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1.  Overexpression of parkin in rat nigrostriatal dopamine system protects against methamphetamine neurotoxicity 
Experimental neurology  2013;247:359-372.
Methamphetamine (METH) is a central nervous system psychostimulant with a high potential for abuse. At high doses, METH causes a selective degeneration of dopaminergic terminals in the striatum, sparing other striatal terminals and cell bodies. We previously detected a deficit in parkin after binge METH in rat striatal synaptosomes. Parkin is an ubiquitin-protein E3 ligase capable of protecting dopamine neurons from diverse cellular insults. Whether the deficit in parkin mediates the toxicity of METH and whether parkin can protect from toxicity of the drug is unknown. The present study investigated whether overexpression of parkin attenuates degeneration of striatal dopaminergic terminals exposed to binge METH. Parkin overexpression in rat nigrostriatal dopamine system was achieved by microinjection of adeno-associated viral transfer vector 2/6 encoding rat parkin (AAV2/6-parkin) into the substantia nigra pars compacta. The microinjections of AAV2/6-parkin dose-dependently increased parkin levels in both the substantia nigra pars compacta and striatum. The levels of dopamine synthesizing enzyme, tyrosine hydroxylase, remained at the control levels; therefore, tyrosine hydroxylase immunoreactivity was used as an index of dopaminergic terminal integrity. In METH-exposed rats, the increase in parkin levels attenuated METH-induced decreases in striatal tyrosine hydroxylase immunoreactivity in a dose-dependent manner, indicating that parkin can protect striatal dopaminergic terminals against METH neurotoxicity.
doi:10.1016/j.expneurol.2013.01.001
PMCID: PMC4321803  PMID: 23313192
methamphetamine; toxicity; parkin; neuroprotection; dopamine; striatum
2.  Complete genome sequence and transcriptomics analyses reveal pigment biosynthesis and regulatory mechanisms in an industrial strain, Monascus purpureus YY-1 
Scientific Reports  2015;5:8331.
Monascus has been used to produce natural colorants and food supplements for more than one thousand years, and approximately more than one billion people eat Monascus-fermented products during their daily life. In this study, using next-generation sequencing and optical mapping approaches, a 24.1-Mb complete genome of an industrial strain, Monascus purpureus YY-1, was obtained. This genome consists of eight chromosomes and 7,491 genes. Phylogenetic analysis at the genome level provides convincing evidence for the evolutionary position of M. purpureus. We provide the first comprehensive prediction of the biosynthetic pathway for Monascus pigment. Comparative genomic analyses show that the genome of M. purpureus is 13.6–40% smaller than those of closely related filamentous fungi and has undergone significant gene losses, most of which likely occurred during its specialized adaptation to starch-based foods. Comparative transcriptome analysis reveals that carbon starvation stress, resulting from the use of relatively low-quality carbon sources, contributes to the high yield of pigments by repressing central carbon metabolism and augmenting the acetyl-CoA pool. Our work provides important insights into the evolution of this economically important fungus and lays a foundation for future genetic manipulation and engineering of this strain.
doi:10.1038/srep08331
PMCID: PMC4321180  PMID: 25660389
3.  Assessing Cholesterol Storage in Live Cells and C. elegans by Stimulated Raman Scattering Imaging of Phenyl-Diyne Cholesterol 
Scientific Reports  2015;5:7930.
We report a cholesterol imaging method using rationally synthesized phenyl-diyne cholesterol (PhDY-Chol) and stimulated Raman scattering (SRS) microscope. The phenyl-diyne group is biologically inert and provides a Raman scattering cross section that is 88 times larger than the endogenous C = O stretching mode. SRS microscopy offers an imaging speed that is faster than spontaneous Raman microscopy by three orders of magnitude, and a detection sensitivity of 31 μM PhDY-Chol (~1,800 molecules in the excitation volume). Inside living CHO cells, PhDY-Chol mimics the behavior of cholesterol, including membrane incorporation and esterification. In a cellular model of Niemann-Pick type C disease, PhDY-Chol reflects the lysosomal accumulation of cholesterol, and shows relocation to lipid droplets after HPβCD treatment. In live C. elegans, PhDY-Chol mimics cholesterol uptake by intestinal cells and reflects cholesterol storage. Together, our work demonstrates an enabling platform for study of cholesterol storage and trafficking in living cells and vital organisms.
doi:10.1038/srep07930
PMCID: PMC4302291  PMID: 25608867
4.  PPARγ Upregulation Induced by Vagus Nerve Stimulation Exerts Anti-Inflammatory Effect in Cerebral Ischemia/Reperfusion Rats 
Background
It is well known that peroxisome proliferator-activated receptor gamma (PPARγ), a ligand-activated transcription factor, plays a protective role in anti-inflammatory responses in both acute and chronic central nerve system (CNS) insults. Emerging evidence in rats suggests that vagus nerve stimulation (VNS), while restraining inflammatory cytokine production in the peripheral nervous system, also exerts a significant CNS neuroprotective function against ischemic stroke injury. The aim of this study was to explore the role of PPARγ in VNS-mediated anti-inflammatory protection against ischemic stroke damage.
Material/Methods
Adult male Sprague-Dawley rats (total n=160) preconditioned through transfection with either PPARγ small interfering RNA (siRNA) or lentiviral vector without siRNA and surgically subjected to middle cerebral artery occlusion and reperfusion subsequently received VNS treatment at 30 min post-occlusion. The expression of PPARγ after VNS treatment was measured by real-time PCR and Western blotting, also supported by immunofluorescence staining. Subsequently, the neurological deficits scores, the infarct volume, and the brain histopathology were all evaluated. Additionally, the influence on the pro-inflammatory cytokines expression and neuro-immune cells activation was determined by ELISA and immunofluorescence staining.
