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1.  Selection of reliable reference genes for normalization of quantitative RT-PCR from different developmental stages and tissues in amphioxus 
Scientific Reports  2016;6:37549.
Amphioxus is a closest living proxy to the ancestor of cephalochordates with vertebrates, and key animal for novel understanding in the evolutionary origin of vertebrate body plan, genome, tissues and immune system. Reliable analyses using quantitative real-time PCR (qRT-PCR) for answering these scientific questions is heavily dependent on reliable reference genes (RGs). In this study, we evaluated stability of thirteen candidate RGs in qRT-PCR for different developmental stages and tissues of amphioxus by four independent (geNorm, NormFinder, BestKeeper and deltaCt) and one comparative algorithms (RefFinder). The results showed that the top two stable RGs were the following: (1) S20 and 18 S in thirteen developmental stages, (2) EF1A and ACT in seven normal tissues, (3) S20 and L13 in both intestine and hepatic caecum challenged with lipopolysaccharide (LPS), and (4) S20 and EF1A in gill challenged with LPS. The expression profiles of two target genes (EYA and HHEX) in thirteen developmental stages were used to confirm the reliability of chosen RGs. This study identified optimal RGs that can be used to accurately measure gene expression under these conditions, which will benefit evolutionary and functional genomics studies in amphioxus.
doi:10.1038/srep37549
PMCID: PMC5116582  PMID: 27869224
2.  The Anti-tumor Toxin CD437 is a Direct Inhibitor of DNA Polymerase α 
Nature chemical biology  2016;12(7):511-515.
CD437 is a retinoid-like small molecule that selectively induces apoptosis in cancer but not normal cells through an unknown mechanism. We used a forward genetic strategy to discover mutations in POLA1 that coincide with CD437 resistance (POLA1R). Introduction of one of these mutations into cancer cells by CRISPR/Cas9 genome editing conferred CD437 resistance demonstrating causality. POLA1 encodes DNA polymerase α, the enzyme responsible for initiating DNA synthesis during the S phase of the cell cycle. CD437 inhibits DNA replication in cells and recombinant POLA1 activity in vitro. Both effects are abrogated by mutations associated with POLA1R. In addition, we detected an increase in the total fluorescence intensity and anisotropy of CD437 in the presence of increasing concentrations of POLA1 consistent with a direct binding interaction. The discovery of POLA1 as the direct anti-cancer target for CD437 has the potential to catalyze its development into an anti-cancer therapeutic.
doi:10.1038/nchembio.2082
PMCID: PMC4912453  PMID: 27182663
3.  Matrine Exerts a Strong Anti-Arthritic Effect on Type II Collagen-Induced Arthritis in Rats by Inhibiting Inflammatory Responses 
To investigate anti-arthritic effects of matrine isolated from the roots of S. flavescens on type II collagen-induced arthritis (CIA) in rats and to explore its related potential mechanisms, CIA rats were established and administered with matrine (20, 40 or 80 mg/kg/days, for 30 days). Subsequently, blood was collected to determine serum levels of TNF-α, IL-1β, IL-6, IL-8, IL-17A, IL-10, MMP-2, MMP-3 and MMP-9, and hind paws and knee joints were collected for histopathological examination. Furthermore, indices of the thymus and spleen were determined, and synovial tissues were collected to determine the protein expressions of p-IκB, IκB, Cox-2 and iNOS. Our results indicated that matrine significantly suppressed inflammatory reactions and synovial tissue destruction. Matrine inhibited paw swelling, arthritis indices and weight loss in CIA rats. Additionally, matrine decreased the levels of TNF-α, IL-1β, IL-6, IL-8, IL-17A, MMP-2, MMP-3 and MMP-9. Matrine also down-regulated expressions of p-IκB, Cox-2, and iNOS but up-regulated IκB in synovial tissues in CIA rats. The results suggested matrine possesses an anti-arthritic effect in CIA rats via inhibiting the release of pro-inflammatory cytokines and proteins that promote the NF-κB pathway.
doi:10.3390/ijms17091410
PMCID: PMC5037690  PMID: 27571073
matrine; Sophora flavescens; rheumatoid arthritis; anti-arthritic effect; type II collagen
4.  Pruinosanones A-C, anti-inflammatory isoflavone derivatives from Caragana pruinosa 
Scientific Reports  2016;6:31743.
