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1.  Multigenerational exposure to dietary zearalenone (ZEA), an estrogenic mycotoxin, affects puberty and reproduction in female mice 
This study investigated potential cumulative effects of multiple pregnancy and multigenerational exposure to dietary ZEA (0, 0.8, 4, or 20 ppm) on female puberty and reproduction in C57BL/6J mice. Multiple pregnancies did not significantly affect litter size or offspring puberty. Significant effects were observed in 20 ppm ZEA-treated females: advanced puberty onset in F0, F1, and F2 generations; decreased implantation rate, pregnancy rate, and litter size, and increased pregnancy gap and gestation period in F1 and F2 generations; and reduced fertility index in F2 generation. F3 females from 0 and 20 ppm groups were split into 0 or 20 ppm ZEA diets at weaning, with advanced puberty onset seen in 0-20 and 20-20 groups and decreased implantation rate observed in 20-20 group. In summary, 20 ppm dietary ZEA advanced puberty onset without obvious cumulative effect and impaired fertility with multigenerational cumulative effect, which could be partially alleviated upon exposure cessation.
doi:10.1016/j.reprotox.2014.06.005
PMCID: PMC4137769  PMID: 24972337
Zearalenone; multipregnancy; multigeneration; vaginal opening; embryo implantation; litter size; female reproduction
2.  Multiple pathogenic proteins implicated in neuronopathic Gaucher disease mice 
Human Molecular Genetics  2014;23(15):3943-3957.
Gaucher disease, a prevalent lysosomal storage disease (LSD), is caused by insufficient activity of acid β-glucosidase (GCase) and the resultant glucosylceramide (GC)/glucosylsphingosine (GS) accumulation in visceral organs (Type 1) and the central nervous system (Types 2 and 3). Recent clinical and genetic studies implicate a pathogenic link between Gaucher and neurodegenerative diseases. The aggregation and inclusion bodies of α-synuclein with ubiquitin are present in the brains of Gaucher disease patients and mouse models. Indirect evidence of β-amyloid pathology promoting α-synuclein fibrillation supports these pathogenic proteins as a common feature in neurodegenerative diseases. Here, multiple proteins are implicated in the pathogenesis of chronic neuronopathic Gaucher disease (nGD). Immunohistochemical and biochemical analyses showed significant amounts of β-amyloid and amyloid precursor protein (APP) aggregates in the cortex, hippocampus, stratum and substantia nigra of the nGD mice. APP aggregates were in neuronal cells and colocalized with α-synuclein signals. A majority of APP co-localized with the mitochondrial markers TOM40 and Cox IV; a small portion co-localized with the autophagy proteins, P62/LC3, and the lysosomal marker, LAMP1. In cultured wild-type brain cortical neural cells, the GCase-irreversible inhibitor, conduritol B epoxide (CBE), reproduced the APP/α-synuclein aggregation and the accumulation of GC/GS. Ultrastructural studies showed numerous larger-sized and electron-dense mitochondria in nGD cerebral cortical neural cells. Significant reductions of mitochondrial adenosine triphosphate production and oxygen consumption (28–40%) were detected in nGD brains and in CBE-treated neural cells. These studies implicate defective GCase function and GC/GS accumulation as risk factors for mitochondrial dysfunction and the multi-proteinopathies (α-synuclein-, APP- and Aβ-aggregates) in nGD.
doi:10.1093/hmg/ddu105
PMCID: PMC4082362  PMID: 24599400
3.  Bevacizumab promotes venous thromboembolism through the induction of PAI-1 in a mouse xenograft model of human lung carcinoma 
Molecular Cancer  2015;14:140.
Background
An increased incidence of venous thromboembolism (VTE) is associated with anti-vascular endothelial growth factor (VEGF) treatment in cancer. However, the mechanism underlying this effect remains elusive. In this study, we examined the effect of bevacizumab, a humanized monoclonal antibody against VEGF-A, on VTE in a murine xenograft A549 cell tumor model.
Methods
Inferior vena cava stenosis model and FeCl3-induced saphenous vein thrombosis model were performed in a mouse xenograft models of human lung adenocarcinoma.
Results
We found that treatment with bevacizumab significantly increased the thrombotic response to inferior vena cava obstruction and femoral vein injury. Plasminogen activator inhibitor (PAI-1) expression in tumors, plasma, and thrombi was significantly increased by bevacizumab. However, bevacizumab did not enhance VTE in PAI-1-deficient mice, suggesting that PAI-1 is a major mediator of bevacizumab’s prothrombotic effect. VEGF inhibited expression of PAI-1 by A549 cells, and this effect was neutralized by bevacizumab, suggesting that bevacizumab increases PAI-1 expression in vivo by blocking the inhibitory effect of VEGF on PAI-1 expression by tumor cells. Pharmacological inhibition of PAI-1 with PAI-039 blocked bevacizumab-induced venous thrombosis.
