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1.  Aquaporin 3 promotes epithelial-mesenchymal transition in gastric cancer 
Gastric carcinoma (GC) is a common and lethal malignancy, and epithelial-mesenchymal transition (EMT) is believed to contribute to invasive and metastatic tumor growth. Aquaporin 3 (AQP3) is overexpressed in human GC tissues, while human epidermal growth factor (EGF) and hepatocyte growth factor, which can induce EMT, are able to up-regulate AQP3 expression, subsequently promoting GC cell migration and proliferation. The purpose of this study was to investigate the effects of AQP3 on EMT in human GC.
AQP3 and EMT-related proteins were detected by immunohistochemistry in human GC specimens and their clinical significance evaluated. AQP3 knockdown was attempted using small interfering RNAs, while EGF was used to up-regulate AQP3 expression. Western blotting, real-time quantitative polymerase chain reaction assays and immunofluorescence were used to evaluate changes in expression of AQP3 and EMT-related proteins in the SGC7901 and MGC803 human GC cell lines.
AQP3 up-expression was associated with EMT-related proteins in human GC specimens, which correlated with poor prognosis for GC. AQP3 modulated GC cell proliferation, migration and invasion in vitro, and induced E-cadherin repression. AQP3 also up-regulated the expression of vimentin and fibronectin in vitro. The PI3K/AKT/SNAIL signaling pathway was likely involved in the induction of EMT by AQP3 in GC.
AQP3 promotes EMT in human cases of GC, allowing us to understand the mechanisms of AQP3 in GC progression, thus providing a potential strategy for its treatment.
PMCID: PMC4036310  PMID: 24887009
Gastric cancer; Aquaporin 3; Epithelial-mesenchymal transition; E-cadherin; Vimentin
2.  Risk of Budd-Chiari Syndrome Associated with Factor V Leiden and G20210A Prothrombin Mutation: A Meta-Analysis 
PLoS ONE  2014;9(4):e95719.
Various studies have demonstrated that factor V Leiden (FVL) and G20210A prothrombin mutation contribute to the risk of Budd-Chiari syndrome (BCS), while other studies provided conflicting findings. In order to derive more precise estimations of the relationships, a meta-analysis was performed.
Eligible articles were identified through search of databases including Pubmed, Chinese Biomedical Database (CBM, Chinese), and Chinese National Knowledge Infrastructure (CNKI, Chinese). Odd ratios (ORs) with 95% confidence intervals (CIs) were calculated using random- or fixed- model.
Finally, twelve studies were included for FVL and nine studies were included for G20210A prothrombin mutation. With respect to FVL, significantly increased BCS risk was found in the overall population (OR = 6.29, 95%CI = 4.23–9.36). Subgroup analyses suggested that FVL was associated with an increased risk of BCS in the population with high background mutation prevalence (>1% in the normal population). No significant association was found between BCS and G20210A prothrombin mutation (OR = 1.78, 95%CI = 0.77–4.11).
The presence of FVL should be evaluated in patients with BCS. Conversely, G20210A prothrombin mutation is not significantly associated with risk of BCS. Large-scale well designed studies are necessary to be conducted to further confirm or refute the observed association.
PMCID: PMC3995749  PMID: 24755609
3.  Drosophila SNAP-29 Is an Essential SNARE That Binds Multiple Proteins Involved in Membrane Traffic 
PLoS ONE  2014;9(3):e91471.
Each membrane fusion event along the secretory and endocytic pathways requires a specific set of SNAREs to assemble into a 4-helical coiled-coil, the so-called trans-SNARE complex. Although most SNAREs contribute one helix to the trans-SNARE complex, members of the SNAP-25 family contribute two helixes. We report the characterization of the Drosophila homologue of SNAP-29 (dSNAP-29), which is expressed throughout development. Unlike the other SNAP-25 like proteins in fruit fly (i.e., dSNAP-25 and dSNAP-24), which form SDS-resistant SNARE complexes with their cognate SNAREs, dSNAP-29 does not participate in any SDS-resistant complexes, despite its interaction with dsyntaxin1 and dsyntaxin16 in vitro. Immunofluorescence studies indicated that dSNAP-29 is distributed in various tissues, locating in small intracellular puncta and on the plasma membrane, where it associates with EH domain-containing proteins implicated in the endocytic pathway. Overexpression and RNAi studies suggested that dSNAP-29 mediates an essential process in Drosophila development.
PMCID: PMC3953403  PMID: 24626111
4.  Neuroprotective Effects of Sevoflurane against Electromagnetic Pulse-Induced Brain Injury through Inhibition of Neuronal Oxidative Stress and Apoptosis 
PLoS ONE  2014;9(3):e91019.