Pruinosanone A (1), a novel spirochromone, was isolated from the roots of Caragana pruinosa. Two biogenetically related isoflavone intermediates, pruinosanones B and C (2 and 3), were also isolated, together with five known analogs identified as 3-hydroxy-9-methoxypterocarpan (4), 7,2′-dihydroxy-4′-methoxyisoflavanol (5), retusin-8-methylether (6), 7,2′-dihydroxy-8,4′-dimethoxy isoflavone (7) and 7,3′-dihydroxy-8,4′-dimethoxy isoflavone (8). The structures of 1–3 were elucidated based on extensive spectroscopic methods. Notably, 1 is the first example of a spirochromone possessing an unprecedented pentacyclic skeleton containing a spiro[benzo[d][1,3]dioxole-2,3′-chroman]-4′-one motif, which was confirmed by X-ray diffraction analysis. A plausible biosynthetic pathway for 1 was also proposed. Compounds 1–8 were tested for their ability to inhibit nitric oxide (NO) production in LPS-induced RAW 264.7 macrophages, and compounds 1–3 were the most potent inhibitors of NO production, with IC50 values of 1.96, 1.93 and 1.58 μM, respectively. A structure-activity relationship analysis revealed that the fused 2-isopropenyl-2,3-dihydrofuran moiety plays a vital role in the potency of these compounds. Moreover, 1 was found to significantly inhibit inducible nitric oxide synthase (iNOS) protein expression, which accounts for the potent inhibition of NO production by this spirochromone.
doi:10.1038/srep31743
PMCID: PMC4992842  PMID: 27545283
5.  The antinociception of oxytocin on colonic hypersensitivity in rats was mediated by inhibition of mast cell degranulation via Ca2+-NOS pathway 
Scientific Reports  2016;6:31452.
This study was conducted to investigate the effects of oxytocin (OT) on visceral hypersensitivity/pain and mast cell degranulation and the underlying mechanisms. We found that oxytocin receptor (OTR) was expressed in colonic mast cells in humans and rats, as well as in human mast cell line-1 (HMC-1), rat basophilic leukemia cell line (RBL-2H3) and mouse mastocytoma cell line (P815). OT decreased 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced visceral hypersensitivity, colonic mast cell degranulation and histamine release after mast cell degranulation in rats. Also, OT attenuated the compound 48/80 (C48/80)-evoked histamine release in P815 cells and inward currents, responsible for the mast cell degranulation, in HMC-1, RBL-2H3 and P815 cells. Moreover, these protective effects of OT against visceral hypersensitivity and mast cell degranulation were eliminated by coadministration of OTR antagonist atosiban or a nonselective inhibitor of nitric oxide synthase (NOS), NG-Methyl-L-arginine acetate salt (L-NMMA). Notably, OT evoked a concentration-dependent increase of intracellular Ca2+ in HMC-1, RBL-2H3 and P815 cells, which was responsible for the activation of neuronal NOS (NOS1) and endothelial NOS (NOS3). Our findings strongly suggest that OT might exert the antinociception on colonic hypersensitivity through inhibition of mast cell degranulation via Ca2+-NOS pathway.
doi:10.1038/srep31452
PMCID: PMC4990927  PMID: 27538454
6.  On the Origin of De Novo Genes in Arabidopsis thaliana Populations 
Genome Biology and Evolution  2016;8(7):2190-2202.
De novo genes, which originate from ancestral nongenic sequences, are one of the most important sources of protein-coding genes. This origination process is crucial for the adaptation of organisms. However, how de novo genes arise and become fixed in a population or species remains largely unknown. Here, we identified 782 de novo genes from the model plant Arabidopsis thaliana and divided them into three types based on the availability of translational evidence, transcriptional evidence, and neither transcriptional nor translational evidence for their origin. Importantly, by integrating multiple types of omics data, including data from genomes, epigenomes, transcriptomes, and translatomes, we found that epigenetic modifications (DNA methylation and histone modification) play an important role in the origination process of de novo genes. Intriguingly, using the transcriptomes and methylomes from the same population of 84 accessions, we found that de novo genes that are transcribed in approximately half of the total accessions within the population are highly methylated, with lower levels of transcription than those transcribed at other frequencies within the population. We hypothesized that, during the origin of de novo gene alleles, those neutralized to low expression states via DNA methylation have relatively high probabilities of spreading and becoming fixed in a population. Our results highlight the process underlying the origin of de novo genes at the population level, as well as the importance of DNA methylation in this process.
doi:10.1093/gbe/evw164
PMCID: PMC4987118  PMID: 27401176
de novo genes; DNA methylation; origin; process; protein-coding genes
7.  Approaching Defect-free Amorphous Silicon Nitride by Plasma-assisted Atomic Beam Deposition for High Performance Gate Dielectric 
Scientific Reports  2016;6:28326.