Results
We found that VNS upregulated expression of PPARγ in ischemia penumbra, diminished the extent of ischemic infarct, alleviated neuronal injury, and suppressed pro-inflammatory cytokine expression and immune cell activation (P<0.05). However, rats with PPARγ silencing failed to manifest significant neuroprotection and anti-inflammatory effect induced by VNS treatment (p>0.05).
Conclusions
PPARγ may participate in the process by which VNS modulates the neuro-inflammatory response following ischemia/reperfusion in rats.
doi:10.12659/MSM.891407
PMCID: PMC4310716  PMID: 25619160
Cholinergic Fibers; Hypoxia-Ischemia, Brain; Peroxisome Proliferator-Activated Receptors; Vagus Nerve Stimulation
5.  Monochromatic energy computed tomography image for active intestinal hemorrhage: A model investigation 
AIM: To investigate the value of computed tomography (CT) spectral imaging in the evaluation of intestinal hemorrhage.
METHODS: Seven blood flow rates were simulated in vitro. Energy spectral CT and mixed-energy CT scans were performed for each rate (0.5, 0.4, 0.3, 0.2, 0.1, 0.05 and 0.025 mL/min). The detection rates and the contrast-to-noise ratios (CNRs) of the contrast agent extravasation regions were compared between the two scanning methods in the arterial phase (AP) and the portal venous phase (PVP). Comparisons of the CNR values between the PVP and the AP were made for each energy level and carried out using a completely random t test. A χ2 test was used to compare the detection rates obtained from the two scanning methods.
RESULTS: The total detection rates for energy spectral CT and mixed-energy CT in the AP were 88.57% (31/35) and 65.71% (23/35), respectively, and the difference was significant (χ2 = 5.185, P = 0.023); the total detection rates in the PVP were 100.00% (35/35) and 91.4% (32/35), respectively, and the difference was not significant (χ2 = 1.393, P = 0.238). In the AP, the CNR of the contrast agent extravasation regions was 3.58 ± 2.09 on the mixed-energy CT images, but the CNRs were 8.78 ± 7.21 and 8.83 ± 6.75 at 50 and 60 keV, respectively, on the single-energy CT images, which were significantly different (3.58 ± 2.09 vs 8.78 ± 7.21, P = 0.031; 3.58 ± 2.09 vs 8.83 ± 6.75, P = 0.029). In the PVP, the differences between the CNRs at 40, 50 and 60 keV different monochromatic energy levels and the polychromatic energy images were significant (19.35 ± 10.89 vs 11.68 ± 6.38, P = 0.010; 20.82 ± 11.26 vs 11.68 ± 6.38, P = 0.001; 20.63 ± 10.07 vs 11.68 ± 6.38, P = 0.001). The CNRs at the different energy levels in the AP and the PVP were significantly different (t = -2.415, -2.380, -2.575, -2.762, -2.945, -3.157, -3.996 and -3.189).
CONCLUSION: Monochromatic energy imaging spectral CT is superior to polychromatic energy images for the detection of intestinal hemorrhage, and the detection was easier in the PVP compared with the AP.
doi:10.3748/wjg.v21.i1.214
PMCID: PMC4284337  PMID: 25574093
Spectral imaging; Computed tomography; Monochromatic energy imaging; Small bowel bleeding
6.  Ryanodine receptor phosphorylation by oxidized CaMKII contributes to the cardiotoxic effects of cardiac glycosides 
Cardiovascular Research  2013;101(1):165-174.
Aims
Recent studies suggest that proarrhythmic effects of cardiac glycosides (CGs) on cardiomyocyte Ca2+ handling involve generation of reactive oxygen species (ROS). However, the specific pathway(s) of ROS production and the subsequent downstream molecular events that mediate CG-dependent arrhythmogenesis remain to be defined.
Methods and results
We examined the effects of digitoxin (DGT) on Ca2+ handling and ROS production in cardiomyocytes using a combination of pharmacological approaches and genetic mouse models. Myocytes isolated from mice deficient in NADPH oxidase type 2 (NOX2KO) and mice transgenically overexpressing mitochondrial superoxide dismutase displayed markedly increased tolerance to the proarrhythmic action of DGT as manifested by the inhibition of DGT-dependent ROS and spontaneous Ca2+ waves (SCW). Additionally, DGT-induced mitochondrial membrane potential depolarization was abolished in NOX2KO cells. DGT-dependent ROS was suppressed by the inhibition of PI3K, PKC, and the mitochondrial KATP channel, suggesting roles for these proteins, respectively, in activation of NOX2 and in mitochondrial ROS generation. Western blot analysis revealed increased levels of oxidized CaMKII in WT but not in NOX2KO hearts treated with DGT. The DGT-induced increase in SCW frequency was abolished in myocytes isolated from mice in which the Ser 2814 CaMKII phosphorylation site on RyR2 is constitutively inactivated.