Electromagnetic pulse (EMP) causes central nervous system damage and neurobehavioral disorders, and sevoflurane protects the brain from ischemic injury. We investigated the effects of sevoflurane on EMP-induced brain injury. Rats were exposed to EMP and immediately treated with sevoflurane. The protective effects of sevoflurane were assessed by Nissl staining, Fluoro-Jade C staining and electron microscopy. The neurobehavioral effects were assessed using the open-field test and the Morris water maze. Finally, primary cerebral cortical neurons were exposed to EMP and incubated with different concentration of sevoflurane. The cellular viability, lactate dehydrogenase (LDH) release, superoxide dismutase (SOD) activity and malondialdehyde (MDA) level were assayed. TUNEL staining was performed, and the expression of apoptotic markers was determined. The cerebral cortexes of EMP-exposed rats presented neuronal abnormalities. Sevoflurane alleviated these effects, as well as the learning and memory deficits caused by EMP exposure. In vitro, cell viability was reduced and LDH release was increased after EMP exposure; treatment with sevoflurane ameliorated these effects. Additionally, sevoflurane increased SOD activity, decreased MDA levels and alleviated neuronal apoptosis by regulating the expression of cleaved caspase-3, Bax and Bcl-2. These findings demonstrate that Sevoflurane conferred neuroprotective effects against EMP radiation-induced brain damage by inhibiting neuronal oxidative stress and apoptosis.
PMCID: PMC3948751  PMID: 24614080
5.  Anion Exchange HPLC Isolation of High-Density Lipoprotein (HDL) and On-Line Estimation of Proinflammatory HDL 
PLoS ONE  2014;9(3):e91089.
Proinflammatory high-density lipoprotein (p-HDL) is a biomarker of cardiovascular disease. Sickle cell disease (SCD) is characterized by chronic states of oxidative stress that many consider to play a role in forming p-HDL. To measure p-HDL, apolipoprotein (apo) B containing lipoproteins are precipitated. Supernatant HDL is incubated with an oxidant/LDL or an oxidant alone and rates of HDL oxidation monitored with dichlorofluorescein (DCFH). Although apoB precipitation is convenient for isolating HDL, the resulting supernatant matrix likely influences HDL oxidation. To determine effects of supernatants on p-HDL measurements we purified HDL from plasma from SCD subjects by anion exchange (AE) chromatography, determined its rate of oxidation relative to supernatant HDL. SCD decreased total cholesterol but not triglycerides or HDL and increased cell-free (cf) hemoglobin (Hb) and xanthine oxidase (XO). HDL isolated by AE-HPLC had lower p-HDL levels than HDL in supernatants after apoB precipitation. XO+xanthine (X) and cf Hb accelerated purified HDL oxidation. Although the plate and AE-HPLC assays both showed p-HDL directly correlated with cf-Hb in SCD plasma, the plate assay yielded p-HDL data that was influenced more by cf-Hb than AE-HPLC generated p-HDL data. The AE-HPLC p-HDL assay reduces the influence of the supernatants and shows that SCD increases p-HDL.
PMCID: PMC3946658  PMID: 24609013
6.  Negative Regulation of RIG-I-Mediated Innate Antiviral Signaling by SEC14L1 
Journal of Virology  2013;87(18):10037-10046.
Retinoic acid-inducible gene I (RIG-I) is a key sensor for recognizing nucleic acids derived from RNA viruses and triggers beta interferon (IFN-β) production. Because of its important role in antiviral innate immunity, the activity of RIG-I must be tightly controlled. Here, we used yeast two-hybrid screening to identify a SEC14 family member, SEC14L1, as a RIG-I-associated negative regulator. Transfected SEC14L1 interacted with RIG-I, and endogenous SEC14L1 associated with RIG-I in a viral infection-inducible manner. Overexpression of SEC14L1 inhibited transcriptional activity of the IFN-β promoter induced by RIG-I but not TANK-binding kinase 1 (TBK1) and interferon regulatory factor 3 (IRF3). Knockdown of endogenous SEC14L1 in both HEK293T cells and HT1080 cells potentiated RIG-I and Sendai virus-triggered IFN-β production as well as attenuated the replication of Newcastle disease virus. SEC14L1 interacted with the N-terminal domain of RIG-I (RIG-I caspase activation and recruitment domain [RIG-I-CARD]) and competed with VISA/MAVS/IPS-1/Cardif for RIG-I-CARD binding. Domain mapping further indicated that the PRELI-MSF1 and CRAL-TRIO domains but not the GOLD domain of SEC14L1 are required for interaction and inhibitory function. These findings suggest that SEC14L1 functions as a novel negative regulator of RIG-I-mediated antiviral signaling by preventing RIG-I interaction with the downstream effector.