In the past few decades, gate insulators with a high dielectric constant (high-k dielectric) enabling a physically thick but dielectrically thin insulating layer, have been used to replace traditional SiOx insulator and to ensure continuous downscaling of Si-based transistor technology. However, due to the non-silicon derivative natures of the high-k metal oxides, transport properties in these dielectrics are still limited by various structural defects on the hetero-interfaces and inside the dielectrics. Here, we show that another insulating silicon compound, amorphous silicon nitride (a-Si3N4), is a promising candidate of effective electrical insulator for use as a high-k dielectric. We have examined a-Si3N4 deposited using the plasma-assisted atomic beam deposition (PA-ABD) technique in an ultra-high vacuum (UHV) environment and demonstrated the absence of defect-related luminescence; it was also found that the electronic structure across the a-Si3N4/Si heterojunction approaches the intrinsic limit, which exhibits large band gap energy and valence band offset. We demonstrate that charge transport properties in the metal/a-Si3N4/Si (MNS) structures approach defect-free limits with a large breakdown field and a low leakage current. Using PA-ABD, our results suggest a general strategy to markedly improve the performance of gate dielectric using a nearly defect-free insulator.
doi:10.1038/srep28326
PMCID: PMC4915203  PMID: 27325155
8.  A Friendly Relationship between Endophytic Fungi and Medicinal Plants: A Systematic Review 
Endophytic fungi or endophytes exist widely inside the healthy tissues of living plants, and are important components of plant micro-ecosystems. Over the long period of evolution, some co-existing endophytes and their host plants have established a special relationship with one and another, which can significantly influence the formation of metabolic products in plants, then affect quality and quantity of crude drugs derived from medicinal plants. This paper will focus on the increasing knowledge of relationships between endophytic fungi and medicinal plants through reviewing of published research data obtained from the last 30 years. The analytical results indicate that the distribution and population structure of endophytes can be considerably affected by factors, such as the genetic background, age, and environmental conditions of their hosts. On the other hand, the endophytic fungi can also confer profound impacts on their host plants by enhancing their growth, increasing their fitness, strengthening their tolerances to abiotic and biotic stresses, and promoting their accumulation of secondary metabolites. All the changes are very important for the production of bioactive components in their hosts. Hence, it is essential to understand such relationships between endophytic fungi and their host medicinal plants. Such knowledge can be well exploited and applied for the production of better and more drugs from medicinal plants.
doi:10.3389/fmicb.2016.00906
PMCID: PMC4899461  PMID: 27375610
endophytic fungi; medicinal plant; population structure; plant-microbe interaction; secondary metabolite
9.  Integrated miRNA–risk gene–pathway pair network analysis provides prognostic biomarkers for gastric cancer 
OncoTargets and therapy  2016;9:2975-2986.
Purpose
This study aimed to identify molecular prognostic biomarkers for gastric cancer.
Methods
mRNA and miRNA expression profiles of eligible gastric cancer and control samples were downloaded from Gene Expression Omnibus to screen the differentially expressed genes (DEGs) and differentially expressed miRNAs (DEmiRs), using MetaDE and limma packages, respectively. Target genes of the DEmiRs were also collected from both predictive and experimentally validated target databases of miRNAs. The overlapping genes between selected targets and DEGs were identified as risk genes, followed by functional enrichment analysis. Human pathways and their corresponding genes were downloaded from the Kyoto Encyclopedia of Genes and Genomes (KEGG) database for the expression analysis of each pathway in gastric cancer samples. Next, co-pathway pairs were selected according to the Pearson correlation coefficients. Finally, the co-pathway pairs, miRNA–target pairs, and risk gene–pathway pairs were merged into a complex interaction network, the most important nodes (miRNAs/target genes/co-pathway pairs) of which were selected by calculating their degrees.
Results
Totally, 1,260 DEGs and 144 DEmiRs were identified. There were 336 risk genes found in the 9,572 miRNA–target pairs. Judging from the pathway expression files, 45 co-pathway pairs were screened out. There were 1,389 interactive pairs and 480 nodes in the integrated network. Among all nodes in the network, focal adhesion/extracellular matrix–receptor interaction pathways, CALM2, miR-19b, and miR-181b were the hub nodes with higher degrees.
Conclusion
CALM2, hsa-miR-19b, and hsa-miR-181b might be used as potential prognostic targets for gastric cancer.
doi:10.2147/OTT.S95129
PMCID: PMC4881735  PMID: 27284247
gastric cancer; dysfunction; co-pathway pairs; integrated network; miRNA targets
10.  Sp1 and COX2 expression is positively correlated with a poor prognosis in pancreatic ductal adenocarcinoma 
Oncotarget  2016;7(19):28207-28217.
Previous studies showed that celecoxib, a cyclooxygenase-2 (COX2) inhibitor, can inhibit angiogenesis and metastasis of pancreatic ductal adenocarcinoma (PDAC) via the suppression of specificity protein 1 (Sp1). In this study, we investigated the prognostic value of Sp1 and COX2 in 88 PDAC patients. Our study showed there was a positive correlation between Sp1 and COX2 expression (P=0.001) by using the Spearman's rank test. Pearson Chi-square test revealed that Sp1 and COX2 expression were positively associated with lymph node metastasis (P<0.05, both). In addition, the Kaplan–Meier analysis showed that patients with Sp1- or COX2-positive expression exhibited poorer overall survival (OS) than those with Sp1- or COX2-negative expression (P<0.05, all). Most importantly, Sp1- and COX2-negative patients had the best OS (P=0.01). In multivariate analysis, Sp1 expression (P=0.03), COX2 expression (P=0.04), and nuclear grade (P=0.009) were found to be independent predictors for OS. Moreover, we confirmed that Sp1 could upregulate the expression of COX2 in PDAC cell lines by western blot analysis, and both are of important prognostic value in PDAC.