Conclusion
These results suggest that the arrhythmogenic adverse effects of CGs on Ca2+ handling involve PI3K- and PKC-mediated stimulation of NOX2 and subsequent NOX2-dependent ROS release from the mitochondria; mitochondria-derived ROS then activate CaMKII with consequent phosphorylation of RyR2 at Ser 2814.
doi:10.1093/cvr/cvt233
PMCID: PMC3868350  PMID: 24104877
Calcium; Reactive oxygen species; NADPH oxidase; Mitochondria; CaMKII
7.  Silencing of HIV-1 gag gene from epidemic strains among men who have sex with men (MSM) in Tianjin, China by a broad-spectrum short hairpin RNA 
Virusdisease  2014;25(3):294-301.
RNA interference (RNAi) has been successfully used as a promising method to inhibit the replication of different viruses, including human immunodeficiency virus (HIV). Gene mutation is a hurdle for the anti-HIV by RNAi. Although prone to mutation, some genes are conserved and limited in functionally important regions. The gag gene is conserved in different subtypes and plays an important role in the assembly of HIV viral particle. Here, we identified subtypes and conserved sequences within forty-four gag genes from the epidemic strains among men who have sex with men. Three subtypes of gag gene, including CRF01_AE (47.7 %), CRF07_BC (40.9 %) and B (11.4 %) were analyzed by online blast. We designed five small hairpin RNAs (shRNAs) based on the conserved sequences. The gag–EGFP fusion transcript reporter system was used to select the most efficient shRNA. Among the five candidate shRNAs, gag-shRNA-3 represented a broad-spectrum inhibition against all chosen targets. This broad-spectrum shRNA diminished the titer of subtypes B and C of HIV-1 for a hundred orders of magnitude. The gag-shRNA-3 described here is a potential therapeutic agent in the HIV-1 gene therapy.
doi:10.1007/s13337-014-0209-9
PMCID: PMC4188215
HIV-1; MSM; gag; shRNA
8.  Gadd45b is a Novel Mediator of Neuronal Apoptosis in Ischemic Stroke 
Apoptosis plays an essential role in ischemic stroke pathogenesis. Research on the process of neuronal apoptosis in models of ischemic brain injury seems promising. The role of growth arrest and DNA-damage-inducible protein 45 beta (Gadd45b) in brain ischemia has not been fully examined to date. This study aims to investigate the function of Gadd45b in ischemia-induced apoptosis. Adult male Sprague-Dawley rats were subjected to brain ischemia by middle cerebral artery occlusion (MCAO). RNA interference (RNAi) system, which is mediated by a lentiviral vector (LV), was stereotaxically injected into the ipsilateral lateral ventricle to knockdown Gadd45b expression. Neurologic scores and infarct volumes were assessed 24 h after reperfusion. Apoptosis-related molecules were studied using immunohistochemistry and Western blot analysis. We found that Gadd45b-RNAi significantly increased infarct volumes and worsened the outcome of transient focal cerebral ischemia. Gadd45b-RNAi also significantly increased neuronal apoptosis as indicated by increased levels of Bax and active caspase-3, and decreased levels of Bcl-2. These results indicate that Gadd45b is a beneficial mediator of neuronal apoptosis.
doi:10.7150/ijbs.9813
PMCID: PMC4323375
MCAO; Gadd45b; BDNF; Apoptosis
9.  Fetal Growth Is Associated with Maternal Fasting Plasma Glucose at First Prenatal Visit 
PLoS ONE  2014;9(12):e116352.
Aims
Fasting plasma glucose (FPG) concentration measured at the first prenatal visit is a predictor of gestational diabetes mellitus (GDM); however, whether this test is indicative of fetal growth has not been clarified. Thus, the purpose of this study was to determine whether birth weight and birth length were related to FPG levels at the first prenatal visit.
Materials and Methods
Research samples were collected from pregnant women who took an FPG test at their first prenatal visit (10–24 gestational weeks), received regular prenatal care, and delivered in our center. FPG value, maternal pre-gravid BMI, weight gain before FPG test, before and after Oral Glucose Tolerance Test (OGTT), neonatal birthweight, birth length, Ponderal Index and birthing method were recorded for analysis. Data were analyzed by independent sample t test, Pearson correlation, and Chi-square test, followed by partial correlation or logistic regression to confirm differences. Statistical significance level was α = 0.05.
Results
2284 pregnant women, including 462 GDM and 1822 with normal glucose tolerance (NGT) were recruited for the present study. FPG concentration at the first prenatal visit was associated with neonatal birth weight (partial correlation coefficient r′ = 0.089, P<0.001) and birth length (partial correlation coefficient r′ = 0.061, P = 0.005), but not with Ponderal Index or birthing method. Maternal pre-gravid BMI was associated with FPG value (partial correlation coefficient r′ = 0.113, P<0.001). FPG concentration at the first prenatal visit (OR = 2.945, P<0.001), weight gain before OGTT test (OR = 1.039, P = 0.010), and age (OR = 1.107, P<0.001) were independent related factors of GDM.
Conclusion
Fasting plasma glucose concentration at the first prenatal visit is associated with fetal growth. Maternal pre-gravid BMI and weight gain are related to glucose metabolism.
doi:10.1371/journal.pone.0116352
PMCID: PMC4281143  PMID: 25551824
10.  SIRT1 protects against apoptosis by promoting autophagy in degenerative human disc nucleus pulposus cells 
Scientific Reports  2014;4:7456.
