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1.  Signal Regulatory Protein-α Protects Against Cardiac Hypertrophy Via the Disruption of Toll-Like Receptor 4 Signaling 
Hypertension  2013;63(1):96-104.
Signal regulatory protein-α (SIRPA/SIRPα) is a transmembrane protein that is expressed in various tissues, including the heart. Previous studies have demonstrated that SIRPA is involved in multiple biological processes, including macrophage multinucleation, skeletal muscle differentiation, neuronal survival, protection against diabetes mellitus, and negative regulation of immune cells. However, the role of SIRPA in cardiac hypertrophy remains unknown. To examine the role of SIRPA in pathological cardiac hypertrophy, we used SIRPA knockout mice and transgenic mice that overexpressed mouse SIRPA in the heart. Cardiac hypertrophy was evaluated by echocardiographic, hemodynamic, pathological, and molecular analyses. We observed downregulation of SIRPA expression in dilated cardiomyopathy human hearts and in animal hearts after aortic banding surgery. Accordingly, SIRPA−/− mice displayed augmented cardiac hypertrophy, which was accompanied by increased cardiac fibrosis and reduced contractile function, as compared with SIRPA+/+ mice 4 weeks after aortic banding. In contrast, transgenic mice with the cardiac-specific SIRPA overexpression exhibited the opposite phenotype in response to pressure overload. Likewise, SIRPA protected against angiotensin II–induced cardiomyocyte hypertrophy in vitro. Mechanistically, we revealed that SIRPA-mediated protection during cardiac hypertrophy involved inhibition of the Toll-like receptor 4/nuclear factor-κB signaling axis. Furthermore, we demonstrated that the disruption of Toll-like receptor 4 rescued the adverse effects of SIRPA deficiency on pressure overload–triggered cardiac remodeling. Thus, our results identify that SIRPA plays a protective role in cardiac hypertrophy through negative regulation of the Toll-like receptor 4/nuclear factor-κB pathway.
doi:10.1161/HYPERTENSIONAHA.113.01506
PMCID: PMC4422401  PMID: 24101669
cardiomegaly; fibrosis; SIRPA protein; human; TLR4 receptor
2.  Synergistic Activity of Carfilzomib and Panobinostat in Multiple Myeloma Cells via Modulation of ROS Generation and ERK1/2 
BioMed Research International  2015;2015:459052.
Relapse of disease and subsequent resistance to established therapies remain as major challenges in the treatment of multiple myeloma (MM). New therapeutic options are needed for these extensively pretreated patients. To explore an optimized combinational therapy, interactions between the irreversible proteasome inhibitor carfilzomib exhibiting a well-tolerated side-effect profile and histone deacetylase inhibitor (HDACi) panobinostat (LBH589) were examined in MM cells. Coadministration of carfilzomib and LBH589 led to a synergistic inhibition of proliferation in MM cells. Further studies showed that the combined treatment synergistically increased mitochondrial injury, caspase activation, and apoptosis in MM cells. Lethality of the carfilzomib/LBH589 combination was associated with the reactive oxygen species (ROS) generation and ERK1/2 inactivation. In addition, the free radical scavenger N-acetylcysteine (NAC) could block carfilzomib and LBH589-induced oxidative stress and the subsequent apoptosis. Together, these findings argue that the strategy of combining carfilzomib and LBH589 warrants attention in MM.
doi:10.1155/2015/459052
PMCID: PMC4427084  PMID: 26000292
4.  Meteorological Variables and Bacillary Dysentery Cases in Changsha City, China 
This study aimed to investigate the association between meteorological-related risk factors and bacillary dysentery in a subtropical inland Chinese area: Changsha City. The cross-correlation analysis and the Autoregressive Integrated Moving Average with Exogenous Variables (ARIMAX) model were used to quantify the relationship between meteorological factors and the incidence of bacillary dysentery. Monthly mean temperature, mean relative humidity, mean air pressure, mean maximum temperature, and mean minimum temperature were significantly correlated with the number of bacillary dysentery cases with a 1-month lagged effect. The ARIMAX models suggested that a 1°C rise in mean temperature, mean maximum temperature, and mean minimum temperature might lead to 14.8%, 12.9%, and 15.5% increases in the incidence of bacillary dysentery disease, respectively. Temperature could be used as a forecast factor for the increase of bacillary dysentery in Changsha. More public health actions should be taken to prevent the increase of bacillary dysentery disease with consideration of local climate conditions, especially temperature.
doi:10.4269/ajtmh.13-0198
PMCID: PMC3973515  PMID: 24591435
5.  ZBRK1, a novel tumor suppressor, activates VHL gene transcription through formation of a complex with VHL and p300 in renal cancer 
Oncotarget  2015;6(9):6959-6976.