doi:10.18632/oncotarget.8593
PMCID: PMC5053721  PMID: 27057636
pancreatic ductal adenocarcinoma; specificity protein 1; cyclooxygenase-2; correlation; prognosis
11.  The effect of resveratrol on beta amyloid-induced memory impairment involves inhibition of phosphodiesterase-4 related signaling 
Oncotarget  2016;7(14):17380-17392.
Resveratrol, a natural polyphenol found in red wine, has wide spectrum of pharmacological properties including antioxidative and antiaging activities. Beta amyloid peptides (Aβ) are known to involve cognitive impairment, neuroinflammatory and apoptotic processes in Alzheimer's disease (AD). Activation of cAMP and/or cGMP activities can improve memory performance and decrease the neuroinflammation and apoptosis. However, it remains unknown whether the memory enhancing effect of resveratrol on AD associated cognitive disorders is related to the inhibition of phosphodiesterase 4 (PDE4) subtypes and subsequent increases in intracellular cAMP and/or cGMP activities. This study investigated the effect of resveratrol on Aβ1-42-induced cognitive impairment and the participation of PDE4 subtypes related cAMP or cGMP signaling. Mice microinfused with Aβ1-42 into bilateral CA1 subregions displayed learning and memory impairment, as evidenced by reduced memory acquisition and retrieval in the water maze and retention in the passive avoidance tasks; it was also significant that neuroinflammatory and pro-apoptotic factors were increased in Aβ1-42-treated mice. Aβ1-42-treated mice also increased in PDE4A, 4B and 4D expression, and decreased in PKA level. However, PKA inhibitor H89, but not PKG inhibitor KT5823, prevented resveratrol's effects on these parameters. Resveratrol also reversed Aβ1-42-induced decreases in phosphorylated cAMP response-element binding protein (pCREB), brain derived neurotrophic factor (BDNF) and anti-apoptotic factor BCl-2 expression, which were reversed by H89. These findings suggest that resveratrol reversing Aβ-induced learning and memory disorder may involve the regulation of neuronal inflammation and apoptosis via PDE4 subtypes related cAMP-CREB-BDNF signaling.
doi:10.18632/oncotarget.8041
PMCID: PMC4951219  PMID: 26980711
resveratrol; beta amyloid peptide; learning and memory; PDE4; apoptosis; Gerotarget
12.  Aberrant expression of nuclear HDAC3 and cytoplasmic CDH1 predict a poor prognosis for patients with pancreatic cancer 
Oncotarget  2016;7(13):16505-16516.
Previous studies showed that aberrant CDH1 or/and HDAC3 localization is essential for the progression of some human cancers. Here, we investigate the prognostic significance of aberrant CDH1 and HDAC3 localization in 84 pancreatic cancer patients. Our results show that increases in both membrane and cytoplasmic CDH1 correlate with lymph node metastasis (P = 0.026 and P < 0.001, respectively) and clinical stage (P = 0.020 and P < 0.001, respectively). Increased nuclear HDAC3 correlates with lymph node metastasis (P < 0.001) and advanced clinical stage (P < 0.001), but increased cytoplasmic HDAC3 does not (P > 0.05). Multivariate analysis showed that nuclear HDAC3 and cytoplasmic CDH1 (P = 0.001 and P = 0.010, respectively), as well as tumor differentiation (P = 0.009) are independent prognostic factors. Most importantly, patients with high co-expression of nuclear HDAC3 and cytoplasmic CDH1 had shorter survival times (P < 0.001), more frequent lymph node metastasis (P < 0.001), and advanced clinical stage (P < 0.001). Our studies provide convincing evidence that nuclear HDAC3 and cytoplasmic CDH1 have independent prognostic value in pancreatic cancer and provide novel targets for prognostic therapeutics.
doi:10.18632/oncotarget.7663
PMCID: PMC4941331  PMID: 26918727
pancreatic cancer; histone deacetylases 3; CDH1; subcellular localization; prognosis
13.  Associations between maternal lipid profile and pregnancy complications and perinatal outcomes: a population-based study from China 
Background
Dyslipidemia in pregnancy are associated with gestational diabetes mellitus (GDM), preeclampsia, preterm birth and other adverse outcomes, which has been extensively studied in western countries. However, similar studies have rarely been conducted in Asian countries. Our study was aimed at investigating the associations between maternal dyslipidemia and adverse pregnancy outcomes among Chinese population.