Conclusion
Collectively, these findings indicate that PAI-1 plays a role in VTE associated with antiangiogenic therapy and the inhibition of PAI-1 shows efficacy as a therapeutic strategy for the prevention of bevacizumab-associated VTE.
doi:10.1186/s12943-015-0418-x
PMCID: PMC4517418  PMID: 26215730
Bevacizumab; Cancer; Plasminogen activator inhibitor 1; VEGF-A; Venous thromboembolism
4.  Effect of Local Basic Fibroblast Growth Factor and Vascular Endothelial Growth Factor on Subcutaneously Allotransplanted Ovarian Tissue in Ovariectomized Mice 
PLoS ONE  2015;10(7):e0134035.
Objective
One of the major obstacles to ovarian tissue preservation is delayed angiogenesis that leads follicles lost after transplantation. The aim of the present study was to investigate the effects of bFGF and VEGF on heterotopic transplanted ovarian tissue using a mouse model.
Methods
Female mice underwent bilateral ovariectomy. Ovarian tissues encapsulated by fibrin hydrogels were transplanted subcutaneously into recipient mice, in which ovarian hormonal cyclicity was absent. The fibrinogen solution was mixed with bFGF, VEGF, or a mixture of bFGF and VEGF. The grafts were recovered 21 days after transplantation. Follicle morphology and follicle numbers were observed by H&E staining. Blood vessels were observed in transplanted intra-ovarian tissue by CD31 antibody IHC staining. Daily vaginal cytology was performed to determine estrous cycle and functional restoration of transplanted ovarian tissue. Blood was collected weekly and serum FSH levels were measured with a radioimmunoassay kit. Apoptosis analysis was performed by anti-AC-3 staining and survivin mRNA expression.
Results
The number of primordial follicles and secondary follicles in the bFGF+VEGF group was significantly higher than in the control group. The vascular density in the bFGF+VEGF groups were significantly higher than in the bFGF and the VEGF groups; there was no significant difference between the bFGF and VEGF groups. Estrous cycle was earlier in the bFGF+VEGF group compared with the control group; all mice in this group restored ovarian function. Serum FSH levels in the bFGF+VEGF group were significantly lower than in the control group by day 14 post-transplantation. The AC-3-positive in control group was significantly higher compared with bFGF group and VEGF group, and in bFGF+VEGF group was significantly lower than bFGF group and VEGF group. Survivin mRNA expression in bFGF+VEGF group was significantly higher than control group.
Conclusion
The combination of bFGF and VEGF has beneficial effects on follicle survival, angiogenesis, and resumption of estrous cycles.
doi:10.1371/journal.pone.0134035
PMCID: PMC4514621  PMID: 26208097
5.  Mechanisms underlying probucol-induced hERG-channel deficiency 
The hERG gene encodes the pore-forming α-subunit of the rapidly activating delayed rectifier potassium channel (IKr), which is important for cardiac repolarization. Reduction of IhERG due to genetic mutations or drug interferences causes long QT syndrome, leading to life-threatening cardiac arrhythmias (torsades de pointes) or sudden death. Probucol is a cholesterol-lowering drug that could reduce hERG current by decreasing plasma membrane hERG protein expression and eventually cause long QT syndrome. Here, we investigated the mechanisms of probucol effects on IhERG and hERG-channel expression. Our data demonstrated that probucol reduces SGK1 expression, known as SGK isoform, in a concentration-dependent manner, resulting in downregulation of phosphorylated E3 ubiquitin ligase Nedd4-2 expression, but not the total level of Nedd4-2. As a result, the hERG protein reduces, due to the enhanced ubiquitination level. On the contrary, carbachol could enhance the phosphorylation level of Nedd4-2 as an alternative to SGK1, and thus rescue the ubiquitin-mediated degradation of hERG channels caused by probucol. These discoveries provide a novel mechanism of probucol-induced hERG-channel deficiency, and imply that carbachol or its analog may serve as potential therapeutic compounds for the handling of probucol cardiotoxicity.
doi:10.2147/DDDT.S86724
PMCID: PMC4516208  PMID: 26229434
long QT; hERG potassium channels; probucol; SGK1; Nedd4-2
6.  Gene Transcriptional and Metabolic Profile Changes in Mimetic Aging Mice Induced by D-Galactose 
PLoS ONE  2015;10(7):e0132088.