SIRT1 could protect degenerative human NP cells against apoptosis, and there were extensive and intimate connection between apoptosis and autophagy. Up to now, the role of autophagy in the process of human IVD degeneration is unclear. We sought to explore the relationship between autophagy and human IVD degeneration and to understand whether autophagy is involved in the protective effect of SIRT1 against apoptosis in NP cells. Our results showed that the autophagosomes number, the mRNA level of LC3 and Beclin-1, the protein expression of LC3-II/I and Beclin-1, decreased in NP from DDD. Resveratrol could increase the protein expression of LC3-II/I and Beclin-1, and reduce apoptosis in degenerative NP cells. In contrast, the protein levels of LC3-II/I and Beclin-1 were down-regulated and apoptosis level was significantly up-regulated in treatment with nicotinamide or SIRT1-siRNA transfection. Further analysis identified that the expression of cleaved Caspase3 and apoptosis incidence significantly increased with the pretreatment of bafilomycin A, whether resveratrol was added or not. These suggested that autophagy may play an important role in IVD degeneration, and SIRT1 protected degenerative human NP cells against apoptosis via promoting autophagy. These findings would aid in the development of novel therapeutic approaches for degenerative disc disease treatment.
doi:10.1038/srep07456
PMCID: PMC4264007  PMID: 25503852
11.  Plasma MicroRNAs as Potential Noninvasive Biomarkers for In-Stent Restenosis 
PLoS ONE  2014;9(11):e112043.
Objective
To investigate whether microRNAs (miRs) can serve as novel biomarkers for in-stent restenosis (ISR).
Methods
This retrospective, observational single-centre study was conducted at the cardiovascular department of a tertiary hospital centre in the north of China. Follow-up coronary angiography at 6 to 12 months was performed in 181 consecutive patients implanted with drug-eluting stents. Fifty-two healthy volunteers served as the control group. The plasma miRs levels were analyzed by quantitative real-time PCR. Receiver-operating characteristic curve (ROC) analysis was performed to investigate the characters of these miRs as potential biomarkers of ISR.
Results
MiR-21 levels in ISR patients were significantly higher than those in non-ISR patients and healthy controls (P<0.05), while miR-100 (P<0.05), miR-143 (P<0.001) and miR-145 (P<0.0001) levels were significantly decreased in ISR patients. Further analysis showed that miR-21 levels were remarkably increased (P = 0.045), while miR-100 (P = 0.041), miR-143 (P = 0.029) and miR-145 (P<0.01) levels were dramatically decreased in patients with diffuse ISR compared to those with focal ISR. ROC analysis demonstrated that the area under curve of miR-145, miR-143, miR-100 and miR-21 were 0.880 (95% confidence interval; CI = 0.791–0.987, P<0.001), 0.818 (95% confidence interval; CI = 0.755–0.963, P<0.001), 0.608 (95% confidence interval; CI = 0.372–0.757, P<0.05) and 0.568 (95% confidence interval; CI = 0.372–0.757, P<0.05), with specificity of 83.1%, 80.1%, 68.9% and 68.6%, and sensitivity of 88.7%, 82.1%, 60.2% and 50.1%, respectively.
Conclusions
Circulating miR-143 and miR-145 levels are associated with the occurrence of ISR and can serve as novel noninvasive biomarkers for ISR.
doi:10.1371/journal.pone.0112043
PMCID: PMC4245195  PMID: 25427155
12.  Human immunodeficiency virus-negative plasmablastic lymphoma in the neck: a rare case report and literature review 
Plasmablastic lymphoma (PBL) is an aggressive neoplasm exclusively occurring in AIDS patients. Recently, increasing cases of human immunodeficiency virus (HIV)-negative PBL have been reported. No standard therapy protocol is currently available since there is a great difference between PBL with and without HIV infection. Here, we present a rather rare case of HIV-negative PBL in the neck that dramatically responded to radiotherapy alone. Our case highlights the possibility of PBL in the neck and helps to expand our understanding of this separate lymphoma. The related literature review summarized the clinicopathological features and treatment status of HIV-negative PBL.
doi:10.1186/s40001-014-0064-6
PMCID: PMC4243291  PMID: 25416032
HIV-negative; Plasmablastic lymphoma; Radiotherapy
13.  Calretinin-positive L5a pyramidal neurons in the development of the paralemniscal pathway in the barrel cortex 
Molecular Brain  2014;7(1):84.
Background
The rodent barrel cortex has been established as an ideal model for studying the development and plasticity of a neuronal circuit. The barrel cortex consists of barrel and septa columns, which receive various input signals through distinct pathways. The lemniscal pathway transmits whisker-specific signals to homologous barrel columns, and the paralemniscal pathway transmits multi-whisker signals to both barrel and septa columns. The integration of information from both lemniscal and paralemniscal pathways in the barrel cortex is critical for precise object recognition. As the main target of the posterior medial nucleus (POm) in the paralemniscal pathway, layer 5a (L5a) pyramidal neurons are involved in both barrel and septa circuits and are considered an important site of information integration. However, information on L5a neurons is very limited. This study aims to explore the cellular features of L5a neurons and to provide a morphological basis for studying their roles in the development of the paralemniscal pathway and in information integration.
Results
1. We found that the calcium-binding protein calretinin (CR) is dynamically expressed in L5a excitatory pyramidal neurons of the barrel cortex, and L5a neurons form a unique serrated pattern similar to the distributions of their presynaptic POm axon terminals.
2. Infraorbital nerve transection disrupts this unique alignment, indicating that it is input dependent.
3. The formation of the L5a neuronal alignment develops synchronously with barrels, which suggests that the lemniscal and paralemniscal pathways may interact with each other to regulate pattern formation and refinement in the barrel cortex.