Methods
Data were derived from 934 pairs of non-diabetic mothers and neonates between 2010 and 2011. Serum blood samples were assayed for fasting total cholesterol (TC), triglycerides (TG), high-density lipoprotein-cholesterol (HDL-C), and low-density lipoprotein-cholesterol (LDL-C) concentrations during the first, second and third trimesters. The present study explored the associations between maternal lipid profile and pregnancy complications and perinatal outcomes. The pregnancy complications included GDM, preeclampsia and intrahepatic cholestasis of pregnancy (ICP); the perinatal outcomes included preterm birth, small/large for gestational age (SGA/LGA) infants and macrosomia. Odds ratios (ORs) and 95 % confidence intervals (95 % CIs) were calculated and adjusted via stepwise logistic regression analysis. Optimal cut-off points were determined by ROC curve analysis.
Results
After adjustments for confounders, every unit elevation in third-trimester TG concentration was associated with increased risk for GDM (OR = 1.37, 95 % CI: 1.18-1.58), preeclampsia (OR = 1.50, 95 % CI: 1.16-1.93), ICP (OR = 1.28, 95 % CI: 1.09-1.51), LGA (OR = 1.13, 95 % CI: 1.02-1.26), macrosomia (OR = 1.19, 95 % CI: 1.02-1.39) and decreased risk for SGA (OR = 0.63, 95 % CI: 0.40-0.99); every unit increase in HDL-C concentration was associated with decreased risk for GDM and macrosomia, especially during the second trimester (GDM: OR = 0.10, 95 % CI: 0.03-0.31; macrosomia: OR = 0.25, 95 % CI: 0.09-0.73). The optimal cut-off points for third-trimester TG predicting GDM, preeclampsia, ICP, LGA and SGA were separately ≥3.871, 3.528, 3.177, 3.534 and ≤2.530 mmol/L. The optimal cut-off points for third-trimester HDL-C identifying GDM, macrosomia and SGA were respectively ≤1.712, 1.817 and ≥2.238 mmol/L.
Conclusions
Among Chinese population, maternal high TG in late pregnancy was independently associated with increased risk of GDM, preeclampsia, ICP, LGA, macrosomia and decreased risk of SGA. Relative low maternal HDL-C during pregnancy was significantly associated with increased risk of GDM and macrosomia; whereas relative high HDL-C was a protective factor for both of them.
doi:10.1186/s12884-016-0852-9
PMCID: PMC4802610  PMID: 27000102
14.  EZH2 promotes cell migration and invasion but not alters cell proliferation by suppressing E-cadherin, partly through association with MALAT-1 in pancreatic cancer 
Oncotarget  2016;7(10):11194-11207.
Enhancer of zeste homolog 2 (EZH2) is an essential component of the polycomb repressive complex 2 (PRC2), which is required for epigenetic silencing of target genes, including those affecting cancer progression. Its role in pancreatic cancer remains to be clarified; therefore, we investigated the effects of aberrantly expressed EZH2 on pancreatic cancer. We found that EZH2 expression is up-regulated in pancreatic cancer tissues and positively correlated with lymph node metastasis and advanced clinical stage in pancreatic cancer patients. EZH2 knockdown in pancreatic cancer cell lines inhibited cell migration and invasion, but did not alter cell proliferation. Silencing of EZH2 also increased E-cadherin expression in vitro, and E-cadherin expression was inversely correlated with EZH2 expression in pancreatic cancer tissue samples. Patients with high EZH2 and low E-cadherin expression had the worst prognosis. RIP and ChIP assays suggest that EZH2 is recruited to the E-cadherin promoter by the long non-coding RNA, MALAT-1 (metastasis associated in lung adenocarcinoma transcript 1), where it represses E-cadherin expression. Our results show that EZH2-based therapies may be an option for the treatment of pancreatic cancer.
doi:10.18632/oncotarget.7156
PMCID: PMC4905466  PMID: 26848980
pancreatic cancer; enhancer of zeste homolog 2; metastasis associated lung adenocarcinoma transcript 1; long non-coding RNA; cell migration
15.  Effects of Xiaoyaosan on Stress-Induced Anxiety-Like Behavior in Rats: Involvement of CRF1 Receptor 
Background. Compared with antidepressant activity of Xiaoyaosan, the role of Xiaoyaosan in anxiety has been poorly studied. Objective. To observe the effects of Xiaoyaosan on anxiety-like behavior induced by chronic immobilization stress (CIS) and further explore whether these effects were related to CRF1R signaling. Methods. Adult male SD rats were randomly assigned to five groups (n = 12): the nonstressed control group, vehicle-treated (saline, p.o.) group, Xiaoyaosan-treated (3.854 g/kg, p.o.) group, vehicle-treated (surgery) group, and antalarmin-treated (surgery) group. Artificial cerebrospinal fluid (0.5 μL/side) or CRF1R antagonist antalarmin (125 ng/0.5 μL, 0.5 μL/side) was bilaterally administered into the basolateral amygdala in the surgery groups. Except for the nonstressed control group, the other four groups were exposed to CIS (14 days, 3 h/day) 30 minutes after treatment. On days 15 and 16, all animals were subjected to the elevated plus-maze (EPM) and novelty suppressed feeding (NSF) test. We then examined the expression of CRF1R, pCREB, and BDNF in the amygdala. Results. Chronic pretreatment with Xiaoyaosan or antalarmin significantly reversed elevated anxiety-like behavior and the upregulated level of CRF1R and BDNF in the amygdala of stressed rats. pCREB did not differ significantly among the groups. Conclusions. These results suggest that Xiaoyaosan exerts anxiolytic-like effects in behavioral tests and the effects may be related to CRF1R signaling in the amygdala.