D-galactose injection has been shown to induce many changes in mice that represent accelerated aging. This mouse model has been widely used for pharmacological studies of anti-aging agents. The underlying mechanism of D-galactose induced aging remains unclear, however, it appears to relate to glucose and 1ipid metabolic disorders. Currently, there has yet to be a study that focuses on investigating gene expression changes in D-galactose aging mice. In this study, integrated analysis of gas chromatography/mass spectrometry-based metabonomics and gene expression profiles was used to investigate the changes in transcriptional and metabolic profiles in mimetic aging mice injected with D-galactose. Our findings demonstrated that 48 mRNAs were differentially expressed between control and D-galactose mice, and 51 potential biomarkers were identified at the metabolic level. The effects of D-galactose on aging could be attributed to glucose and 1ipid metabolic disorders, oxidative damage, accumulation of advanced glycation end products (AGEs), reduction in abnormal substance elimination, cell apoptosis, and insulin resistance.
doi:10.1371/journal.pone.0132088
PMCID: PMC4503422  PMID: 26176541
7.  Effect of red light on the development and quality of mammalian embryos 
Purpose
To assess irradiance and total energy dose from different microscopes during the in-vitro embryonic developmental cycle in mouse and pig and to evaluate its effect on embryonic development and quality in pig.
Method
Spectral scalar irradiance (380–1050 nm) was measured by a fiber-optic microsensor in the focal plane of a dissection microscope, an inverted microscope and a time-lapse incubation system. Furthermore, the effect of three different red light levels was tested in the time-lapse system on mouse zygotes for 5 days, and on porcine zona-intact and zona-free parthenogenetically activated (PA) embryos for 6 days.
Results
The time-lapse system used red light centered at 625 nm and with a lower irradiance level as compared to the white light irradiance levels on the dissection and inverted microscopes, which included more energetic radiation <550 nm. Even after 1000 times higher total energy dose of red light exposure in the time-lapse system, no significant difference was found neither in blastocyst development of mouse zygotes nor in blastocyst rates and total cell number of blastocysts of porcine PA embryos.
Conclusions
Our results indicate that red light (625 nm, 0.34 W/m2) used in the time-lapse incubation system does not decrease the development and quality of blastocysts in both mouse zygotes and porcine PA embryos (both zona-intact and zona-free).
doi:10.1007/s10815-014-0247-7
PMCID: PMC4096879  PMID: 24854483
Spectral irradiance; Microsensor; Dosimetry; Mouse; Pig; Time-lapse observation
8.  Altered regional activity and inter-regional functional connectivity in psychogenic non-epileptic seizures 
Scientific Reports  2015;5:11635.
Although various imaging studies have focused on detecting the cerebral function underlying psychogenic non-epileptic seizures (PNES), the nature of PNES remains poorly understood. In this study, we combined the resting state fMRI with fractional amplitude of low-frequency fluctuations (fALFF) and functional connectivity based on the seed voxel linear correlation approach to examine the alterations of regional and inter-regional network cerebral functions in PNES. A total of 20 healthy controls and 18 patients were enrolled. The PNES patients showed significantly increased fALFF mainly in the dorsolateral prefrontal cortex (DLPFC), parietal cortices, and motor areas, as well as decreased fALFF in the triangular inferior frontal gyrus. Thus, our results add to literature suggesting abnormalities of neural synchrony in PNES. Moreover, PNES exhibited widespread inter-regional neural network deficits, including increased (DLPFC, sensorimotor, and limbic system) and decreased (ventrolateral prefrontal cortex) connectivity, indicating that changes in the regional cerebral function are related to remote inter-regional network deficits. Correlation analysis results revealed that the connectivity between supplementary motor area and anterior cingulate cortex correlated with the PNES frequency, further suggesting the skewed integration of synchronous activity could predispose to the occurrence of PNES. Our findings provided novel evidence to investigate the pathophysiological mechanisms of PNES.
doi:10.1038/srep11635
PMCID: PMC4480007  PMID: 26109123
9.  Solubilisation of Phosphate and Micronutrients by Trichoderma harzianum and Its Relationship with the Promotion of Tomato Plant Growth 
PLoS ONE  2015;10(6):e0130081.
Trichoderma harzianum strain SQR-T037 is a biocontrol agent that has been shown to enhance the uptake of nutrients (macro- and microelements) by plants in fields. The objective of this study was to investigate the contribution of SQR-T037 to P and microelement (Fe, Mn, Cu and Zn) nutrition in tomato plants grown in soil and in hydroponic conditions. Inoculation with SQR-T037 significantly improved the biomass and nutrient uptake of tomato seedlings grown in a nutrient-limiting soil. So we investigated the capability of SQR-T037 to solubilise sparingly soluble minerals in vitro via four known mechanisms: acidification by organic acids, chelation by siderophores, redox by ferric reductase and hydrolysis by phytase. SQR-T037 was able to solubilise phytate, Fe2O3, CuO, and metallic Zn but not Ca3(PO4)2 or MnO2. Organic acids, including lactic acid, citric acid, tartaric acid and succinic acid, were detected by HPLC and LC/MS in two Trichoderma cultures. Additionally, we inoculated tomato seedlings with SQR-T037 using a hydroponic system with specific nutrient deficiencies (i.e., nutrient solutions deficient in P, Fe, Cu or Zn and supplemented with their corresponding solid minerals) to better study the effects of Trichoderma inoculation on plant growth and nutrition. Inoculated seedlings grown in Cu-deficient hydroponic conditions exhibited increases in dry plant biomass (92%) and Cu uptake (42%) relative to control plants. However, we did not observe a significant effect on seedling biomass in plants grown in the Fe- and Zn-deficient hydroponic conditions; by contrast, the biomass decreased by 82% in the P-deficient hydroponic condition. Thus, we demonstrated that Trichoderma SQR-T037 competed for P (phytate) and Zn with tomato seedlings by suppressing root development, releasing phytase and/or chelating minerals. The results of this study suggest that the induction of increased or suppressed plant growth occurs through the direct effect of T. harzianum on root development, in combination with indirect mechanisms, such as mineral solubilisation (including solubilisation via acidification, redox, chelation and hydrolysis).
