modern Application: Chinese Medicine Formula Sini Tang Improves Early Ventricular Remodeling and Cardiac Function after Myocardial Infarction in Rats 
Sini Tang (SNT) is a traditional Chinese herbal formula consisting of four different herbs: the root of Aconitum carmichaelii, the bark of Cinnamomum cassia, the rhizome of Zingiber officinale, and the root of Glycyrrhiza uralensis. This study aims to evaluate the improvement of early ventricular remodeling and cardiac function in myocardial infarction (MI) rats by SNT. A MI model was established by ligation of the left anterior descending coronary artery. Following treatment for 4 weeks, ultrasonic echocardiography was performed. Myocardial histopathological changes were observed using haematoxylin and eosin staining. Collagens (type I and type III), transforming growth factor-β1 (TGF-β1), and Toll-like receptors (TLR-2 and TLR-4) were measured in plasma, serum, and myocardial tissue. SNT treatment decreased the infarct size, the left ventricular cavity area/heart cavity area ratio, and the left ventricle dimension at end systole and increased the left ventricular ejection fraction. SNT reduced the levels of TLR-2 and TLR-4 in myocardial tissue significantly and decreased the collagens content in serum and in myocardial tissue. SNT could partially reduce the level of TGF-β1 in serum and in myocardial tissue. Our data suggest that the Chinese medicine formula SNT has the potential to improve early ventricular remodeling and cardiac function after MI.
PMCID: PMC4058176  PMID: 24971143
24.  Peripheral blood miRNAs as a biomarker for chronic cardiovascular diseases 
Scientific Reports  2014;4:5026.
Vascular diseases are the most prevalent diseases worldwide. This study intended to analyze peripheral blood miRNA levels and their correlation with NT-pro-BNP and cTN-I in patients with atherosclerosis or pre-atherosclerotic conditions to build a dynamic correlation between vascular diseases and their biomarkers. Serum NT-pro-BNP and cTN-I levels were measured by their respective ELISA kits. The miRNA levels were assayed by quantitative PCR. Unique miRNA signatures were identified for both atherosclerosis and pre-atherosclerosis. The levels of miR-92a, 126, 130a, 222, and 370 levels were decreased in the peripheral blood of pre-atherosclerotic subjects. In atherosclerosis, miR-21, 122, 130a, and 211 were significantly increased whereas miR-92a, 126, and 222 were markedly decreased. Serum levels of NT-pro-BNP and cTN-I correlated with each other and increased with the progression of atherosclerosis. Moreover, the levels of cTN-I and NT-pro-BNP were positively correlated with miR-21 and negatively correlated with miR-126. Integrating specific pattern of miRNA levels with NT-pro-BNP and/or cardiac troponin may improve the diagnosis of cardiovascular diseases.
PMCID: PMC4052773  PMID: 24848278
25.  The dirigent multigene family in Isatis indigotica: gene discovery and differential transcript abundance 
BMC Genomics  2014;15(1):388.
Isatis indigotica Fort. is one of the most commonly used traditional Chinese medicines. Its antiviral compound is a kind of lignan, which is formed with the action of dirigent proteins (DIR). DIR proteins are members of a large family of proteins which impart stereoselectivity on the phenoxy radical-coupling reaction, yielding optically active lignans from two molecules of E-coniferyl alcohol. They exist in almost every vascular plant. However, the DIR and DIR-like protein gene family in I. indigotica has not been analyzed in detail yet. This study focuses on discovery and analysis of this protein gene family in I. indigotica for the first time.
Analysis of transcription profiling database from I. indigotica revealed a family of 19 full-length unique DIR and DIR-like proteins. Sequence analysis found that I. indigotica DIR and DIR-like proteins (IiDIR) were all-beta strand proteins, with a signal peptide at the N-terminus. Phylogenetic analysis of the 19 proteins indicated that the IiDIR genes cluster into three distinct subfamilies, DIR-a, DIR-b/d, and DIR-e, of a larger plant DIR and DIR-like gene family. Gene-specific primers were designed for 19 unique IiDIRs and were used to evaluate patterns of constitutive expression in different organs. It showed that most IiDIR genes were expressed comparatively higher in roots and flowers than stems and leaves.
New DIR and DIR-like proteins were discovered from the transcription profiling database of I. indigotica through bioinformatics methods for the first time. Sequence characteristics and transcript abundance of these new genes were analyzed. This study will provide basic data necessary for further studies.
Electronic supplementary material
The online version of this article (doi:10.1186/1471-2164-15-388) contains supplementary material, which is available to authorized users.
PMCID: PMC4052678  PMID: 24885106
Dirigent and dirigent-like proteins; Isatis indigotica; Bioinformatics; Secondary structures; Tertiary structures; Phylogenetic analysis; Transcript abundance

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