Inactivation or mutation of the VHL gene causes various tumors, including clear cell renal cell carcinoma (ccRCC). In the present study, we identified ZBRK1 as a novel VHL interacting protein by yeast two-hybrid screening, and found a single ZBRK1-binding site located in the VHL promoter region. Ectopic expression of ZBRK1 increases transcriptional activity of the VHL, whereas the depletion of endogenous ZBRK1 by shRNA leads to reduction of VHL expression. We also demonstrate that the inhibition of VEGF transcription by ZBRK1 overexpression is dependent on VHL/HIF pathway. Moreover, VHL is confirmed to serve as a bridge component for the association of ZBRK1 and p300, which leads to an increase in ZBRK1 transcriptional activity in the VHL promoter. We further provide striking evidences that ZBRK1 acts as a tumor suppressor in renal carcinoma by a variety of in vitro and in vivo assays, and ZBRK1 may represent a molecular marker to distinguish patients with ccRCC at high risk from those with a better survival prognosis. Taken together, these findings suggest that ZBRK1 suppresses renal cancer progression perhaps by regulating VHL expression.
PMCID: PMC4466662  PMID: 25749518
ZBRK1; VHL; p300; renal cancer; tumor suppressor
6.  miR-191 promotes tumorigenesis of human colorectal cancer through targeting C/EBPβ 
Oncotarget  2014;6(6):4144-4158.
MicroRNA-191 (miR-191), a small non-coding RNA, is involved in disease development and cancer diagnosis and prognosis. However, how miR-191 functions in colorectal cancer remains largely unclear. In this study, we show that miR-191 is highly expressed in colon tumor tissues, and that inhibition of miR-191 leads to decreased cell growth, proliferation and tumorigenicity in a xenograft model. Overexpression of miR-191 in colorectal cancer cell lines alters cell cycle progression and cell resistance to 5-Fu induced cell apoptosis. Mechanistic studies demonstrated that miR-191 directly binds to the 3′UTR of the C/EBPβ mRNA and mediates a decrease in the mRNA and protein expression of C/EBPβ. We further showed that C/EBPβ induces growth arrest in a colorectal cancer cell line and that its expression is negatively correlated with the miR-191 level in patient samples. Our findings suggest that miR-191 may be a potential gene therapy target for the treatment of colorectal cancer.
PMCID: PMC4414178  PMID: 25784653
microRNA-191; colorectal cancer; apoptosis; C/EBPβ; tumorigenesis
7.  Influenza Surveillance and Incidence in a Rural Area in China during the 2009/2010 Influenza Pandemic 
PLoS ONE  2014;9(12):e115347.
Background
Most influenza surveillance is based on data from urban sentinel hospitals; little is known about influenza activity in rural communities. We conducted influenza surveillance in a rural region of China with the aim of detecting influenza activity in the 2009/2010 influenza season.
Methods
The study was conducted from October 2009 to March 2010. Real-time polymerase chain reaction was used to confirm influenza cases. Over-the-counter (OTC) drug sales were daily collected in drugstores and hospitals/clinics. Space-time scan statistics were used to identify clusters of ILI in community. The incidence rate of ILI/influenza was estimated on the basis of the number of ILI/influenza cases detected by the hospitals/clinics.
Results
A total of 434 ILI cases (3.88% of all consultations) were reported; 64.71% of these cases were influenza A (H1N1) pdm09. The estimated incidence rate of ILI and influenza were 5.19/100 and 0.40/100, respectively. The numbers of ILI cases and OTC drug purchases in the previous 7 days were strongly correlated (Spearman rank correlation coefficient [r] = 0.620, P = 0.001). Four ILI outbreaks were detected by space-time permutation analysis.
Conclusions
This rural community surveillance detected influenza A (H1N1) pdm09 activity and outbreaks in the 2009/2010 influenza season and enabled estimation of the incidence rate of influenza. It also provides a scientific data for public health measures.
doi:10.1371/journal.pone.0115347
PMCID: PMC4277345  PMID: 25542003
8.  Interferon regulatory factor 9 is critical for neointima formation following vascular injury 
Nature Communications  2014;5:5160.
Interferon regulatory factor 9 (IRF9) has various biological functions and regulates cell survival; however, its role in vascular biology has not been explored. Here we demonstrate a critical role for IRF9 in mediating neointima formation following vascular injury. Notably, in mice, IRF9 ablation inhibits the proliferation and migration of vascular smooth muscle cells (VSMCs) and attenuates intimal thickening in response to injury, whereas IRF9 gain-of-function promotes VSMC proliferation and migration, which aggravates arterial narrowing. Mechanistically, we show that the transcription of the neointima formation modulator SIRT1 is directly inhibited by IRF9. Importantly, genetic manipulation of SIRT1 in smooth muscle cells or pharmacological modulation of SIRT1 activity largely reverses the neointima-forming effect of IRF9. Together, our findings suggest that IRF9 is a vascular injury-response molecule that promotes VSMC proliferation and implicate a hitherto unrecognized ‘IRF9–SIRT1 axis’ in vasculoproliferative pathology modulation.