doi:10.1371/journal.pone.0130081
PMCID: PMC4482446  PMID: 26110536
10.  Short-Term Sleep Deprivation Stimulates Hippocampal Neurogenesis in Rats Following Global Cerebral Ischemia/Reperfusion 
PLoS ONE  2015;10(6):e0125877.
Background
Sleep deprivation (SD) plays a complex role in central nervous system (CNS) diseases. Recent studies indicate that short-term SD can affect the extent of ischemic damage. The aim of this study was to investigate whether short-term SD could stimulate hippocampal neurogenesis in a rat model of global cerebral ischemia/reperfusion (GCIR).
Methods
One hundred Sprague-Dawley rats were randomly divided into Sham, GCIR and short-term SD groups based on different durations of SD; the short-term SD group was randomly divided into three subgroups: the GCIR+6hSD*3d-treated, GCIR+12hSD-treated and GCIR+12hSD*3d-treated groups. The GCIR rat model was induced via the bilateral occlusion of the common carotid arteries and hemorrhagic hypotension. The rats were sleep-deprived starting at 48 h following GCIR. A Morris water maze test was used to assess learning and memory ability; cell proliferation and differentiation were analyzed via 5-bromodeoxyuridine (BrdU) and neuron-specific enolase (NSE), respectively, at 14 and 28 d; the expression of hippocampal BDNF was measured after 7 d.
Results
The different durations of short-term SD designed in our experiment exhibited improvement in cognitive function as well as increased hippocampal BDNF expression. Additionally, the short-term SD groups also showed an increased number of BrdU- and BrdU/NSE-positive cells compared with the GCIR group. Of the three short-term SD groups, the GCIR+12hSD*3d-treated group experienced the most substantial beneficial effects.
Conclusions
Short-term SD, especially the GCIR+12hSD*3d-treated method, stimulates neurogenesis in the hippocampal dentate gyrus (DG) of rats that undergo GCIR, and BDNF may be an underlying mechanism in this process.
doi:10.1371/journal.pone.0125877
PMCID: PMC4454510  PMID: 26039740
11.  Effects of Radiation Therapy on Breast Epithelial Cells in BRCA1/2 Mutation Carriers 
Women carrying BRCA1 and BRCA2 mutations have significantly elevated risk of developing breast and ovarian cancers. BRCA1-associated breast cancer likely originates from progenitors of the luminal epithelial lineage. Recent studies indicate that radiation therapy (RT) for BRCA1 cancer patients is associated with lower incidence of developing subsequent ipsilateral breast cancer. In the current study, we analyzed tumor-free breast tissue procured via prophylactic bilateral mastectomy from three BRCA1 and one BRCA2 mutation carriers, who had been previously treated with RT for unilateral breast cancers. Freshly isolated breast cells from the irradiated and nonirradiated breast tissue of the same individuals were subjected to flow cytometry, using established cell-surface markers. Two out of the three BRCA1 carriers and one BRCA2 carrier exhibited significantly diminished luminal cell population in the irradiated breast versus the nonirradiated side. There was also RT-associated reduction in the colony-forming ability of the breast epithelial cells. Our finding suggests that prior RT could result in the depletion of the luminal epithelial compartment and thus reduced incidence of BRCA1/2-associated breast cancer.
doi:10.4137/BCBCR.S26774
PMCID: PMC4454133  PMID: 26052229
BRCA1/2; radiation therapy; luminal epithelial cells
12.  Mmu-miR-193 Is Involved in Embryo Implantation in Mouse Uterus by Regulating GRB7 Gene Expression 
Reproductive Sciences  2014;21(6):733-742.