4. CR is specifically expressed in the paralemniscal pathway, and CR deletion disrupts the unique L5a neuronal pattern, which indicates that CR may be required for the development of the paralemniscal pathway.
Conclusions
Our results demonstrate that L5a neurons form a unique, input-dependent serrated alignment during the development of cortical barrels and that CR may play an important role in the development of the paralemniscal pathway. Our data provide a morphological basis for studying the role of L5a pyramidal neurons in information integration within the lemniscal and paralemniscal pathways.
doi:10.1186/s13041-014-0084-8
PMCID: PMC4246560  PMID: 25404384
Calretinin; L5a pyramidal neuron; Paralemniscal pathway; Posterior medial nucleus; Barrel cortex
14.  Erythrocyte Stiffness during Morphological Remodeling Induced by Carbon Ion Radiation 
PLoS ONE  2014;9(11):e112624.
The adverse effect induced by carbon ion radiation (CIR) is still an unavoidable hazard to the treatment object. Thus, evaluation of its adverse effects on the body is a critical problem with respect to radiation therapy. We aimed to investigate the change between the configuration and mechanical properties of erythrocytes induced by radiation and found differences in both the configuration and the mechanical properties with involving in morphological remodeling process. Syrian hamsters were subjected to whole-body irradiation with carbon ion beams (1, 2, 4, and 6 Gy) or X-rays (2, 4, 6, and 12 Gy) for 3, 14 and 28 days. Erythrocytes in peripheral blood and bone marrow were collected for cytomorphological analysis. The mechanical properties of the erythrocytes were determined using atomic force microscopy, and the expression of the cytoskeletal protein spectrin-α1 was analyzed via western blotting. The results showed that dynamic changes were evident in erythrocytes exposed to different doses of carbon ion beams compared with X-rays and the control (0 Gy). The magnitude of impairment of the cell number and cellular morphology manifested the subtle variation according to the irradiation dose. In particular, the differences in the size, shape and mechanical properties of the erythrocytes were well exhibited. Furthermore, immunoblot data showed that the expression of the cytoskeletal protein spectrin-α1 was changed after irradiation, and there was a common pattern among its substantive characteristics in the irradiated group. Based on these findings, the present study concluded that CIR could induce a change in mechanical properties during morphological remodeling of erythrocytes. According to the unique characteristics of the biomechanical categories, we deduce that changes in cytomorphology and mechanical properties can be measured to evaluate the adverse effects generated by tumor radiotherapy. Additionally, for the first time, the current study provides a new strategy for enhancing the assessment of the curative effects and safety of clinical radiotherapy, as well as reducing adverse effects.
doi:10.1371/journal.pone.0112624
PMCID: PMC4234377  PMID: 25401336
15.  Independent oncogenic and therapeutic significance of phosphatase PRL-3 in FLT3-ITD–negative acute myeloid leukemia 
Cancer  2014;120(14):2130-2141.
BACKGROUND
Internal tandem duplication of FMS-like tyrosine kinase (FLT3-ITD) is well known to be involved in acute myeloid leukemia (AML) progression, but FLT3-ITD–negative AML cases account for 70% to 80% of AML, and the mechanisms underlying their pathology remain unclear. This study identifies protein tyrosine phophatase PRL-3 as a key mediator of FLT3-ITD–negative AML.
METHODS
A total of 112 FLT3-ITD–negative AML patients were sampled between 2010 and 2013, and the occurrence of PRL-3 hyperexpression in FLT3-ITD–negative AML was evaluated by multivariate probit regression analysis. Overexpression or depletion of endogenous PRL-3 expression with the specific small interfering RNAs was performed to investigate the role of PRL-3 in AML progression. Xenograft models were also used to confirm the oncogenic role of PRL-3.
RESULTS
Compared to healthy donors, PRL-3 is upregulated more than 3-fold in 40.2% of FLT3-ITD–negative AML patients. PRL-3 expression level is adversely correlated to the overall survival of the AML patients, and the AML relapses accompany with re-upregulation of PRL-3. Mechanistically, aberrant PRL-3 expression promoted cell cycle progression and enhanced the antiapoptotic machinery of AML cells to drug cytotoxicity through downregulation of p21 and upregulation of Cyclin D1 and CDK2 and activation of STAT5 and AKT. Depletion of endogenous PRL-3 sensitizes AML cells to therapeutic drugs, concomitant with apoptosis by upregulation of cleaved PARP (poly ADP ribose polymerase) and apoptosis-related caspases. Xenograft assays further confirmed PRL-3’s oncogenic role in leukemogenesis.
CONCLUSIONS
Our results demonstrated that PRL-3 is a novel independent crucial player in both FLT3-ITD–positive and FLT3-ITD–negative AML and could be a potential therapeutic target. Cancer 2014;120:2130–2141. © 2014 The Authors. Cancer published by Wiley Periodicals, Inc. on behalf of American Cancer Society.
FLT3-ITD–negative acute myeloid leukemia (AML) accounts for up to approximately 70% to 80% of all cases. This study demonstrates that PRL-3, an independent driver in FLT3-ITD–negative AML, is adversely correlated to patient survival. Mechanistically, PRL-3 can promote AML cell cycle progression and render antiapoptosis features to AML cells, suggesting it could be an independent factor for AML diagnosis and therapy.
doi:10.1002/cncr.28668
PMCID: PMC4231236  PMID: 24737397
acute myeloid leukemia; PRL-3; FLT3-ITD–negative; apoptosis; drug resistance; cell proliferation
16.  Dihydromyricetin induces mouse hepatoma Hepal-6 cell apoptosis via the transforming growth factor-β pathway 
Molecular Medicine Reports  2014;11(3):1609-1614.