Blood vessels respond to injury by thickening the supportive smooth muscle layer in a process known as neointima formation. Here the authors describe a novel regulatory pathway of neointima formation that involves a transcription factor, Interferon Regulating Factor 9, and its downstream target, the deacetylase SIRT1.
doi:10.1038/ncomms6160
PMCID: PMC4218966  PMID: 25319116
9.  Role of distinct surfaces of the G9a ankyrin repeat domain in histone and DNA methylation during embryonic stem cell self-renewal and differentiation 
Background
Epigenetic modifications such as histone and DNA methylation are essential for silencing pluripotency genes during embryonic stem cell (ESC) differentiation. G9a is the major histone H3 Lys9 (H3K9) methyltransferase in euchromatin and is required for the de novo DNA methylation of the key regulator of pluripotency Oct3/4 during ESC differentiation. Surprisingly, the catalytic activity of G9a is not required for its role in de novo DNA methylation and the precise molecular mechanisms of G9a in this process are poorly understood. It has been suggested that the G9a ankyrin repeat domain, which can interact with both H3K9me2 and the DNA methyltransferase DNMT3A, could facilitate de novo DNA methylation by bridging the interaction between DNMT3A and H3K9me2-marked chromatin.
Results
Here, we demonstrate that the G9a ankyrin domain H3K9me2-binding function is not required for the de novo DNA methylation of Oct3/4 during ESC differentiation. Moreover, we show that the interaction between the G9a ankyrin domain and DNMT3A is not sufficient to ensure efficient de novo DNA methylation. More importantly, we characterize a specific residue of the G9a ankyrin domain (Asp905) that is critical for both maintaining cellular H3K9me2 levels in undifferentiated ESCs and for the establishment of de novo DNA methylation during differentiation.
Conclusions
These results represent an exciting breakthrough, which reveals 1) an unexpected critical biological function of the G9a ankyrin domain in global histone H3K9 methylation and 2) valuable insights into the molecular mechanisms and interaction surfaces through which G9a regulates de novo DNA methylation of Oct3/4 during ESC differentiation.
doi:10.1186/1756-8935-7-27
PMCID: PMC4255711  PMID: 25478012
Histone methylation; DNA methylation; Embryonic stem cell; G9a; Ankyrin; H3K9; DNMT3A; Oct3/4
10.  Early versus Deferred Treatment for Smoldering Multiple Myeloma: A Meta-Analysis of Randomized, Controlled Trials 
PLoS ONE  2014;9(10):e109758.
Purpose
Whether patients with smoldering multiple myeloma (SMM) needed to receive early interventional treatment remains controversial. Herein, we conducted a meta-analysis comparing the efficacy and safety of early treatment over deferred treatment for patients with SMM.
Methods
MEDLINE and Cochrane Library were searched to May 2014 for randomized controlled trials (RCTs) that assessed the effect of early treatment over deferred treatment. Primary outcome measure was mortality, and secondary outcome measures were progression, response rate, and adverse events.
Results
Overall, 5 trials including 449 patients were identified. There was a markedly reduced risk of disease progression with early treatment (Odds Ratio [OR] = 0.13, 95% confidence interval [CI] = 0.07 to 0.24). There were no significant differences in mortality and response rate (OR = 0.85, 95% CI = 0.45 to 1.60, and OR = 0.63, 95% CI = 0.32 to 1.23, respectively). More patients in the early treatment arm experienced gastrointestinal toxicities (OR = 10.02, 95%CI = 4.32 to 23.23), constipation (OR = 8.58, 95%CI = 3.20 to 23.00) and fatigue or asthenia (OR = 2.72, 95%CI = 1.30 to 5.67). No significant differences were seen with the development of acute leukemia (OR = 2.80, 95%CI = 0.42 to 18.81), hematologic cancer (OR = 2.07, 95%CI = 0.43 to 10.01), second primary tumors (OR = 3.45, 95%CI = 0.81 to 14.68), nor vertebral compression (OR = 0.18, 95%CI = 0.02 to 1.59).
Conclusions
Early treatment delayed disease progression but increased the risk of gastrointestinal toxicities, constipation and fatigue or asthenia. The differences on vertebral compression, acute leukemia, hematological cancer and second primary tumors were not statistically significant. Based on the current evidence, early treatment didn’t significantly affect mortality and response rate. However, further much larger trials were needed to provide more evidence.
doi:10.1371/journal.pone.0109758
PMCID: PMC4184905  PMID: 25279718
11.  Interferon Regulatory Factor 7 Protects Against Vascular Smooth Muscle Cell Proliferation and Neointima Formation 
Background
Interferon regulatory factor 7 (IRF7), a member of the interferon regulatory factor family, plays important roles in innate immunity and immune cell differentiation. However, the role of IRF7 in neointima formation is currently unknown.
Methods and Results
Significant decreases in IRF7 expression were observed in vascular smooth muscle cells (VSMCs) following carotid artery injury in vivo and platelet‐derived growth factor‐BB (PDGF‐BB) stimulation in vitro. Compared with non‐transgenic (NTG) controls, SMC‐specific IRF7 transgenic (IRF7‐TG) mice displayed reduced neointima formation and VSMC proliferation in response to carotid injury, whereas a global knockout of IRF7 (IRF7‐KO) resulted in the opposite effect. Notably, a novel IRF7‐KO rat strain was successfully generated and used to further confirm the effects of IRF7 deletion on the acceleration of intimal hyperplasia based on a balloon injury‐induced vascular lesion model. Mechanistically, IRF7's inhibition of carotid thickening and the expression of VSMC proliferation markers was dependent on the interaction of IRF7 with activating transcription factor 3 (ATF3) and its downstream target, proliferating cell nuclear antigen (PCNA). The evidence that IRF7/ATF3‐double‐TG (DTG) and IRF7/ATF3‐double‐KO (DKO) mice abolished the regulatory effects exhibited by the IRF7‐TG and IRF7‐KO mice, respectively, validated the underlying molecular events of IRF7‐ATF3 interaction.