Embryo implantation is a complicated process involving a series of endometrial changes that depend on differential gene expression. MicroRNAs (miRNAs) are important for regulation of gene expression. Previous studies have shown that miRNAs may participate in the regulation of gene expression during embryo implantation. To explore the role of endometrial miRNAs in early murine pregnancy, we used microarrays to investigate whether miRNAs were differentially expressed in the mouse endometrium on pregnancy day 4 (D4) and day 6 (D6). The results demonstrated that 17 miRNAs were upregulated and 18 were downregulated (>2-fold) in D6 endometria compared to D4. We identified that mmu-miR-193 exhibited the highest upregulation on D6, and the upregulation of mmu-miR-193 before embryo implantation could reduce the embryo implantation rate. Further, we demonstrated that mmu-miR-193 influenced embryo implantation by regulating growth factor receptor-bound protein 7 expression. In summary, our study suggests that mmu-miR-193 plays an important role in embryo implantation.
doi:10.1177/1933719113512535
PMCID: PMC4016725  PMID: 24336674
embryo implantation; microRNAs (miRNAs); mmu-miR-193; GRB7
13.  α-Mangostin inhibits hypoxia-driven ROS-induced PSC activation and pancreatic cancer cell invasion 
Cancer letters  2014;347(1):129-138.
Recent advances indicating a key role of microenvironment for tumor progression, we investigated the role of PSCs and hypoxia in pancreatic cancer aggressiveness, and examined the potential protective effect of α-mangostin on hypoxia-driven pancreatic cancer progression. Our data indicate that hypoxic PSCs exploit their oxidative stress due to hypoxia to secrete soluble factors favouring pancreatic cancer invasion. α-mangostin suppresses hypoxia-induced PSC activation and pancreatic cancer cell invasion through the inhibition of HIF-1α stabilization and GLI1 expression. Increased generation of hypoxic ROS is responsible for HIF-1α stabilization and GLI1 upregulation. Therefore, α-mangostin may be beneficial in preventing hypoxia-induced pancreatic cancer progression.
doi:10.1016/j.canlet.2014.02.003
PMCID: PMC4005872  PMID: 24513179
α-mangostin; PSC; hypoxia; ROS; pancreatic cancer
14.  Translational Initiation at a Non-AUG Start Codon for Human and Mouse Negative Elongation Factor-B 
PLoS ONE  2015;10(5):e0127422.
Negative elongation factor (NELF), a four-subunit protein complex in metazoan, plays an important role in regulating promoter-proximal pausing of RNA polymerase II (RNAPII). Genetic studies demonstrate that the B subunit of mouse NELF (NELF-B) is critical for embryonic development and homeostasis in adult tissue. We report here that both human and mouse NELF-B proteins are translated from a non-AUG codon upstream of the annotated AUG. This non-AUG codon sequence is conserved in mammalian NELF-B but not NELF-B orthologs of lower metazoan. The full-length and a truncated NELF-B that starts at the first AUG codon both interact with the other three NELF subunits. Furthermore, these two forms of NELF-B have a similar impact on the transcriptomics and proliferation of mouse embryonic fibroblasts. These results strongly suggest that additional amino acid sequence upstream of the annotated AUG is dispensable for the essential NELF function in supporting cell growth in vitro. The majority of mouse adult tissues surveyed express the full-length NELF-B protein, and some contain a truncated NELF-B protein with the same apparent size as the AUG-initiated version. This result raises the distinct possibility that translational initiation of mouse NELF-B is regulated in a tissue-dependent manner.
doi:10.1371/journal.pone.0127422
PMCID: PMC4444357  PMID: 26010750
15.  Compressive Optical Image Encryption 
Scientific Reports  2015;5:10374.
An optical image encryption technique based on compressive sensing using fully optical means has been proposed. An object image is first encrypted to a white-sense stationary noise pattern using a double random phase encoding (DRPE) method in a Mach-Zehnder interferometer. Then, the encrypted image is highly compressed to a signal using single-pixel compressive holographic imaging in the optical domain. At the receiving terminal, the encrypted image is reconstructed well via compressive sensing theory, and the original image can be decrypted with three reconstructed holograms and the correct keys. The numerical simulations show that the method is effective and suitable for optical image security transmission in future all-optical networks because of the ability of completely optical implementation and substantially smaller hologram data volume.
doi:10.1038/srep10374
PMCID: PMC4438618  PMID: 25992946
16.  A mechanism of leading-edge protrusion in the absence of Arp2/3 complex 
Molecular Biology of the Cell  2015;26(5):901-912.
In the absence of the Arp2/3 complex, fibroblast cells adopt a leading edge with filopodia-like protrusions (FLPs) and maintain an ability to move. In this study, it is proposed that formins are required for the extension of FLPs and myosin II concentrated in arc-like regions in between FLPs is required for coordinated advancement of these regions.