Dihydromyricetin (DHM) is a flavonoid compound which possesses potent antitumor activity. In the present study, it was demonstrated that DHM significantly inhibited proliferation and induced apoptosis in mouse hepatocellular carcinoma Hepal-6 cells. Transforming growth factor β (TGF-β) is recognized as a major profibrogenic cytokine and is therefore a common target for drugs in the treatment of liver disease. The present study aimed to investigate whether TGF-β was involved in DHM-triggered cell-viability inhibition and apoptosis induction. An MTT assay was used to evaluate the viability of Hepal-6 cells following DHM treatment. TGF-β signalling is mediated by Smads and nicotinamide adenine dinucleotide phosphate oxidase 4 (NOX4) is a crucial regulator of reactive oxygen species ROS production. TGF-β, Smad3, phosphorylated (p)-Smad2/3 and NOX4 protein expression levels were evaluated by western blot analysis. TGF-β and NOX4 gene expression levels were determined by quantitative polymerase chain reaction. The results indicated that DHM downregulated TGF-β, Smad3, p-Smad2/3 and NOX4 in a concentration-dependent manner. A cell counting assay indicated that DHM also inhibited Hepal-6 cell growth in a concentration-dependent manner. TGF-β expression was significantly decreased following DHM treatment. In conclusion, the results of the present study defined and supported a novel function for DHM, indicating that it induced cell apoptosis by downregulating ROS production via the TGF-β/Smad3 signaling pathway in mouse hepatocellular carcinoma Hepal-6 cells.
doi:10.3892/mmr.2014.2891
PMCID: PMC4270327  PMID: 25376731
dihydromyricetin; transforming growth factor-β; Smad3; NADPH oxidase 4; reactive oxygen species
17.  DCF intraperitoneal and intravenous dual chemotherapy regimen for advanced gastric cancer: A feasibility study 
Oncology Letters  2014;9(1):491-497.
Gastric cancer is the fourth most common type of cancer globally and accounts for the second highest cancer-associated mortality rate in the world. Current treatment strategies for gastric cancer include surgery, radiotherapy, chemotherapy and targeted therapy. Intraperitoneal (IP) chemotherapy may increase the IP concentrations of chemotherapy drugs and reduce the systemic toxicity. At present, IP chemotherapy is used to treat patients with advanced gastric cancer, which has a high rate of peritoneal recurrence. The present study evaluated the feasibility of using docetaxel, cisplatin and fluorouracil (DCF) in an IP and intravenous (IV) dual chemotherapy regimen for the treatment of advanced gastric cancer. The treatment-associated adverse reactions and preliminary efficacy were reported. The first dose level utilized the full dose of DCF: Docetaxel, day one, 45 mg/m2 (IP) and day eight, 30 mg/m2 (IV); cisplatin (DDP), day one, 75 mg/m2 (IP); and fluorouracil (FU), days one to five, 750 mg/m2 (continuous IV). A total of six patients were treated at this level and two patients withdrew due to serious adverse reactions. Taking into account that the the tolerated doses used in combination regimens for Eastern populations are lower than that of the corresponding doses for Western populations, the dosages of the three drugs were all reduced by 20% in the application of the second dose level: Docetaxel, day one, 30 mg/m2 (IP) and day eight, 30 mg/m2 (IV); DDP, day two, 60 mg/m2 (IP); and FU, days one to five, 600 mg/m2 (continuous IV). A total of 26 patients were treated at this level. The main adverse reaction was bone marrow suppression, with grade III/IV neutropenia, leukopenia and febrile neutropenia accounting for 61.5, 53.8 and 19.2% of reactions, respectively, and grade III/IV anemia and thrombocytopenia accounting for 19.2 and 15.4% of reactions, respectively. Gastrointestinal adverse reactions primarily consisted of abdominal pain, with grade III/IV abdominal pain accounting for 30.8% of reactions. Only 7.7% of the patients withdrew from the treatment. The median time to progression (TTP) was five months [95% confidence interval (CI), 1.0–9.0 months], and the median overall survival (OS) was nine months (95% CI, 7.4–10.6 months). It was concluded that the DCF regimen with reduced dosage should be applied. IP and IV dual chemotherapy for the treatment of unresectable advanced gastric cancer is tolerated and demonstrated a good initial efficacy. Strategies for mitigating and reducing the adverse gastrointestinal reactions, particularly abdominal pain, may be the focus of future studies.
doi:10.3892/ol.2014.2651
PMCID: PMC4246631  PMID: 25436015
gastric cancer; intraperitoneal chemotherapy; dual chemotherapy; docetaxel; cisplatin; fluorouracil
18.  Cassava genome from a wild ancestor to cultivated varieties 
Nature Communications  2014;5:5110.
Cassava is a major tropical food crop in the Euphorbiaceae family that has high carbohydrate production potential and adaptability to diverse environments. Here we present the draft genome sequences of a wild ancestor and a domesticated variety of cassava and comparative analyses with a partial inbred line. We identify 1,584 and 1,678 gene models specific to the wild and domesticated varieties, respectively, and discover high heterozygosity and millions of single-nucleotide variations. Our analyses reveal that genes involved in photosynthesis, starch accumulation and abiotic stresses have been positively selected, whereas those involved in cell wall biosynthesis and secondary metabolism, including cyanogenic glucoside formation, have been negatively selected in the cultivated varieties, reflecting the result of natural selection and domestication. Differences in microRNA genes and retrotransposon regulation could partly explain an increased carbon flux towards starch accumulation and reduced cyanogenic glucoside accumulation in domesticated cassava. These results may contribute to genetic improvement of cassava through better understanding of its biology.