doi:10.1155/2016/1238426
PMCID: PMC4793091  PMID: 27042185
16.  BDNF contributes to IBS-like colonic hypersensitivity via activating the enteroglia-nerve unit 
Scientific Reports  2016;6:20320.
The over-expressed colonic brain-derived neurotrophic factor (BDNF) has been reported to be associated with abdominal pain in patients with irritable bowel syndrome (IBS). However, the neuropathological mechanism is unclear. We here investigated the involvement of enteroglial cells (EGCs) and enteric nerves in IBS-like visceral hypersensitivity. We showed that glial fibrillary acidic protein (GFAP), tyrosine receptor kinase B (TrkB) and substance P (SP) were significantly increased in the colonic mucosa of IBS patients. The upregulation of those proteins was also observed in the colon of mice with visceral hypersensitivity, but not in the colon of BDNF+/− mice. Functionally, TrkB or EGC inhibitors, or BDNF knockdown significantly suppressed visceral hypersensitivity in mice. Using the EGC cell line, we found that recombinant human BDNF (r-HuBDNF) could directly activate EGCs via the TrkB-phospholipase Cγ1 pathway, thereby inducing a significant upregulation of SP. Moreover, supernatants from r-HuBDNF-activated EGC culture medium, rather than r-HuBDNF alone, triggered markedly augmented discharges in isolated intestinal mesenteric afferent nerves. r-HuBDNF alone could cause mesenteric afferent mechanical hypersensitivity independently, and this effect was synergistically enhanced by activated EGCs. We conclude that EGC-enteric nerve unit may be involved in IBS-like visceral hypersensitivity, and this process is likely initiated by BDNF-TrkB pathway activation.
doi:10.1038/srep20320
PMCID: PMC4738267  PMID: 26837784
17.  Identification of mountain-cultivated ginseng and cultivated ginseng using UPLC/oa-TOF MSE with a multivariate statistical sample-profiling strategy 
Journal of Ginseng Research  2015;40(4):344-350.
Background
Mountain-cultivated ginseng (MCG) and cultivated ginseng (CG) both belong to Panax ginseng and have similar ingredients. However, their pharmacological activities are different due to their significantly different growth environments.
Methods
An ultra-performance liquid chromatography/quadrupole time-of-flight mass spectrometry (UPLC-QTOF-MS/MS)-based approach was developed to distinguish MCG and CG. Multivariate statistical methods, such as principal component analysis and supervised orthogonal partial-least-squares discrimination analysis were used to select the influential components.
Results
Under optimized UPLC-QTOF-MS/MS conditions, 40 ginsenosides in both MCG and CG were unambiguously identified and tentatively assigned. The results showed that the characteristic components of CG and MCG included ginsenoside Ra3/isomer, gypenoside XVII, quinquenoside R1, ginsenoside Ra7, notoginsenoside Fe, ginsenoside Ra2, ginsenoside Rs6/Rs7, malonyl ginsenoside Rc, malonyl ginsenoside Rb1, malonyl ginsenoside Rb2, palmitoleic acid, and ethyl linoleate. The malony ginsenosides are abundant in CG, but higher levels of the minor ginsenosides were detected in MCG.
Conclusion
This is the first time that the differences between CG and MCG have been observed systematically at the chemical level. Our results suggested that using the identified characteristic components as chemical markers to identify different ginseng products is effective and viable.