Cells employ protrusive leading edges to navigate and promote their migration in diverse physiological environments. Classical models of leading-edge protrusion rely on a treadmilling dendritic actin network that undergoes continuous assembly nucleated by the Arp2/3 complex, forming ruffling lamellipodia. Recent work demonstrated, however, that, in the absence of the Arp2/3 complex, fibroblast cells adopt a leading edge with filopodia-like protrusions (FLPs) and maintain an ability to move, albeit with altered responses to different environmental signals. We show that formin-family actin nucleators are required for the extension of FLPs but are insufficient to produce a continuous leading edge in fibroblasts lacking Arp2/3 complex. Myosin II is concentrated in arc-like regions of the leading edge in between FLPs, and its activity is required for coordinated advancement of these regions with formin-generated FLPs. We propose that actomyosin contraction acting against membrane tension advances the web of arcs between FLPs. Predictions of this model are verified experimentally. The dependence of myosin II in leading-edge advancement helps explain the previously reported defect in directional movement in the Arpc3-null fibroblasts. We provide further evidence that this defect is cell autonomous during chemotaxis.
doi:10.1091/mbc.E14-07-1250
PMCID: PMC4342026  PMID: 25568333
17.  Special suppressive role of miR-29b in HER2-positive breast cancer cells by targeting Stat3 
Objectives: MiR-29b has been reported to function as a tumor suppressor in a variety of cancers. However, its role in the regulation of breast cancer is controversial. Materials and methods: In this paper, we explored the expression of miR-29b in a cohort of 67 pairs of formalin-fixed paraffin-embedded specimens with detailed pathological and clinical characteristics, and further analyzed the effects of miR-29b on the malignant phenotype of HER-2-positive breast cancer cells and the relevant mechanisms involved. Results: We found that the miR-29b expression is negatively associated with HER-2 expression in breast cancer tissues. Moreover, overexpression of miR-29b induced a complex phenotype in HER-2-positive breast cancer cells, namely an inhibition of cell proliferation, block of G1/S phase transition, induction of cell apoptosis, suppression of cell invasion in vitro, as well as inhibition on tumor growth in vivo, indicating that miR-29b functions as a tumor suppressor in HER2-positive breast cancer cells. Further bioinformatic prediction suggested that oncogene Stat3, which is an up-stream regulator of HER-2, was a target gene of miR-29b in breast cancer cells. We have shown that knocking down of Stat3 attenuated the malignant phenotype of breast cancer cells similar to overexpression of miR-29b, while restore expression of Stat3 in HER-2-positive breast cancer cells partially abolished the suppressive effects of miR-29b. Conclusion: Collectively, our data suggest that miR-29b could reverse the malignant phenotype of HER-2-positvie breast cancer through, at least partially, targeting Stat3 signaling pathway.
PMCID: PMC4494139  PMID: 26175849
miR-29b; HER2; breast cancer; Stat3 signaling pathway
18.  Bone marrow-derived mesenchymal stem cell transplantation ameliorates oxidative stress and restores intestinal mucosal permeability in chemically induced colitis in mice 
Background: Ulcerative colitis (UC) can be viewed as an autoimmune disease. Bone marrow-derived mesenchymal stem cells (MSCs) with its regenerative, cellular multi-lineage and immunomodulatory abilities can influence the repair of damaged tissues in UC. This study investigated the effects of MSCs transplantation on the mice intestinal barrier in response to oxidative stress injury. Methods: Colitis was induced by daily consecutive administration of 5% dextran sulfate sodium (DSS) solution for 7 days. Male murine MSCs were isolated and transplanted into female mice via injection in the tail vein. Serum and colon specimens were collected at 12 h, 24 h, 3 d, 7 d and 14 d after injection. Serum levels of D-lactate (D-LAC), diamine oxidase (DAO), colonic levels of malondialdehyde (MDA) and superoxide dismutase (SOD) were quantified. The SRY protein of the male sex determinant gene expression and E-cadherin were also ascertained intracellularly. Results: Three days after receiving male MSCs transplantation, SRY protein expression was detected. The quantity increased on successive days. Serum levels of D-LAC and DAO, colonic MDA and SOD normalized in a shorter time period compared to controls (p<0.05). Not surprisingly, histological regeneration of tissue and E-cadherin expression in the colon of MSCs transplanted mice also occurred in a shorter time period than controls. Conclusions: Transplanted MSCs restored mucosal permeability, and minimized oxidative stress related injury.
PMCID: PMC4494140  PMID: 26175850
Mesenchymal stem cell; ulcerative colitis; intestinal barrier; cell transplantation; mice
19.  Chromosome microduplication in somatic cells decreases the genetic stability of human reprogrammed somatic cells and results in pluripotent stem cells 
Scientific Reports  2015;5:10114.
Human pluripotent stem cells, including cloned embryonic and induced pluripotent stem cells, offer a limitless cellular source for regenerative medicine. However, their derivation efficiency is limited, and a large proportion of cells are arrested during reprogramming. In the current study, we explored chromosome microdeletion/duplication in arrested and established reprogrammed cells. Our results show that aneuploidy induced by somatic cell nuclear transfer technology is a key factor in the developmental failure of cloned human embryos and primary colonies from implanted cloned blastocysts and that expression patterns of apoptosis-related genes are dynamically altered. Overall, ~20%–53% of arrested primary colonies in induced plurpotent stem cells displayed aneuploidy, and upregulation of P53 and Bax occurred in all arrested primary colonies. Interestingly, when somatic cells with pre-existing chromosomal mutations were used as donor cells, no cloned blastocysts were obtained, and additional chromosomal mutations were detected in the resulting iPS cells following long-term culture, which was not observed in the two iPS cell lines with normal karyotypes. In conclusion, aneuploidy induced by the reprogramming process restricts the derivation of pluripotent stem cells, and, more importantly, pre-existing chromosomal mutations enhance the risk of genome instability, which limits the clinical utility of these cells.