Conclusions
These findings demonstrated that IRF7 modulated VSMC proliferation and neointima formation by interacting with ATF3, thereby inhibiting the ATF3‐mediated induction of PCNA transcription. The results of this study indicate that IRF7 is a novel modulator of neointima formation and VSMC proliferation and may represent a promising target for vascular disease therapy.
doi:10.1161/JAHA.114.001309
PMCID: PMC4323813  PMID: 25304854
ATF3; IRF7; neointima formation; proliferation
12.  Proliferative ductular reactions correlate with hepatic progenitor cell and predict recurrence in HCC patients after curative resection 
Cell & Bioscience  2014;4:50.
Background
Ductular reactions (DRs) are well documented in many acute and chronic liver disease.The DRs are thought to be the transit amplifying cells deriving from activation of the stem/progenitor cell compartments of the liver. The aim of this study was to examine the presence of proliferative index of DR (PI-DR) and HPC markers’ expression in HCCs after curative hepatectomy, as well as their relationship with clinicopathological features and prognosis.
Results
Tissue microarray with peritumoral and intratumoral tissue samples of 120 HCCs after hepatectomy was analysed for peritumoral expression of proliferating cell nuclear antigen for PI-DR. Peritumoral and intratumoral expression status of HPC markers including EpCAM, OV6, CD133 and c-kit were also examined by immunohistochemistry. TMA analysis of HCCs revealed that peritumoral PI-DR strongly correlated with the degree of inflammation and fibrosis. The peritumoral PI-DR positively correlated with peritumoral HPC markers EpCAM, OV6, CD133 and c-kit expression. Moreover, there were highly significant correlations between peritumoral PI-DR and intratumoral HPC markers EpCAM, OV6, CD133 and c-kit expression. Further, multivariate analysis showed that peritumoral PI-DR was the independent prognostic factor for overall survival (HR; 3.316, P < 0.001), and peritumoral PI-DR had a better power to predict disease-free survival (HR; 2.618, P < 0.001).
Conclusions
Peritumoral PI-DR, as a valid surrogate for peritumoral and intratumoral expression of HPC markers, could be served as a potential prognostic marker for recurrence and survival in HCC after hepatectomy.
doi:10.1186/2045-3701-4-50
PMCID: PMC4156622  PMID: 25197550
Proliferative index of ductular reaction; Hepatic progenitor cell; Recurrence; Hepatocellular carcinoma
13.  Activation of autophagy protects against cholestasis-induced hepatic injury 
Cell & Bioscience  2014;4:47.
Background
Cholestasis is characterized by an abnormal accumulation of bile acids and causes hepatocellular injury. Recent studies show that autophagy is involved in the pathophysiology of many liver diseases. The potential role of autophagy in preventing cholestatic hepatotoxicity, however, has rarely been investigated. The aim of this study was to examine whether autophagy is involved in the cholestatic hepatotoxicity.
Results
We found that bile duct ligation (BDL) led to cholestatic liver injury and hepatocytic autophagy activation in the mice. Suppression of autophagy with Chloroquine (CQ) increased liver injury and hepatocytes apoptosis; while activation of autophagy by rapamycin reduced cholestasis hepatotoxicity. In L02 normal liver cells, Glycochenodeoxycholate (GCDC) treatment would induce autophagy. Inhibition of autophagy by CQ could promote GCDC-induced cell apoptosis. In contrast, rapamycin treatment could protect against GCDC-induced cell death. Furthermore, autophagy contributed to the liver cells survival via modulation of reactive oxygen species (ROS).
Conclusions
These findings indicate that autophagy protects against cholestasis induced liver injury and hepatocyte apoptosis by eliminating ROS accumulation. Our data suggest that enhancement of autophagy may be a therapeutic strategy to mitigate cholestatic liver injury.
doi:10.1186/2045-3701-4-47
PMCID: PMC4412295  PMID: 25922659
Autophagy; Bile acid; Cholestasis; Hepatocyte; Reactive oxygen species
14.  Interferon Regulatory Factor 8 Modulates Phenotypic Switching of Smooth Muscle Cells by Regulating the Activity of Myocardin 
Molecular and Cellular Biology  2014;34(3):400-414.
Interferon regulatory factor 8 (IRF8), a member of the IRF transcription factor family, was recently implicated in vascular diseases. In the present study, using the mouse left carotid artery wire injury model, we unexpectedly observed that the expression of IRF8 was greatly enhanced in smooth muscle cells (SMCs) by injury. Compared with the wild-type controls, IRF8 global knockout mice exhibited reduced neointimal lesions and maintained SMC marker gene expression. We further generated SMC-specific IRF8 transgenic mice using an SM22α-driven IRF8 plasmid construct. In contrast to the knockout mice, mice with SMC-overexpressing IRF8 exhibited a synthetic phenotype and enhanced neointima formation. Mechanistically, IRF8 inhibited SMC marker gene expression through regulating serum response factor (SRF) transactivation in a myocardin-dependent manner. Furthermore, a coimmunoprecipitation assay indicated a direct interaction of IRF8 with myocardin, in which a specific region of myocardin was essential for recruiting acetyltransferase p300. Altogether, IRF8 is crucial in modulating SMC phenotype switching and neointima formation in response to vascular injury via direct interaction with the SRF/myocardin complex.
doi:10.1128/MCB.01070-13
PMCID: PMC3911522  PMID: 24248596
15.  A Mixed Method to Evaluate Burden of Malaria Due to Flooding and Waterlogging in Mengcheng County, China: A Case Study 
PLoS ONE  2014;9(5):e97520.