PMCID: PMC3754010  PMID: 23843640
7.  A Systematic Review and Meta-Analysis of Unilateral versus Bilateral Pedicle Screw Fixation in Transforaminal Lumbar Interbody Fusion 
PLoS ONE  2014;9(1):e87501.
Transforaminal lumbar interbody fusion (TLIF) has become one of the most widely used procedures for lumbar spinal disorders. However, it is still unclear whether TLIF with unilateral pedicle screw (PS) fixation is as effective as that with bilateral PS fixation. We performed a meta-analysis of the literatures and aimed to gain a better understanding of whether TLIF with unilateral PS fixation was safe and effective for lumbar diseases.
Methodology/Principal Findings
We systematically searched Ovid, Springer, and Medline databases for relevant randomized controlled trials (RCTs) that compared the clinical and radiological outcomes of unilateral versus bilateral PS fixation in TLIF. Risk of bias in included studies was assessed using the Cochrane Risk of Bias tool. We generated pooled risk ratios or weighted mean differences across studies. According to our predefined inclusion criteria, seven RCTs with a total of 441 patients were included in this study. Baseline characteristics were similar between the unilateral and bilateral groups. Our meta-analysis showed that no significant difference was detected between the two groups in terms of postoperative clinical function, fusion status, reoperation rate, complication rate, and hospital stay (p>0.05). Pooled estimates revealed that the unilateral group was associated with significantly reduced implant cost, operative time and blood loss (p<0.05).
Our meta-analysis suggested TLIF with unilateral PS fixation was as safe and effective as that with bilateral PS fixation for lumbar diseases in selected patients. Despite these findings, our meta-analysis was based on studies with small sample size and different study characteristics that might lead to the inconsistent results such as various functional outcomes among the included studies. Therefore, high-quality randomized controlled trials with larger sample size are also needed to further clarify these issues and to provide the long-term outcomes.
PMCID: PMC3906181  PMID: 24489929
8.  Thapsigargin Induces Apoptosis by Impairing Cytoskeleton Dynamics in Human Lung Adenocarcinoma Cells 
The Scientific World Journal  2014;2014:619050.
The objective of this study was performed to investigate the effects of thapsigargin on apoptosis, actin cytoskeletal dynamics, and actin cytoskeletal proteins in human lung adenocarcinoma cell. Thapsigargin is a specific irreversible inhibitor of ER calcium-ATPase, which may promote ER stress by depletion of lumenal calcium stores and show potential to induce cell death. The effects of thapsigargin on the apoptosis in A549 cells were assayed by Hoechst staining. Moreover, the F-actin staining by Rhodamine-phalloidin and RhoA antibody for cytoskeleton organizations were applied to A549 cells. To confirm the impairment of cytoskeletal dynamics treated with thapsigargin, western blots were applied to analyze the protein levels of p-Cofilin-1 (Ser3), Cofilin-1, and pPaxillin (Tyr118), as well as RhoA and pS6 (S240/244). Results suggest that thapsigargin may induce cell death in A549 cells with a time- and dose-dependent manner. The F-actin fibers and RhoA signals are also reduced with a time- and dose-dependent manner by thapsigargin treatment. The phosphorylation forms of Cofilin-1 and paxillin are attenuated by 1 μM thapsigargin treatment for 24 h. These alternations may be caused by the inhibition of of mTORC1 activities (indicated by pS6 (Ser240/244)) and RhoA pathways after thapsigargin treatment. The present findings highlight important roles of calcium entry in cytoskeleton organization and apoptosis in human lung adenocarcinoma cells and will help to set a stage to the clinical treatment of cancer cell metastasis.
PMCID: PMC3926280  PMID: 24605059
9.  Application of a Catalytic Asymmetric Povarov Reaction using Chiral Ureas to the Synthesis of a Tetrahyroquinoline Library 
ACS combinatorial science  2012;14(11):621-630.
A 2328-membered library of 2,3,4-trisubstituted tetrahydroquinolines was produced using a combination of solution- and solid-phase synthesis techniques. A tetrahydroquinoline (THQ) scaffold was prepared via an asymmetric Povarov reaction using cooperative catalysis to generate three contiguous stereogenic centers. A matrix of 4 stereoisomers of the THQ scaffold was prepared to enable the development of stereo/structure-activity relationships (SSAR) upon biological testing. A sparse matrix design strategy was employed to select library members to be synthesized with the goal of generating a diverse collection of tetrahydroquinolines with physicochemical properties suitable for downstream discovery.
PMCID: PMC3577964  PMID: 23088641
10.  Complex modulation of the expression of PKC isoforms in the rat brain during chronic type 1 diabetes mellitus 
Brain research  2012;1490C:202-209.