doi:10.1016/j.jgr.2015.11.001
PMCID: PMC5052403  PMID: 27746686
cultivated ginseng; identification; mountain-cultivated ginseng; OPLS-DA; UPLC-QTOF-MS/MS
18.  Metabolite Profile of Cervicovaginal Fluids from Early Pregnancy Is Not Predictive of Spontaneous Preterm Birth 
In our study, we used a mass spectrometry-based metabolomic approach to search for biomarkers that may act as early indicators of spontaneous preterm birth (sPTB). Samples were selected as a nested case-control study from the Screening for Pregnancy Endpoints (SCOPE) biobank in Auckland, New Zealand. Cervicovaginal swabs were collected at 20 weeks from women who were originally assessed as being at low risk of sPTB. Samples were analysed using gas chromatography-mass spectrometry (GC-MS). Despite the low amount of biomass (16–23 mg), 112 compounds were detected. Statistical analysis showed no significant correlations with sPTB. Comparison of reported infection and plasma inflammatory markers from early pregnancy showed two inflammatory markers were correlated with reported infection, but no correlation with any compounds in the metabolite profile was observed. We hypothesise that the lack of biomarkers of sPTB in the cervicovaginal fluid metabolome is simply because it lacks such markers in early pregnancy. We propose alternative biofluids be investigated for markers of sPTB. Our results lead us to call for greater scrutiny of previously published metabolomic data relating to biomarkers of sPTB in cervicovaginal fluids, as the use of small, high risk, or late pregnancy cohorts may identify metabolite biomarkers that are irrelevant for predicting risk in normal populations.
doi:10.3390/ijms161126052
PMCID: PMC4661910  PMID: 26610472
metabolomics; cervicovaginal; biomarkers; spontaneous preterm birth
19.  The strength of a remorseful heart: psychological and neural basis of how apology emolliates reactive aggression and promotes forgiveness 
Frontiers in Psychology  2015;6:1611.
Apology from the offender facilitates forgiveness and thus has the power to restore a broken relationship. Here we showed that apology from the offender not only reduces the victim’s propensity to react aggressively but also alters the victim’s implicit attitude and neural responses toward the offender. We adopted an interpersonal competitive game which consisted of two phases. In the first, “passive” phase, participants were punished by high or low pain stimulation chosen by the opponents when losing a trial. During the break, participants received a note from each of the opponents, one apologizing and the other not. The second, “active” phase, involved a change of roles where participants could punish the two opponents after winning. Experiment 1 included an Implicit Association Test (IAT) in between the reception of notes and the second phase. Experiment 2 recorded participants’ brain potentials in the second phase. We found that participants reacted less aggressively toward the apologizing opponent than the non-apologizing opponent in the active phase. Moreover, female, but not male, participants responded faster in the IAT when positive and negative words were associated with the apologizing and the non-apologizing opponents, respectively, suggesting that female participants had enhanced implicit attitude toward the apologizing opponent. Furthermore, the late positive potential (LPP), a component in brain potentials associated with affective/motivational reactions, was larger when viewing the portrait of the apologizing than the non-apologizing opponent when participants subsequently selected low punishment. Additionally, the LPP elicited by the apologizing opponents’ portrait was larger in the female than in the male participants. These findings confirm the apology’s role in reducing reactive aggression and further reveal that this forgiveness process engages, at least in female, an enhancement of the victim’s implicit attitude and a prosocial motivational change toward the offender.
doi:10.3389/fpsyg.2015.01611
PMCID: PMC4621397  PMID: 26579005
apology; forgiveness; reactive aggression; Implicit Association Test; ERP; LPP
20.  A geminivirus-based guide RNA delivery system for CRISPR/Cas9 mediated plant genome editing 
Scientific Reports  2015;5:14926.
CRISPR/Cas has emerged as potent genome editing technology and has successfully been applied in many organisms, including several plant species. However, delivery of genome editing reagents remains a challenge in plants. Here, we report a virus-based guide RNA (gRNA) delivery system for CRISPR/Cas9 mediated plant genome editing (VIGE) that can be used to precisely target genome locations and cause mutations. VIGE is performed by using a modified Cabbage Leaf Curl virus (CaLCuV) vector to express gRNAs in stable transgenic plants expressing Cas9. DNA sequencing confirmed VIGE of endogenous NbPDS3 and NbIspH genes in non-inoculated leaves because CaLCuV can infect plants systemically. Moreover, VIGE of NbPDS3 and NbIspH in newly developed leaves caused photo-bleached phenotype. These results demonstrate that geminivirus-based VIGE could be a powerful tool in plant genome editing.
doi:10.1038/srep14926
PMCID: PMC4598821  PMID: 26450012
21.  HES-Mediated Repression of Pten in Caenorhabditis elegans 
G3: Genes|Genomes|Genetics  2015;5(12):2619-2628.
The hairy/enhancer-of-split (HES) group of transcription factors controls embryonic development, often by acting downstream of the Notch signaling pathway; however, little is known about postembryonic roles of these proteins. In Caenorhabditis elegans, the six proteins that make up the REF-1 family are considered to be HES orthologs that act in both Notch-dependent and Notch-independent pathways to regulate embryonic events. To further our understanding of how the REF-1 family works to coordinate postembryonic cellular events, we performed a functional characterization of the REF-1 family member, HLH-25. We show that, after embryogenesis, hlh-25 expression persists throughout every developmental stage, including dauer, into adulthood. Like animals that carry loss-of-function alleles in genes required for normal cell-cycle progression, the phenotypes of hlh-25 animals include reduced brood size, unfertilized oocytes, and abnormal gonad morphology. Using gene expression microarray, we show that the HLH-25 transcriptional network correlates with the phenotypes of hlh-25 animals and that the C. elegans Pten ortholog, daf-18, is one major hub in the network. Finally, we show that HLH-25 regulates C. elegans lifespan and dauer recovery, which correlates with a role in the transcriptional repression of daf-18 activity. Collectively, these data provide the first genetic evidence that HLH-25 may be a functional ortholog of mammalian HES1, which represses PTEN activity in mice and human cells.