Background
Malaria is a highly climate-sensitive vector-borne infectious disease that still represents a significant public health problem in Huaihe River Basin. However, little comprehensive information about the burden of malaria caused by flooding and waterlogging is available from this region. This study aims to quantitatively assess the impact of flooding and waterlogging on the burden of malaria in a county of Anhui Province, China.
Methods
A mixed method evaluation was conducted. A case-crossover study was firstly performed to evaluate the relationship between daily number of cases of malaria and flooding and waterlogging from May to October 2007 in Mengcheng County, China. Stratified Cox models were used to examine the lagged time and hazard ratios (HRs) of the risk of flooding and waterlogging on malaria. Years lived with disability (YLDs) of malaria attributable to flooding and waterlogging were then estimated based on the WHO framework of calculating potential impact fraction in the Global Burden of Disease study.
Results
A total of 3683 malaria were notified during the study period. The strongest effect was shown with a 25-day lag for flooding and a 7-day lag for waterlogging. Multivariable analysis showed that an increased risk of malaria was significantly associated with flooding alone [adjusted hazard ratio (AHR)  = 1.467, 95% CI = 1.257, 1.713], waterlogging alone (AHR = 1.879, 95% CI = 1.696, 2.121), and flooding and waterlogging together (AHR = 2.926, 95% CI = 2.576, 3.325). YLDs per 1000 of malaria attributable to flooding alone, waterlogging alone and flooding and waterlogging together were 0.009 per day, 0.019 per day and 0.022 per day, respectively.
Conclusion
Flooding and waterlogging can lead to higher burden of malaria in the study area. Public health action should be taken to avoid and control a potential risk of malaria epidemics after these two weather disasters.
doi:10.1371/journal.pone.0097520
PMCID: PMC4022516  PMID: 24830808
16.  Lenalidomide after stem-cell transplantation for multiple myeloma: a meta-analysis of randomized controlled trials 
The efficacy and safety of lenalidomide maintenance therapy after ASCT in patients with MM has been in question. In order to address the issue, we conducted a meta-analysis of two randomized double-blind placebo-controlled studies encompassing 1074 patients treated with lenalidomide or placebo maintenance therapy after ASCT. The predominant clinical outcomes of interest were overall survival (OS), progression-free survival (PFS), and adverse events. There was a marked benefit in PFS with lenalidomide (Odds Ratio [OR] = 2.5, 95% confidence interval [CI] = 1.93 to 3.24). There was statistically non-significant tendency toward benefit in OS with lenalidomide (OR = 1.21, 95% CI = 0.65 to 2.24). For adverse events, more patients in lenalidomide treatment arm experienced neutropenia (OR = 4.88, 95% CI = 3.67 to 6.50), infection (OR = 2.82, 95% CI = 1.67 to 4.73), hematologic cancers (OR = 3.31, 95% CI = 1.30 to 8.41), and solid tumors (OR = 2.24, 95% CI = 1.01 to 4.98). No significant differences were seen with deep vein thrombosis (OR = 2.15, 95% CI = 0.92 to 5.06), peripheral neuropathy (OR = 1.50, 95% CI = 0.53 to 4.25), thrombocytopenia (OR = 1.05, 95% CI = 0.12 to 9.54), and anemia (OR = 1.36, 95% CI = 0.02 to 83.86). Based on these results, we conclude that lenalidomide maintenance therapy for patients with MM after ASCT was effective in the improvement of PFS. However, treatment-related adverse events must be close monitored. Although there was a trend for increased OS with lenalidomide, there was no statistically significant difference in OS between lenalidomide maintenance therapy arm and placebo maintenance therapy arm. Therefore, longer follow-up and additional high quality RCTs were needed to evaluate the effects of lenalidomide maintenance on OS.
PMCID: PMC4097223  PMID: 25031726
Lenalidomide; multiple myeloma; maintenance therapy; meta-analysis
17.  Uncoupling Transcription from Covalent Histone Modification 
PLoS Genetics  2014;10(4):e1004202.