We previously demonstrated that chronic hyperglycemia has a detrimental influence on neurovascular coupling in the brain—an effect linked to an alteration in the protein kinase C (PKC)-mediated phosphorylation pattern. Moreover, the activity of PKC was increased, in diabetic rat brain, in a tissue fraction composed primarily of the superficial glia limitans and pial vessels, but trended toward a decrease in cerebral cortical gray matter. However, that study did not examine the expression patterns of PKC isoforms in the rat brain. Thus, , in a rat model of streptozotocin (STZ)-induced chronic type 1 diabetes mellitus (T1DM), and in non-diabetic (ND) controls, two hypotheses were addressed. First, chronic T1DM is accompanied by changes in the expression of PKC-α, βII, γ, δ, and ε. Second, those changes differ when comparing cerebral cortex and glio-pial tissue. In addition, we analyzed the expression of a form of PKC-γ, phosphorylated on threonine 514 (pT514- PKC-γ), as well as the receptor for activated C kinase 1 (RACK1). The expression pattern of different PKC isoforms was altered in a complex and tissue-specific manner during chronic hyperglycemia. Notably, in the gray matter, PKC-α expression significantly decreased, while pT514-PKC-γ expression increased. However, PKC-βII, -γ, -δ, -ε, and RACK1 expressions did not change. Conversely, in glio-pial tissue, PKC-α and RACK1 were upregulated, whereas PKC-γ, pT514-PKCγ, and PKC-ε were downregulated. PKC-βII, and PKC-δ, were unchanged. These findings suggest that the PKC activity increase previously seen in the glio-pial tissue of diabetic rats may be due to the selective upregulation of PKC-α, and ultimately lead to the impairment of neurovascular coupling.
PMCID: PMC3529837  PMID: 23103504
Neurovascular coupling; Diabetes; cerebrovascular disease; pial vessels; PKC isoform; Western blot
11.  miR482 Regulation of NBS-LRR Defense Genes during Fungal Pathogen Infection in Cotton 
PLoS ONE  2013;8(12):e84390.
In this study, we characterized the miR482 family in cotton using existing small RNA datasets and the recently released draft genome sequence of Gossypium raimondii, a diploid cotton species whose progenitor is the putative contributor of the Dt (representing the D genome of tetraploid) genome of the cultivated tetraploid cotton species G. hirsutum and G. barbadense. Of the three ghr-miR482 members reported in G. hirsutum, ghr-miR482a has no homolog in G. raimondii, ghr-miR482b and ghr-miR482c each has a single homolog in G. raimondii. Gra-miR482d has five homologous loci (gra-miR482d, f-i) in G. raimondii and also exists in G. hirsutum (ghr-miR482d). A variant, miR482.2 that is a homolog of miR2118 in other species, is produced from several GHR-MIR482 loci in G. hirsutum. Approximately 12% of the G. raimondii NBS-LRR genes were predicted targets of various members of the gra-miR482 family. Based on the rationale that the regulatory relationship between miR482 and NBS-LRR genes will be conserved in G. raimondii and G. hirsutum, we investigated this relationship using G. hirsutum miR482 and G. raimondii NBS-LRR genes, which are not currently available in G. hirsutum. Ghr-miR482/miR482.2-mediated cleavage was confirmed for three of the four NBS-LRR genes analysed. As in tomato, miR482-mediated cleavage of NBS-LRR genes triggered production of phased secondary small RNAs in cotton. In seedlings of the susceptible cultivar Sicot71 (G. hirsutum) infected with the fungal pathogen Verticillium dahliae, the expression levels of ghr-miR482b/miR482b.2, ghr-miR482c and ghr-miR482d.2 were down-regulated, and several NBS-LRR targets of ghr-miR482c and ghr-miR482d were up-regulated. These results imply that, like tomato plants infected with viruses or bacteria, cotton plants are able to induce expression of NBS-LRR defence genes by suppression of the miRNA-mediated gene silencing pathway upon fungal pathogen attack.
PMCID: PMC3877274  PMID: 24391949
13.  Chloroquine reduces osteoclastogenesis in murine osteoporosis by preventing TRAF3 degradation 
The cytokines RANKL and TNF activate NF-κB signaling in osteoclast precursors (OCPs) to induce osteoclast (OC) formation. Conversely, TNF can limit OC formation through NF-κB p100, which acts as an inhibitor, and TNF receptor–associated receptor 3 (TRAF3); however, a role for TRAF3 in RANKL-mediated OC formation is unknown. We found that TRAF3 limits RANKL-induced osteoclastogenesis by suppressing canonical and noncanonical NF-κB signaling. Conditional OC-specific Traf3-KO (cKO) mice had mild osteoporosis and increased OC formation. RANKL induced TRAF3 degradation via the lysosome/autophagy system. The autophagy/lysosome inhibitor chloroquine reduced RANKL-induced OC formation and function by increasing TRAF3 expression in OCPs in vitro and in vivo. Although chloroquine had no effect on basal bone resorption, it inhibited parathyroid hormone– and ovariectomy-induced OC activation in WT, but not cKO, mice. Deletion of the transcription factor gene Relb resulted in increased TRAF3 expression in OCPs, which was associated with decreased RANKL-induced TRAF3 degradation. RelB directly increased expression of BECN1, a key autophagy regulator, by binding to its promoter. These data indicate that autophagic/lysosomal degradation of TRAF3 is an important step in RANKL-induced NF-κB activation in OCPs. Furthermore, treatments that increase TRAF3 levels in OCPs, including pharmacological inhibition of its degradation with compounds such as chloroquine, may limit bone destruction in common bone diseases.