doi:10.1038/srep10114
PMCID: PMC4428033  PMID: 25965553
20.  Immune responses of ducks infected with duck Tembusu virus 
Duck Tembusu virus (DTMUV) can cause serious disease in ducks, characterized by reduced egg production. Although the virus has been isolated and detection methods developed, the host immune responses to DTMUV infection are unclear. Therefore, we systematically examined the expression of immune-related genes and the viral distribution in DTMUV-infected ducks, using quantitative real-time PCR. Our results show that DTMUV replicates quickly in many tissues early in infection, with the highest viral titers in the spleen 1 day after infection. Rig-1, Mda5, and Tlr3 are involved in the host immune response to DTMUV, and the expression of proinflammatory cytokines (Il-1β, –2, –6, Cxcl8) and antiviral proteins (Mx, Oas, etc.) are also upregulated early in infection. The expression of Il-6 increased most significantly in the tissues tested. The upregulation of Mhc-I was observed in the brain and spleen, but the expression of Mhc-II was upregulated in the brain and downregulated in the spleen. The expression of the interferons was also upregulated to different degrees in the spleen but that of the brain was various. Our study suggests that DTMUV replicates rapidly in various tissues and that the host immune responses are activated early in infection. However, the overexpression of cytokines may damage the host. These results extend our understanding of the immune responses of ducks to DTMUV infection, and provide insight into the pathogenesis of DTMUV attributable to host factors.
doi:10.3389/fmicb.2015.00425
PMCID: PMC4424876  PMID: 26005441
duck; DTMUV; host innate immune response; proinflammatory cytokines; antiviral proteins
21.  Integrated microRNA, mRNA, and protein expression profiling reveals microRNA regulatory networks in rat kidney treated with a carcinogenic dose of aristolochic acid 
BMC Genomics  2015;16(1):365.
Background
Aristolochic Acid (AA), a natural component of Aristolochia plants that is found in a variety of herbal remedies and health supplements, is classified as a Group 1 carcinogen by the International Agency for Research on Cancer. Given that microRNAs (miRNAs) are involved in cancer initiation and progression and their role remains unknown in AA-induced carcinogenesis, we examined genome-wide AA-induced dysregulation of miRNAs as well as the regulation of miRNAs on their target gene expression in rat kidney.
Results
We treated rats with 10 mg/kg AA and vehicle control for 12 weeks and eight kidney samples (4 for the treatment and 4 for the control) were used for examining miRNA and mRNA expression by deep sequencing, and protein expression by proteomics. AA treatment resulted in significant differential expression of miRNAs, mRNAs and proteins as measured by both principal component analysis (PCA) and hierarchical clustering analysis (HCA). Specially, 63 miRNAs (adjusted p value < 0.05 and fold change > 1.5), 6,794 mRNAs (adjusted p value < 0.05 and fold change > 2.0), and 800 proteins (fold change > 2.0) were significantly altered by AA treatment. The expression of 6 selected miRNAs was validated by quantitative real-time PCR analysis. Ingenuity Pathways Analysis (IPA) showed that cancer is the top network and disease associated with those dysregulated miRNAs. To further investigate the influence of miRNAs on kidney mRNA and protein expression, we combined proteomic and transcriptomic data in conjunction with miRNA target selection as confirmed and reported in miRTarBase. In addition to translational repression and transcriptional destabilization, we also found that miRNAs and their target genes were expressed in the same direction at levels of transcription (169) or translation (227). Furthermore, we identified that up-regulation of 13 oncogenic miRNAs was associated with translational activation of 45 out of 54 cancer-related targets.
Conclusions
Our findings suggest that dysregulated miRNA expression plays an important role in AA-induced carcinogenesis in rat kidney, and that the integrated approach of multiple profiling provides a new insight into a post-transcriptional regulation of miRNAs on their target repression and activation in a genome-wide scale.
Electronic supplementary material
The online version of this article (doi:10.1186/s12864-015-1516-2) contains supplementary material, which is available to authorized users.
doi:10.1186/s12864-015-1516-2
PMCID: PMC4456708  PMID: 25952319
Aristolochic acid; Carcinogenesis; Kidney tumor; microRNA; Proteomics; Deep-Sequencing; RNA array; Target prediction; Rat
22.  Association of Obesity and Circulating Adipose Stromal Cells Among Breast Cancer Survivors 
Molecular biology reports  2014;41(5):2907-2916.