It is widely accepted that transcriptional regulation of eukaryotic genes is intimately coupled to covalent modifications of the underlying chromatin template, and in certain cases the functional consequences of these modifications have been characterized. Here we present evidence that gene activation in the silent heterochromatin of the yeast Saccharomyces cerevisiae can occur in the context of little, if any, covalent histone modification. Using a SIR-regulated heat shock-inducible transgene, hsp82-2001, and a natural drug-inducible subtelomeric gene, YFR057w, as models we demonstrate that substantial transcriptional induction (>200-fold) can occur in the context of restricted histone loss and negligible levels of H3K4 trimethylation, H3K36 trimethylation and H3K79 dimethylation, modifications commonly linked to transcription initiation and elongation. Heterochromatic gene activation can also occur with minimal H3 and H4 lysine acetylation and without replacement of H2A with the transcription-linked variant H2A.Z. Importantly, absence of histone modification does not stem from reduced transcriptional output, since hsp82-ΔTATA, a euchromatic promoter mutant lacking a TATA box and with threefold lower induced transcription than heterochromatic hsp82-2001, is strongly hyperacetylated in response to heat shock. Consistent with negligible H3K79 dimethylation, dot1Δ cells lacking H3K79 methylase activity show unimpeded occupancy of RNA polymerase II within activated heterochromatic promoter and coding regions. Our results indicate that large increases in transcription can be observed in the virtual absence of histone modifications often thought necessary for gene activation.
Author Summary
The proper regulation of gene expression is of fundamental importance in the maintenance of normal growth and development. Misregulation of genes can lead to such outcomes as cancer, diabetes and neurodegenerative disease. A key step in gene regulation occurs during the transcription of the chromosomal DNA into messenger RNA by the enzyme, RNA polymerase II. Histones are small, positively charged proteins that package genomic DNA into arrays of bead-like particles termed nucleosomes, the principal components of chromatin. Increasing evidence suggests that nucleosomal histones play an active role in regulating transcription, and that this is derived in part from reversible chemical (“covalent”) modifications that take place on their amino acids. These histone modifications create novel surfaces on nucleosomes that can serve as docking sites for other proteins that control a gene's expression state. In this study we present evidence that contrary to the general case, covalent modifications typically associated with transcription are minimally used by genes embedded in a specialized, condensed chromatin structure termed heterochromatin in the model organism baker's yeast. Our observations are significant, for they suggest that gene transcription can occur in a living cell in the virtual absence of covalent modification of the chromatin template.
doi:10.1371/journal.pgen.1004202
PMCID: PMC3983032  PMID: 24722509
18.  Inhibition of mammalian target of rapamycin improves neurobehavioral deficit and modulates immune response after intracerebral hemorrhage in rat 
Background
Mammalian target of rapamycin (mTOR), a serine/threonine kinase, regulates many processes, including cell growth and the immune response. mTOR is also dysregulated in several neurological diseases, such as traumatic brain injury (TBI), stroke, and neurodegenerative disease. However, the role of mTOR in intracerebral hemorrhage (ICH) remains unexplored. The aims of our study were to determine whether inhibiting mTOR signaling could affect the outcome after ICH and to investigate the possible underlying mechanism.
Methods
A rat ICH model was induced by intracerebral injection of collagenase IV into the striatum, and mTOR activation was inhibited by administration of rapamycin. mTOR signaling activation was determined by western blotting. Neurobehavioral deficit after ICH was determined by a set of modified Neurological Severity Scores (mNSS). The levels of CD4+CD25+Foxp3+ regulatory T cells (Tregs) and cytokines were examined using flow cytometry and ELISA, respectively.
Results
Our results demonstrated thatmTOR signaling was activated 30 minutes and returned to its basal level 1 day after ICH. Increased p-mTOR, which mean that mTOR signaling was activated, was predominantly located around the hematoma. Rapamycin treatment significantly improved the neurobehavioral deficit after ICH, increased the number of Tregs, increased levels of interleukin-10 and transforming growth factor-β and reduced interferon-γ both in peripheral blood and brain.
Conclusions
Our study suggests that mTOR improves ICH outcome and modulates immune response after ICH.
doi:10.1186/1742-2094-11-44
PMCID: PMC3975837  PMID: 24602288
ICH; mTOR; Rapamycin; Outcome; Immune response
19.  Transplanted Neural Stem Cells Modulate Regulatory T, γδ T Cells and Corresponding Cytokines after Intracerebral Hemorrhage in Rats 
The immune system, particularly T lymphocytes and cytokines, has been implicated in the progression of brain injury after intracerebral hemorrhage (ICH). Although studies have shown that transplanted neural stem cells (NSCs) protect the central nervous system (CNS) from inflammatory damage, their effects on subpopulations of T lymphocytes and their corresponding cytokines are largely unexplored. Here, rats were subjected to ICH and NSCs were intracerebrally injected at 3 h after ICH. The profiles of subpopulations of T cells in the brain and peripheral blood were analyzed by flow cytometry. We found that regulatory T (Treg) cells in the brain and peripheral blood were increased, but γδT cells (gamma delta T cells) were decreased, along with increased anti-inflammatory cytokines (IL-4, IL-10 and TGF-β) and decreased pro-inflammatory cytokines (IL-6, and IFN-γ), compared to the vehicle-treated control. Our data suggest that transplanted NSCs protect brain injury after ICH via modulation of Treg and γδT cell infiltration and anti- and pro-inflammatory cytokine release.
doi:10.3390/ijms15034431
PMCID: PMC3975405  PMID: 24633197
ICH; transplantation; NSCs; T lymphocyte subpopulations; immunomodulation
20.  Carotid intima-media thickness progression to predict cardiovascular events in the general population (the PROG-IMT collaborative project): a meta-analysis of individual participant data 
Lancet  2012;379(9831):2053-2062.