PMCID: PMC3871219  PMID: 24316970
14.  Potential Use of Hyperoxygenated Solution as a Treatment Strategy for Carbon Monoxide Poisoning 
PLoS ONE  2013;8(12):e81779.
Carbon monoxide (CO) poisoning can cause permanent damage in tissues that are sensitive to hypoxia. We explored the feasibility and efficacy of using a hyperoxygenated solution (HOS) to treat severe acute CO poisoning in an animal model.
Male Sprague-Dawley rats were subjected to CO poisoning. The HOS was administered into the femoral vein of these rats through a catheter (10 ml/kg). Carboxyhemoglobin (COHb) and blood gases were used to assess the early damage caused by CO poisoning. S100β was measured to predict the development of late cognitive sequelae of CO. The Morris water maze test was performed to assess cognitive function, and Nissl staining was performed to observe histologic change.
The COHb concentrations rapidly decreased at 5 min after the HOS administration; however, the PaO2 and SaO2 in rats treated with HOS increased significantly 5 min after the HOS administration. The S100β concentrations, which increased significantly after CO poisoning, increased at a much slower rate in the rats treated with HOS (HOS group) compared with the rats treated with O2 inhalation (O2 group). The escape latency in the place navigation test was shortened after CO poisoning on days 11-15 and days 26-30, and the swimming time in quadrant 4 in the spatial probe test on days 15 and 30 after CO poisoning was prolonged in the rats treated with HOS injection compared with the rats treated with oxygen inhalation or normal saline injection. The neuronal degeneration in the HOS group was alleviated than that in the CO or O2 group.
HOS efficiently alleviates the brain damage in acute CO-poisoned rats and thus may serve as a new way to treat human patients with CO poisoning in clinical practice.
PMCID: PMC3847038  PMID: 24312588
15.  Potential benefits of Chinese Herbal Medicine for elderly patients with cardiovascular diseases 
Chinese Herbal Medicine (CHM), as the most common form of traditional Chinese medicine (TCM), has been playing an important role in the treatment of elderly cardiovascular diseases (CVDs) in China. In this paper, we briefly discuss on the potential benefits of CHM for elderly patients with CVDs. Initially, we summarize the characteristics of CVDs in the elderly, the present treatment of CVDs in the elderly, and the clinical applications of CHM for CVDs. Secondly, in addition to introducing the features of CHM, we discuss the differences between CHM and Western medicine. Lastly, the potential benefits of CHM are presented. We came to a conclusion that as mutual complementary, Western medicine and TCM together shall benefit the elderly patients with CVDs.
PMCID: PMC3888910  PMID: 24454321
Cardiovascular diseases; Elderly patients; Chinese medicine; Herb
16.  Icariin Augments Bone Formation and Reverses the Phenotypes of Osteoprotegerin-Deficient Mice through the Activation of Wnt/β-Catenin-BMP Signaling 
Icariin has been mostly reported to enhance bone fracture healing and treat postmenopausal osteoporosis in ovariectomized animal model. As another novel animal model of osteoporosis, there is few publication about the effect of Icariin on osteoprotegerin-deficient mice. Therefore, the goal of this study is to find the effect on bone formation and underlying mechanisms of Icariin in osteoprotegerin (OPG) knockout (KO) mice. We found that Icariin significantly stimulated new bone formation after local injection over the surface of calvaria at the dose of 5 mg/kg per day. With this dose, Icariin was also capable of significantly reversing OPG-deficient-induced bone loss and bone strength reduction. Real-time PCR analysis showed that Icariin significantly upregulated the expression of BMP2, BMP4, RUNX2, OC, Wnt1, and Wnt3a in OPG KO mice. Icariin also significantly increased the expression of AXIN2, DKK1, TCF1, and LEF1, which are the direct target genes of β-catenin signaling. The in vitro studies showed that Icariin induced osteoblast differentiation through the activation of Wnt/β-catenin-BMP signaling by in vitro deletion of the β-catenin gene using β-cateninfx/fx mice. Together, our findings demonstrate that Icariin significantly reverses the phenotypes of OPG-deficient mice through the activation of Wnt/β-catenin-BMP signaling.