A positive association of obesity with breast cancer incidence and mortality is well established. Recent reports indicate that adipose stromal cells (ASCs) play an important role in breast cancer development and progression by producing estrogens and tumor-promoting cytokines. Furthermore, circulating ASCs have been uniquely detected in obese individuals, which is likely due to increased tissue remodeling and cell mobilization. The number of circulating ASCs is even more prominent in obese patients with colon and prostate cancers, both of which are exacerbated by obesity. To determine whether a similar association exists for breast cancer, we collected blood samples from a cohort of breast cancer survivors and enumerated circulating ASCs by flow cytometry on the basis of the previously established ASC-associated immunophenotype (CD34+/CD31−/CD45−). We found significantly higher levels of circulating ASCs (p < 0.001) in breast cancer survivors with body mass index (BMI) ≥ 30 kg/m2 than their non-obese counterparts (BMI < 30). We also compared circulating ASCs before and after exercise of only the obese subjects enrolled in a 6-month individualized exercise program, but found no statistically significant difference, likely due to limited number of subjects in the study. Our findings suggest that circulating ASCs can serve as a potential biomarker for future studies of the impacts of obesity and physical activity on breast cancer recurrence and survival.
doi:10.1007/s11033-014-3146-1
PMCID: PMC4016178  PMID: 24458825
circulating adipose stromal cells (ASC); obesity; breast cancer; exercise
23.  Expression of PRMT5 correlates with malignant grade in gliomas and plays a pivotal role in tumor growth in vitro 
Journal of neuro-oncology  2014;118(1):61-72.
Protein arginine methyltransferase 5 (PRMT5) catalyzes the formation of ω-NG,N'G-symmetric dimethylarginine residues on histones as well as other proteins. These modifications play an important role in cell differentiation and tumor cell growth. However, the role of PRMT5 in human glioma cells has not been characterized. In this study, we assessed protein expression profiles of PRMT5 in control brain, WHO grade II astrocytomas, anaplastic astrocytomas, and glioblastoma multiforme (GBM) by immunohistochemistry. PRMT5 was low in glial cells in control brain tissues and low grade astrocytomas. Its expression increased in parallel with malignant progression, and was highly expressed in GBM. Knockdown of PRMT5 by small hairpin RNA caused alterations of p-ERK1/2 and significantly repressed the clonogenic potential and viability of glioma cells. These findings indicate that PRMT5 is a marker of malignant progression in glioma tumors and plays a pivotal role in tumor growth.
doi:10.1007/s11060-014-1419-0
PMCID: PMC4076054  PMID: 24664369
Diffuse astrocytoma; Anaplastic astrocytoma; Glioblastoma; PRMT5; ERK1/2
24.  Three-dimensional reconstructions of actin filaments capped by Arp2/3 complex 
European journal of cell biology  2014;93(0):179-183.
The primary function of Arp2/3 complex is the generation of free barbed ends by nucleating new filaments from the sides of pre-existing filaments. The pathway of branch formation is complex and involves nucleation promoting factors, actin monomers and nucleotides. A less prominent function of Arp2/3 complex is capping of actin filament pointed ends. Here we show, using electron microscopy, electron tomography, and image reconstruction of negatively-stained samples at ~2–3 nm resolution, that Arp2/3 complex bound to the pointed ends of actin filaments has a conformation similar to that in the branch junction with the Arps arranged in an actin-filament like configuration. This is direct evidence for the existence of two distinct activation pathways for Arp2/3 complex, one in the context of branch formation, one in the context of pointed-end capping, with essentially the same conformational end point.
doi:10.1016/j.ejcb.2014.01.003
PMCID: PMC4110117  PMID: 24552843
Cell motility; actin cytoskeleton; electron microscopy; image analysis; fitting
25.  Improving the Understanding of Pathogenesis of Human Papillomavirus 16 via Mapping Protein-Protein Interaction Network 
BioMed Research International  2015;2015:890381.
The human papillomavirus 16 (HPV16) has high risk to lead various cancers and afflictions, especially, the cervical cancer. Therefore, investigating the pathogenesis of HPV16 is very important for public health. Protein-protein interaction (PPI) network between HPV16 and human was used as a measure to improve our understanding of its pathogenesis. By adopting sequence and topological features, a support vector machine (SVM) model was built to predict new interactions between HPV16 and human proteins. All interactions were comprehensively investigated and analyzed. The analysis indicated that HPV16 enlarged its scope of influence by interacting with human proteins as much as possible. These interactions alter a broad array of cell cycle progression. Furthermore, not only was HPV16 highly prone to interact with hub proteins and bottleneck proteins, but also it could effectively affect a breadth of signaling pathways. In addition, we found that the HPV16 evolved into high carcinogenicity on the condition that its own reproduction had been ensured. Meanwhile, this work will contribute to providing potential new targets for antiviral therapeutics and help experimental research in the future.
doi:10.1155/2015/890381
PMCID: PMC4414230  PMID: 25961044

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