Cassava is a major source of food in tropical and subtropical regions. Here the authors sequence the genomes of wild and domesticated cassava varieties and identify genes that have been selected for and against during the evolution and domestication of this economically important crop.
doi:10.1038/ncomms6110
PMCID: PMC4214410  PMID: 25300236
19.  Emerging Applications of Conjugated Polymers in Molecular Imaging 
In recent years, conjugated polymers have attracted considerable attention from the imaging community as a new class of contrast agent due to their intriguing structural, chemical, and optical properties. Their size and emission wavelength tunability, brightness, photostability, and low toxicity have been demonstrated in a wide range of in vitro sensing and cellular imaging applications, and have just begun to show impact in in vivo settings. In this Perspective, we summarize recent advances in engineering conjugated polymers as imaging contrast agents, their emerging applications in molecular imaging (referred to as in vivo uses in this paper), as well as our perspectives on future research.
doi:10.1039/c3cp51763b
PMCID: PMC3785565  PMID: 23860904
20.  Aberrant expression of Per1, Per2 and Per3 and their prognostic relevance in non-small cell lung cancer 
The objective of the current study was to investigate the expression pattern and clinicopathological significance of Period1 (Per1), Period2 (Per2) and Period3 (Per3) in patients with non-small cell lung cancer (NSCLC). In 130 archived NSCLC tissues, the positive rate of Per1 (86/130, 66.2%), Per2 (77/130, 59.2%) and Per3 (82/130, 63.1%) were reduced in human lung cancer samples compared with adjacent normal lung tissues (Per1, 119/130, 91.5%; Per2, 115/130, 88.5%; Per3, 121/130, 93.1%), as measured by immunohistochemical staining. Loss of Per1 was correlated with poor differentiation (P < 0.001), tumor status (P=0.04), high p-TNM stage (P < 0.001) and lymph node metastasis (P=0.045). The similar tendencies were also found in the correlation of the expression of Per2 and Per3 with clinicopathological factors. In addition, a significant correlation was found between Per1 and Per2 (P < 0.001) in 130 cases of NSCLC. Similarly, a significant correlation was found between Per2 and Per3 (P=0.045). Patients with lower expression of Per1, Per2 and Per3 had a shorter survival time than those with higher expression. These results indicate that loss of Per may promote tumor progression in NSCLC, and may serve as a novel prognostic biomarker of NSCLC.
PMCID: PMC4270614  PMID: 25550826
Period1; Period2; Period3; non-small cell lung cancer; immunohistochemistry; prognosis
21.  NK Cell Phenotypic Modulation in Lung Cancer Environment 
PLoS ONE  2014;9(10):e109976.
Background
Nature killer (NK) cells play an important role in anti-tumor immunotherapy. But it indicated that tumor cells impacted possibly on NK cell normal functions through some molecules mechanisms in tumor microenvironment.
Materials and methods
Our study analyzed the change about NK cells surface markers (NK cells receptors) through immunofluorescence, flow cytometry and real-time PCR, the killed function from mouse spleen NK cell and human high/low lung cancer cell line by co-culture. Furthermore we certificated the above result on the lung cancer model of SCID mouse.
Results
We showed that the infiltration of NK cells in tumor periphery was related with lung cancer patients' prognosis. And the number of NK cell infiltrating in lung cancer tissue is closely related to the pathological types, size of the primary cancer, smoking history and prognosis of the patients with lung cancer. The expression of NK cells inhibitor receptors increased remarkably in tumor micro-environment, in opposite, the expression of NK cells activated receptors decrease magnificently.
Conclusions
The survival time of lung cancer patient was positively related to NK cell infiltration degree in lung cancer. Thus, the down-regulation of NKG2D, Ly49I and the up-regulation of NKG2A may indicate immune tolerance mechanism and facilitate metastasis in tumor environment. Our research will offer more theory for clinical strategy about tumor immunotherapy.
doi:10.1371/journal.pone.0109976
PMCID: PMC4192363  PMID: 25299645
22.  Recurrent intrathoracic solitary fibrous tumor: Remarkable response to radiotherapy 
Annals of Thoracic Medicine  2014;9(4):245-247.
Solitary Fibrous Tumor of the Pleura (SFTP) is an uncommon neoplasm which grows slowly. For some cases, surgery is warranted. However, for unresectable ones, the standard strategy has not been established yet. We presented a rare case of recurrent malignant intrathoracic solitary fibrous tumor. It was impossible to resect the tumor. Radiotherapy alone achieved a significant improvement effect.