PMCID: PMC3835354  PMID: 24348713
17.  Comparison between posterior lumbar interbody fusion and posterolateral fusion with transpedicular screw fixation for isthmic spondylolithesis: a meta-analysis 
Primary aim of this study was to compare long-term pain relief and quality of life in adults with isthmic spondylolisthesis (IS) who were treated with posterior lumbar interbody fusion (PLIF) and posterolateral fusion (PLF). Secondary aim was to compare the fusion and infection rates of PLIF- or PLF-treated groups.
Materials and methods
We searched four databases and the cited reference lists of the included studies. Inclusion criteria were pain assessment with visual analog scale (VAS), and clinical studies that compared long-term pain relief of PLF and PLIF-treated adults with IS. Exclusion criteria were use of only one treatment and non-English language.
Three of five included studies used VAS to assess the decline in low back pain, radicular pain, or leg pains in PLF- or PLIF-treated patients during the follow-up periods (0.5–6 years). Long-term pain relief significantly improved in both treatment groups. Pooled differences in mean improvement of Oswestry disability index after the operation revealed no significant difference in pain relief between the PLF and PLIF groups (P = 0.856). The five studies together indicated that fusion rate was significantly greater in the PLIF group than that in the PLF group.
The majority of PLIF- and PLF-treated adults with low-grade IS experienced long-term pain relief to a similar extent in most studies. PLIF treatment provided significantly better fusion rates than PLF treatment. This meta-analysis indicates that the use of separate, well-defined scales for pain relief and functional outcomes are needed in studies of PLF or PLIF-treated patients.
PMCID: PMC3828496  PMID: 24136445
Posterior lumbar interbody fusion; PLIF; Posterolateral fusion; PLF; Spondylolisthesis; Pain; Fusion rate; Infection rate; Isthmic
18.  Enoyl Coenzyme A Hydratase Domain–Containing 2, a Potential Novel Regulator of Myocardial Ischemia Injury 
We reported previously that Brown Norway (BN) rats are more resistant to myocardial ischemia/reperfusion (I/R) injury than are Dahl S (SS) rats. To identify the unique genes differentially expressed in the hearts of these rats, we used DNA microarray analysis and observed that enoyl coenzyme A hydratase–containing domain 2 (ECHDC2) is highly expressed (≈18‐fold) in the SS hearts compared with the BN hearts.
Methods and Results
RT‐PCR, Western blot, and immunohistochemistry analyses verified that ECHDC2 was highly expressed in SS hearts compared with the BN hearts. ECHDC2 gene locates at chromosome 5 of rat and is expressed in mitochondria of the heart, mainly in cardiomyocytes but not in cardiofibroblasts. Overexpression of ECHDC2 in cells increased susceptibility to I/R injury while knockdown of ECHDC2 enhanced resistance to I/R injury. Furthermore, we observed that left anterior descending coronary artery ligation–induced myocardial infarction was more severe in the SS hearts than in the BN hearts or SSBN5 hearts, which was built on SS rats but had the substitution of chromosome 5 from BN rats. We also demonstrated that ECHDC2 did not alter mitochondrial O2 consumption, metabolic intermediates and ATP production. By gas chromatography–mass spectrometry, we found that ECHDC2 overexpression increased the levels of the cellular branched chain amino acids leucine and valine.
ECHDC2, a mitochondrial protein, may be involved in regulating cell death and myocardial injury. Its deficiency in BN rats contributes to their increased resistance to myocardial I/R compared with SS rats. ECHDC2 increases branched chain amino acid metabolism and appears to be a novel regulator linking cell metabolism with cardiovascular disease.
PMCID: PMC3835224  PMID: 24108764
branched amino acid metabolism; cell death; ECHDC2; ischemia/reperfusion injury; myocardial infarction
19.  Community Core Evolution in Mobile Social Networks 
The Scientific World Journal  2013;2013:781281.
Community detection in social networks attracts a lot of attention in the recent years. Existing methods always depict the relationship of two nodes using the temporary connection. However, these temporary connections cannot be fully recognized as the real relationships when the history connections among nodes are considered. For example, a casual visit in Facebook cannot be seen as an establishment of friendship. Hence, our question is the following: how to cluster the real friends in mobile social networks? In this paper, we study the problem of detecting the stable community core in mobile social networks. The cumulative stable contact is proposed to depict the relationship among nodes. The whole process is divided into timestamps. Nodes and their connections can be added or removed at each timestamp, and historical contacts are considered when detecting the community core. Also, community cores can be tracked through the incremental computing, which can help to recognize the evolving of community structure. Empirical studies on real-world social networks demonstrate that our proposed method can effectively detect stable community cores in mobile social networks.