doi:10.1534/g3.115.019463
PMCID: PMC4683635  PMID: 26438299
hairy/enhancer-of-split; dauer recovery; gonad morphology; unfertilized oocytes; gene expression microarray
22.  Luteolin Ameliorates Hypertensive Vascular Remodeling through Inhibiting the Proliferation and Migration of Vascular Smooth Muscle Cells 
Objectives. Preliminary researches showed that luteolin was used to treat hypertension. However, it is still unclear whether luteolin has effect on the hypertensive complication such as vascular remodeling. The present study was designed to investigate the effect of luteolin on the hypertensive vascular remodeling and its molecular mechanism. Method and Results. We evaluated the effect of luteolin on aorta thickening of hypertension in spontaneous hypertensive rats (SHRs) and found that luteolin could significantly decrease the blood pressure and media thickness of aorta in vivo. Luteolin could inhibit angiotensin II- (Ang II-) induced proliferation and migration of vascular smooth muscle cells (VSMCs). Dichlorofluorescein diacetate (DCFH-DA) staining result showed that luteolin reduced Ang II-stimulated ROS production in VSMCs. Furthermore, western blot and gelatin zymography results showed that luteolin treatment leaded to a decrease in ERK1/2, p-ERK1/2, p-p38, MMP2, and proliferating cell nuclear antigen (PCNA) protein level. Conclusion. These data support that luteolin can ameliorate hypertensive vascular remodeling by inhibiting the proliferation and migration of Ang II-induced VSMCs. Its mechanism is mediated by the regulation of MAPK signaling pathway and the production of ROS.
doi:10.1155/2015/364876
PMCID: PMC4606148  PMID: 26495010
23.  Functional significance of macrophages in pancreatic cancer biology 
Tumour Biology  2015;36(12):9119-9126.
Pancreatic ductal adenocarcinoma (PDA) is a lethal disease that is usually diagnosed at late stage with few effective therapies. Despite the rapid progress on the genomics and proteomics of the neoplastic cells, therapies that targeted the pancreatic cancer cells proved to be inefficient, which promoted the researchers to turn their attentions to the microenvironment. Currently, various studies had proposed the microenvironment to be a contributing factor for PDA and pervasive researches showed that macrophages within the malignancy correlate with the malignant phenotype of the disease and were reported to a new therapeutic target. Generally, the pro-tumoral effects of macrophages can be summarized as angiogenesis promotion, immunosuppression, matrix remodeling and so on. Hence, a comprehensive understanding of the biologic behaviors of macrophages and their critical role in PDA development may provide new directions for the managements of the lethal disease. In this review, we will summarize the recent advancements on macrophages as pivotal players in PDA biology and the current knowledge about anti-macrophages as a novel strategy against cancer, with the expectation that more efficient therapies will be developed in the near future.
doi:10.1007/s13277-015-4127-2
PMCID: PMC4689759  PMID: 26411672
PDA; Macrophages; Desmoplasia; Angiogenesis; CSCs
24.  P7C3 Neuroprotective Chemicals Function by Activating the Rate-limiting Enzyme in NAD Salvage 
Cell  2014;158(6):1324-1334.
SUMMARY
The P7C3 class of aminopropyl carbazole chemicals fosters the survival of neurons in a variety of rodent models of neurodegeneration or nerve cell injury. To uncover its mechanism of action, an active derivative of P7C3 was modified to contain both a benzophenone for photo-crosslinking and an alkyne for CLICK chemistry. This derivative was found to bind nicotinamide phosphoribosyltransferase (NAMPT), the rate limiting enzyme involved in the conversion of nicotinamide into nicotinamide adenine dinucleotide (NAD). Administration of active P7C3 chemicals to cells treated with doxorubicin, which induces NAD depletion, led to a rebound in intracellular levels of NAD and concomitant protection from doxorubicin-mediated toxicity. Active P7C3 variants likewise enhanced the activity of the purified NAMPT enzyme, providing further evidence that they act by increasing NAD levels through its NAMPT-mediated salvage.
doi:10.1016/j.cell.2014.07.040
PMCID: PMC4163014  PMID: 25215490
25.  Driving glioblastoma growth by alternative polyadenylation 
Cell Research  2014;24(9):1023-1024.
doi:10.1038/cr.2014.88
PMCID: PMC4152745  PMID: 24993033

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