doi:10.4103/1817-1737.140142
PMCID: PMC4166074  PMID: 25276246
Radiotherapy; recurrent; solitary fibrous tumor of the pleura
23.  The Protective Effect of MicroRNA-320 on Left Ventricular Remodeling after Myocardial Ischemia-Reperfusion Injury in the Rat Model 
The primary objective of this study investigated the role of microRNA-320 (miR-320) on left ventricular remodeling in the rat model of myocardial ischemia-reperfusion (I/R) injury, and we intended to explore the myocardial mechanism of miR-320-mediated myocardium protection. We collected 120 male Wistar rats (240–280 g) in this study and then randomly divided them into three groups: (1) sham surgery group (sham group: n = 40); (2) ischemia-reperfusion model group (I/R group: n = 40); and (3) I/R model with antagomir-320 group (I/R + antagomir-320 group: n = 40). Value changes of heart function in transesophageal echocardiography were recorded at various time points (day 1, day 3, day 7, day 15 and day 30) after surgery in each group. Myocardial sections were stained with hematoxylin and eosin (H&E) and examined with optical microscope. The degree of myocardial fibrosis was assessed by Sirius Red staining. Terminal dUTP nick end-labeling (TUNEL) and qRT-PCR methods were used to measure the apoptosis rate and to determine the miR-320 expression levels in myocardial tissues. Transesophageal echocardiography showed that the values of left ventricular ejection fraction (LVEF), left ventricular fractional shortening (LVFS), left ventricular systolic pressure (LVSP) and ±dp/dtmax in the I/R group were obviously lower than those in the sham group, while the left ventricular end-diastolic pressure (LVEDP) value was higher than that in the sham group. The values of LVEF, LVFS, LVSP and ±dp/dtmax showed a gradual decrease in the I/R group, while the LVEDP value showed an up tendency along with the extension of reperfusion time. The H&E staining revealed that rat myocardial tissue in the I/R group presented extensive myocardial damage; for the I/R + antagomir-320 group, however, the degree of damage in myocardial cells was obviously better than that of the I/R group. The Sirius Red staining results showed that the degree of myocardial fibrosis in the I/R group was more severe along with the extension of the time of reperfusion. For the I/R + antagomir-320 group, the degree of myocardial fibrosis was less severe than that in the I/R group. Tissues samples in both the sham and I/R + antagomir-320 groups showed a lower apoptosis rate compared to I/R group. The qRT-PCR results indicated that miR-320 expression in the I/R group was significantly higher than that in both the sham and I/R + antagomir-320 groups. The expression level of miR-320 is significantly up-regulated in the rat model of myocardial I/R injury, and it may be implicated in the prevention of myocardial I/R injury-triggered left ventricular remodeling.
doi:10.3390/ijms151017442
PMCID: PMC4227171  PMID: 25268616
microRNA-320; myocardial ischemia-reperfusion injury; left ventricular remodeling
24.  Adaptive Evolution of the STRA6 Genes in Mammalian 
PLoS ONE  2014;9(9):e108388.
Stimulated by retinoic acid 6 (STRA6) is the receptor for retinol binding protein and is relevant for the transport of retinol to specific sites such as the eye. The adaptive evolution mechanism that vertebrates have occupied nearly every habitat available on earth and adopted various lifestyles associated with different light conditions and visual challenges, as well as their role in development and adaptation is thus far unknown. In this work, we have investigated different aspects of vertebrate STRA6 evolution and used molecular evolutionary analyses to detect evidence of vertebrate adaptation to the lightless habitat. Free-ratio model revealed significant rate shifts immediately after the species divergence. The amino acid sites detected to be under positive selection are within the extracellular loops of STRA6 protein. Branch-site model A test revealed that STRA6 has undergone positive selection in the different phyla of mammalian except for the branch of rodent. The results suggest that interactions between different light environments and host may be driving adaptive change in STRA6 by competition between species. In support of this, we found that altered functional constraints may take place at some amino acid residues after speciation. We suggest that STRA6 has undergone adaptive evolution in different branch of vertebrate relation to habitat environment.
doi:10.1371/journal.pone.0108388
PMCID: PMC4177561  PMID: 25251323
25.  Comparison of hand-sewn and stapled anastomoses in surgeries of gastrointestinal tumors based on clinical practice of China 
Background
There is a lack of studies comparing stapled suturing and hand-sewn suturing in the surgeries of gastrointestinal tumors based on the clinical practice of Chinese surgeons.
Methods
Data were retrospectively collected from 499 patients who underwent surgery to remove gastrointestinal tumors from January 2008 to December 2009. The patients were divided into two groups according to the method of digestive tract reconstruction: 296 patients received stapled suturing and 203 patients received hand-sewn suturing. The operation time, postoperative hospital stay, postoperative recovery and complications of the patients were evaluated and compared between the two groups.
Results
The stapling procedure took shorter operative time compared to the hand-sewn procedure for gastric carcinoma, colorectal cancer and esophageal carcinoma (P < 0.05). There was no significant difference between the two groups in postoperative hospital stay (P > 0.05). Patients receiving stapled suturing also showed shorter recovery for gastric cancer, colorectal cancer, and shorter time to recovery of normal gastrocolorectal motility compared with patients in the hand-sewn group (P < 0.05). However, there was no difference between the two groups in terms of normal time to commencing liquid diet for esophageal cancer patients (P > 0.05). We also found that the stapled procedure showed a lower incidence of anastomotic leakage, anastomotic hemorrhage and stump leakage in treating colorectal cancer or gastric carcinoma compared with the hand-sewn procedure (P < 0.05).
Conclusions
Application of the stapler in treating gastrointestinal tumors demonstrated better effects on patients in terms of surgical operation time, recovery time to normal functions, and occurrence of complications compared to hand-sewn anastomosis, especially in gastric carcinoma and colorectal cancer.
doi:10.1186/1477-7819-12-292
PMCID: PMC4194420  PMID: 25240386
Stapler; Gastrocolorectal tumor; Anastomosis; Surgery

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