PMCID: PMC3791665  PMID: 24163629
20.  Optimizing Prescription of Chinese Herbal Medicine for Unstable Angina Based on Partially Observable Markov Decision Process 
Objective. Initial optimized prescription of Chinese herb medicine for unstable angina (UA). Methods. Based on partially observable Markov decision process model (POMDP), we choose hospitalized patients of 3 syndrome elements, such as qi deficiency, blood stasis, and turbid phlegm for the data mining, analysis, and objective evaluation of the diagnosis and treatment of UA at a deep level in order to optimize the prescription of Chinese herb medicine for UA. Results. The recommended treatment options of UA for qi deficiency, blood stasis, and phlegm syndrome patients were as follows: Milkvetch Root + Tangshen + Indian Bread + Largehead Atractylodes Rhizome (ADR = 0.96630); Danshen Root + Chinese Angelica + Safflower + Red Peony Root + Szechwan Lovage Rhizome Orange Fruit (ADR = 0.76); Snakegourd Fruit + Longstamen Onion Bulb + Pinellia Tuber + Dried Tangerine peel + Largehead Atractylodes Rhizome + Platycodon Root (ADR = 0.658568). Conclusion. This study initially optimized prescriptions for UA based on POMDP, which can be used as a reference for further development of UA prescription in Chinese herb medicine.
PMCID: PMC3776539  PMID: 24078826
21.  Structure of the Archaeoglobus fulgidus orphan ORF AF1382 determined by sulfur SAD from a moderately diffracting crystal 
The crystal structure of the 11.14 kDa orphan ORF 1382 from Archaeoglobus fulgidus (AF1382) has been determined by sulfur SAD phasing using data collected from a moderately diffracting crystal and 1.9 Å synchrotron X-rays.
The crystal structure of the 11.14 kDa orphan ORF 1382 from Archaeoglobus fulgidus (AF1382) has been determined by sulfur SAD phasing using a moderately diffracting crystal and 1.9 Å wavelength synchrotron X-rays. AF1382 was selected as a structural genomics target by the Southeast Collaboratory for Structural Genomics (SECSG) since sequence analyses showed that it did not belong to the Pfam-A database and thus could represent a novel fold. The structure was determined by exploiting longer wavelength X-rays and data redundancy to increase the anomalous signal in the data. AF1382 is a 95-­residue protein containing five S atoms associated with four methionine residues and a single cysteine residue that yields a calculated Bijvoet ratio (ΔF anom/F) of 1.39% for 1.9 Å wavelength X-rays. Coupled with an average Bijvoet redundancy of 25 (two 360° data sets), this produced an excellent electron-density map that allowed 69 of the 95 residues to be automatically fitted. The S-SAD model was then manually completed and refined (R = 23.2%, R free = 26.8%) to 2.3 Å resolution (PDB entry 3o3k). High-resolution data were subsequently collected from a better diffracting crystal using 0.97 Å wavelength synchrotron X-rays and the S-SAD model was refined (R = 17.9%, R free = 21.4%) to 1.85 Å resolution (PDB entry 3ov8). AF1382 has a winged-helix–turn–helix structure common to many DNA-binding proteins and most closely resembles the N-terminal domain (residues 1–82) of the Rio2 kinase from A. fulgidus, which has been shown to bind DNA, and a number of MarR-family transcriptional regulators, suggesting a similar DNA-binding function for AF1382. The analysis also points out the advantage gained from carrying out data reduction and structure determination on-site while the crystal is still available for further data collection.
PMCID: PMC3489105  PMID: 22948926
AF1382; orphan ORFs; sulfur SAD; Archaeoglobus fulgidus
22.  Oral Panax notoginseng Preparation for Coronary Heart Disease: A Systematic Review of Randomized Controlled Trials 
This systematic review aims to evaluate current evidence for the benefit and side effect of oral Panax notoginseng preparation for coronary heart disease (CHD). We included 17 randomized clinical trials (17 papers and 1747 participants). Comparing with no intervention on the basis of conventional therapy, oral Panax notoginseng did not show significant effect on reducing cardiovascular events, but it could alleviate angina pectoris (including improving the symptoms of angina pectoris [RR 1.20; 95% CI 1.12 to 1.28; 7 trials, n = 791], improving electrocardiogram [RR 1.35; 95% CI 1.19 to 1.53; 8 trials, n = 727], decreasing the recurrence of angina pectoris [RR 0.38; 95% CI 0.16 to 0.94; 1 trials, n = 60], duration of angina pectoris [RR −1.88; 95% CI −2.08 to −1.69; 2 trials, n = 292], and dosage of nitroglycerin [MD −1.13; 95% CI −1.70 to −0.56; 2 trials, n = 212]); oral Panax notoginseng had no significant difference compared with isosorbide dinitrate on immediate effect for angina pectoris [RR 0.96; 95% CI 0.81 to 1.15; 1 trial, n = 80]. In conclusion, oral Panax notoginseng preparation could relieve angina pectoris related symptoms. However, the small sample size and potential bias of most trials influence the convincingness of this conclusion. More rigorous trials with high quality are needed to give high level of evidence, especially for the potential benefit of cardiovascular events.