Summary
Background
Carotid intima-media thickness (cIMT) is related to the risk of cardiovascular events in the general population. An association between changes in cIMT and cardiovascular risk is frequently assumed but has rarely been reported. Our aim was to test this association.
Methods
We identified general population studies that assessed cIMT at least twice and followed up participants for myocardial infarction, stroke, or death. The study teams collaborated in an individual participant data meta-analysis. Excluding individuals with previous myocardial infarction or stroke, we assessed the association between cIMT progression and the risk of cardiovascular events (myocardial infarction, stroke, vascular death, or a combination of these) for each study with Cox regression. The log hazard ratios (HRs) per SD difference were pooled by random effects meta-analysis.
Findings
Of 21 eligible studies, 16 with 36 984 participants were included. During a mean follow-up of 7·0 years, 1519 myocardial infarctions, 1339 strokes, and 2028 combined endpoints (myocardial infarction, stroke, vascular death) occurred. Yearly cIMT progression was derived from two ultrasound visits 2–7 years (median 4 years) apart. For mean common carotid artery intima-media thickness progression, the overall HR of the combined endpoint was 0·97 (95% CI 0·94–1·00) when adjusted for age, sex, and mean common carotid artery intima-media thickness, and 0·98 (0·95–1·01) when also adjusted for vascular risk factors. Although we detected no associations with cIMT progression in sensitivity analyses, the mean cIMT of the two ultrasound scans was positively and robustly associated with cardiovascular risk (HR for the combined endpoint 1·16, 95% CI 1·10–1·22, adjusted for age, sex, mean common carotid artery intima-media thickness progression, and vascular risk factors). In three studies including 3439 participants who had four ultrasound scans, cIMT progression did not correlate between occassions (reproducibility correlations between r=−0·06 and r=−0·02).
Interpretation
The association between cIMT progression assessed from two ultrasound scans and cardiovascular risk in the general population remains unproven. No conclusion can be derived for the use of cIMT progression as a surrogate in clinical trials.
Funding
Deutsche Forschungsgemeinschaft.
doi:10.1016/S0140-6736(12)60441-3
PMCID: PMC3918517  PMID: 22541275
21.  Peritumoral ductular reaction: a poor postoperative prognostic factor for hepatocellular carcinoma 
BMC Cancer  2014;14:65.
Background
The role of ductular reaction (DR) in hepatocellular carcinoma (HCC) remains to be elucidated.
Methods
In this study, we tried to uncover possible effect by correlating peritumoral DR in a necroinflammatory microenvironment with postoperative prognosis in HCC. The expression of peritumoral DR/CK19 by immunohistochemistry, necroinflammation and fibrosis were assessed from 106 patients receiving curative resection for HCC. Prognostic values for these and other clinicopathologic factors were evaluated.
Results
Peritumoral DR significantly correlated with necroinflammation (r = 0.563, p = 3.4E-10), fibrosis (r = 0.435, p = 3.1E-06), AFP level (p = 0.010), HBsAg (p = 4.9E-4), BCLC stage (p = 0.003), TNM stage (p = 0.002), multiple nodules (p = 0.004), absence of tumor capsule (p = 0.027), severe microscopic vascular invasion (p = 0.031) and early recurrence (p = 0.010). Increased DR was significantly associated with decreased RFS/OS (p = 4.8E-04 and p = 2.6E-05, respectively) in univariate analysis and were identified as an independent prognostic factor (HR = 2.380, 95% CI = 1.250-4.534, p = 0.008 for RFS; HR = 4.294, 95% CI = 2.255-8.177, p = 9.3E-6 for OS) in multivariate analysis.
Conclusions
These results suggested that peritumoral DR in a necroinflammatory microenvironment was a poor prognostic factor for HCC after resection.
doi:10.1186/1471-2407-14-65
PMCID: PMC3916808  PMID: 24495509
Ductular reaction (DR); Hepatic progenitor cells (HPCs); Necroinflammation; Fibrosis; Hepatocellular carcinoma (HCC); Prognosis
22.  microRNAs in Spinal Cord Injury: Potential Roles and Therapeutic Implications 
microRNAs (miRNAs) are a novel class of small non-coding RNAs that negatively regulate gene expression at the post-transcriptional level. miRNAs can modulate gene expression and thus play important roles in diverse neurobiological processes, such as cell differentiation, growth, proliferation and neural activity, as well as the pathogenic processes of spinal cord injury (SCI) like inflammation, oxidation, demyelination and apoptosis. Results from animal studies have revealed the temporal alterations in the expression of a large set of miRNAs following SCI in adult rats, and the expressional changes in miRNAs following SCI is bidirectional (increase or decrease). In addition, several miRNAs have distinct roles in prognosis of SCI (protective, detrimental and varied). Taken together, the existing evidence suggests that abnormal miRNA expression following SCI contributes to the pathogenesis of SCI, and miRNAs may become potential targets for the therapy of SCI.
doi:10.7150/ijbs.9058
PMCID: PMC4159691  PMID: 25210498
microRNA; spinal cord injury; therapy; diagnosis.
23.  Identification of Poly(ADP-Ribose) Polymerase-1 as a Cell Cycle Regulator through Modulating Sp1 Mediated Transcription in Human Hepatoma Cells 
PLoS ONE  2013;8(12):e82872.
The transcription factor Sp1 is implicated in the activation of G0/G1 phase genes. Modulation of Sp1 transcription activities may affect G1-S checkpoint, resulting in changes in cell proliferation. In this study, our results demonstrated that activated poly(ADP-ribose) polymerase 1 (PARP-1) promoted cell proliferation by inhibiting Sp1 signaling pathway. Cell proliferation and cell cycle assays demonstrated that PARP inhibitors or PARP-1 siRNA treatment significantly inhibited proliferation of hepatoma cells and induced G0/G1 cell cycle arrest in hepatoma cells, while overexpression of PARP-1 or PARP-1 activator treatment promoted cell cycle progression. Simultaneously, inhibition of PARP-1 enhanced the expression of Sp1-mediated checkpoint proteins, such as p21 and p27. In this study, we also showed that Sp1 was poly(ADP-ribosyl)ated by PARP-1 in hepatoma cells. Poly(ADP-ribosyl)ation suppressed Sp1 mediated transcription through preventing Sp1 binding to the Sp1 response element present in the promoters of target genes. Taken together, these data indicated that PARP-1 inhibition attenuated the poly(ADP-ribosyl)ation of Sp1 and significantly increased the expression of Sp1 target genes, resulting in G0/G1 cell cycle arrest and the decreased proliferative ability of the hepatoma cells.
doi:10.1371/journal.pone.0082872
PMCID: PMC3868549  PMID: 24367566
24.  Tumor necrosis factor-α attenuates starvation-induced apoptosis through upregulation of ferritin heavy chain in hepatocellular carcinoma cells 
BMC Cancer  2013;13:438.
Background
Tumor microenviroment is characteristic of inflammation, ischemia and starvation of nutrient. TNF-α, which is an extraordinarily pleiotropic cytokine, could be an endogenous tumor promoter in some tumor types. The basic objective of this study was to investigate the effects of TNF-α on the cell viability and apoptosis of hepatocellular carcinoma cells under serum starvation, and to identify the molecular mechanisms involved.
Methods
For this purpose, five different concentrations of TNF-α and two different serum settings (serum-cultured and serum-deprived) were used to investigate the effects of TNF-α on the cell viability and apoptosis of Hep3B and SMMC-7721 cells.
Results
TNF-α (10 ng/ml) attenuated serum starvation-induced apoptosis of hepatocellular carcinoma cells, and autophagy conferred this process. BAY11-7082, a specific inhibitor of NF-κB, reversed the suppression of serum starvation-induced apoptosis by TNF-α. Moreover, TNF-α-induced NF-κB transactivation was suppressed by autophagy inhibitor 3-MA. In addition, TNF-α up-regulated Ferritin heavy chain (FHC) transiently by NF-κB activation and FHC levels were correlated with the TNF-α-induced protection against serum starvation-mediated apoptosis of hepatocellular carcinoma cells. Furthermore, FHC-mediated inhibition of apoptosis depended on suppressing ROS accumulation.
Conclusions
Our findings suggested that autophagy conferred the TNF-α protection against serum starvation-mediated apoptosis of hepatocellular carcinoma cells, the mechanism involved with the activation of the TNF-α/ NF-κB /FHC signaling pathway.
doi:10.1186/1471-2407-13-438
PMCID: PMC3849379  PMID: 24066693
TNF-α; Starvation; NF-κB; Ferritin heavy chain; Autophagy; Hepatocellular carcinoma
25.  Hepatic Stellate Cells Secreted Hepatocyte Growth Factor Contributes to the Chemoresistance of Hepatocellular Carcinoma 
PLoS ONE  2013;8(9):e73312.
As the main source of extracellular matrix proteins in tumor stroma, hepatic stellate cells (HSCs) have a great impact on biological behaviors of hepatocellular carcinoma (HCC). In the present study, we have investigated a mechanism whereby HSCs modulate the chemoresistance of hepatoma cells. We used human HSC line lx-2 and chemotherapeutic agent cisplatin to investigate their effects on human HCC cell line Hep3B. The results showed that cisplatin resistance in Hep3B cells was enhanced with LX-2 CM (cultured medium) exposure in vitro as well as co-injection with LX-2 cells in null mice. Meanwhile, in presence of LX-2 CM, Hep3B cells underwent epithelial to mesenchymal transition (EMT) and upregulation of cancer stem cell (CSC) -like properties. Besides, LX-2 cells synthesized and secreted hepatic growth factor (HGF) into the CM. HGF receptor tyrosine kinase mesenchymal–epithelial transition factor (Met) was activated in Hep3B cells after LX-2 CM exposure. The HGF level of LX-2 CM could be effectively reduced by using HGF neutralizing antibody. Furthermore, depletion of HGF in LX-2 CM abolished its effects on activation of Met as well as promotion of the EMT, CSC-like features and cisplatin resistance in Hep3B cells. Collectively, secreting HGF into tumor milieu, HSCs may decrease hepatoma cells sensitization to chemotherapeutic agents by promoting EMT and CSC-like features via HGF/Met signaling.
doi:10.1371/journal.pone.0073312
PMCID: PMC3759390  PMID: 24023859

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