PMCID: PMC3762143  PMID: 24023585
23.  ITIH4: A New Potential Biomarker of “Toxin Syndrome” in Coronary Heart Disease Patient Identified with Proteomic Method 
Objective. This trial aims to look for the protein biomarker of “toxin syndrome” of CHD patients. Methods. We have performed two trials in this paper. The first trial was a randomized controlled trial (RCT) of the plasma proteome in unstable angina (UA) patients by Maldi-Tof Mass. The second trial was a nested case-control study in 1503 stable CHD patients with one-year followup for acute cardiovascular events (ACEs). Results. In the RCT study, 12 protein spots were found to be the differential protein for the significant differences between the difference of before and after treatment in group A and group B; 2 of them (3207.37 Da and 4279.95 Da) was considered to be unique to “toxin syndrome” for being differential proteins of group B but not group A. These 2 spots were identified as Isoform 1 of Fibrinogen alpha chain precursor (FGA, 3207.37 Da) and Isoform 2 of inter-alpha-trypsin inhibitor heavy chain H4 (ITIH4, 4279.95 Da), respectively. In the nested case-control study, the result of Western blot demonstrated that protein expression of ITIH4 in the group with followup ACEs was significantly lower than the matched group without followup ACEs (P = 0.027). Conclusion. ITIH4 might be a new potential biomarker of CHD “toxin syndrome” in TCM, indicating the potential role in early identifying high-risk CHD patients in stable period.
PMCID: PMC3760120  PMID: 24023573
24.  Integrative Western and Chinese Medicine on Coronary Heart Disease: Where Is the Orientation? 
Coronary heart disease (CHD) is the leading cause of death. As the main treatment of CHD, modern medicine has improved dramatically in recent years. Although researches of TCM and integrative medicine on CHD are witnessed encouraging progress in many respects, the role TCM playing in the prevention and treatment of CHD has been unprecedentedly challenged under such circumstance of the very fast development of modern medicine. In order to share mutual complementary advantages of TCM and western medicine, this review summarizes the relatively prominent researches of TCM and integrative medicine on CHD in recent years, and illuminates the issue of the orientation of the further research of integrative medicine on CHD, including (1) original innovation of TCM etiology and pathogenesis, (2) combination of disease and TCM syndrome, (3) biological basis of TCM syndrome of CHD, (4) clinical design and quality control of integrative medicine research, (5) herb-drug interaction, (6) difficulties and hot issues of modern medicine.
PMCID: PMC3760124  PMID: 24023575
25.  The Effect of Sodium Tanshinone IIA Sulfate and Simvastatin on Elevated Serum Levels of Inflammatory Markers in Patients with Coronary Heart Disease: A Study Protocol for a Randomized Controlled Trial 
Background. Coronary heart disease (CHD) due to atherosclerotic inflammation remains a significant threat to global health despite the success of the lipid-lowering, anti-inflammatory statins. Tanshinone IIA, a potent anti-inflammatory compound derived from Traditional Chinese Medicine (TCM), may be able to supplement statins by further reducing levels of circulating inflammatory markers correlated to cardiovascular risk. Here, we present the protocol of a randomized controlled trial (RCT) that will investigate the synergistic effect of sodium tanshinone IIA sulfate and simvastatin on reducing elevated inflammatory markers in patients with CHD. Participants: Seventy-two inpatients with confirmed CHD, elevated serum high-sensitivity C-reactive protein (Hs-CRP) level, and a TCM diagnosis of blood stasis syndrome will be enrolled and randomized 1 : 1 into the control or experimental group. Intervention. All subjects will receive a standard Western therapy including 20 mg simvastatin orally once per evening. Patients in the experimental group will additionally receive a daily 80 mg dose of sodium tanshinone IIA sulfate intravenously, diluted into 250 mL 0.9% NaCl solution. The treatment period will be 14 days. Outcomes. Primary outcome parameter: serum Hs-CRP level. Secondary outcome parameters: other circulating inflammatory markers (including IL-6, TNFα, VCAM-1, CD40, sCD40L, MCP-1, and MMP-9), improvement in symptoms of angina and blood stasis syndrome, and safety. This trial is registered with ChiCTR-TRC-12002361.
PMCID: PMC3747599  PMID: 23983803

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