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1.  Haploid embryonic stem cells serve as a new tool for mammalian genetic study 
In mammals, all somatic cells carry two sets of chromosomes while haploids are restricted only to gametes and are occasionally found in tumors with genome instability. Mammalian haploid embryonic stem (ES) cells have recently been established successfully in mice and monkeys, from either parthenogenetic or androgenetic haploid embryos. These haploid ES cells maintain haploidy and stable growth during extensive in vitro culture, express pluripotent markers, and possess the ability to differentiate into all three germ layers in vitro and in vivo. The mouse haploid ES cells can also contribute to germlines of chimeras. Moreover, the mouse androgenetic haploid ES cells can produce fertile progenies after intracytoplasmic injection into mature oocytes, and the mouse parthenogenetic haploid ES cells can also achieve this by substitution of the maternal genome, albeit at a lower efficiency. These distinct features of mammalian haploid ES cells empower themselves not only as a valuable tool for genetic screening at a cellular level, but also as a new tool for genome-modified animal production and genetic studies at the animal level. Here we review the current progress on mammalian haploid ES cell research, describe in detail their characteristics, and discuss their potential applications. These achievements may provide a new but powerful tool for mammalian genetic studies, and may also shed light on the some interesting questions regarding genome ploidy maintenance and genomic imprinting.
doi:10.1186/scrt409
PMCID: PMC4054955  PMID: 24499606
2.  Temporal genomic evolution of bird sex chromosomes 
BMC Evolutionary Biology  2014;14(1):250.
Background
Sex chromosomes exhibit many unusual patterns in sequence and gene expression relative to autosomes. Birds have evolved a female heterogametic sex system (male ZZ, female ZW), through stepwise suppression of recombination between chrZ and chrW. To address the broad patterns and complex driving forces of Z chromosome evolution, we analyze here 45 newly available bird genomes and four species’ transcriptomes, over their course of recombination loss between the sex chromosomes.
Results
We show Z chromosomes in general have a significantly higher substitution rate in introns and synonymous protein-coding sites than autosomes, driven by the male-to-female mutation bias (‘male-driven evolution’ effect). Our genome-wide estimate reveals that the degree of such a bias ranges from 1.6 to 3.8 among different species. G + C content of third codon positions exhibits the same trend of gradual changes with that of introns, between chrZ and autosomes or regions with increasing ages of becoming Z-linked, therefore codon usage bias in birds is probably driven by the mutational bias. On the other hand, Z chromosomes also evolve significantly faster at nonsynonymous sites relative to autosomes (‘fast-Z’ evolution). And species with a lower level of intronic heterozygosities tend to evolve even faster on the Z chromosome. Further analysis of fast-evolving genes’ enriched functional categories and sex-biased expression patterns support that, fast-Z evolution in birds is mainly driven by genetic drift. Finally, we show in species except for chicken, gene expression becomes more male-biased within Z-linked regions that have became hemizygous in females for a longer time, suggesting a lack of global dosage compensation in birds, and the reported regional dosage compensation in chicken has only evolved very recently.
Conclusions
In conclusion, we uncover that the sequence and expression patterns of Z chromosome genes covary with their ages of becoming Z-linked. In contrast to the mammalian X chromosomes, such patterns are mainly driven by mutational bias and genetic drift in birds, due to the opposite sex-biased inheritance of Z vs. X.
Electronic supplementary material
The online version of this article (doi:10.1186/s12862-014-0250-8) contains supplementary material, which is available to authorized users.
doi:10.1186/s12862-014-0250-8
PMCID: PMC4272511  PMID: 25527260
Avian genome; Evolutionary strata; Male-driven evolution; Fast-Z evolution; Dosage compensation
3.  Adult hepatic cavernous hemangioma with highly elevated α-fetoprotein: A case report and review of the literature 
Oncology Letters  2014;9(2):637-640.
A 47-year-old male presented with a six-month history of fatigue and a four-month history of alanine and aspartate aminopherase elevation. Laboratory examination revealed that the serum α-fetoprotein (AFP) level was 371.51 μg/l (normal range, 0–20 μg/l), and a computed tomography scan revealed a hypodense lesion in the left hepatic lobe. During laparotomy, a dark red-colored soft tumor (1.5×1.7 cm in diameter) was found in segment eight of the liver. Intra-operative pathology and post-operative histopathology examinations revealed that the tumor was a hepatic cavernous hemangioma. The serum AFP level was decreased to 24.45 μg/l by the second post-operative week. The literature was searched and only three similar cases were found. A brief review of this rare disease entity was produced, which attempted to explain this appearance reasonably.
doi:10.3892/ol.2014.2769
PMCID: PMC4301549  PMID: 25624892
hepatic cavernous hemangioma; α-fetoprotein; cancer stem cell
4.  The role of microRNA-133b and its target gene FSCN1 in gastric cancer 
Background
Increasing evidences have documented that microRNAs (miRNAs) act as oncogenes or tumor suppressors in gastric cancer (GC). In this study, we aimed to investigate the expression of miR-133b in a large number of GC samples and elucidate its role in GC carcinogenesis and the detailed mechanism.
Methods
We used Taqman probe stem-loop real-time PCR to accurately measure the levels of miR-133b in 100 pairs of gastric cancer tissues and the adjacent non-neoplastic tissues. miR-133b mimics were overexpressed in GC cell lines, miR-133b inhibitors were also introduced in GES cells to investigate its role on regulating cell proliferation, cell migration and cell invasion. The target of miR-133b was identified by luciferase reporter assay and western blot. Fascin actin-bundling protein 1 (FSCN1) siRNA was used to achieve the knockdown of FSCN1 in GC cells and to investigate its role on modulating GC cell proliferation and invasion.
Results
miR-133b was significantly down-regulated in GC cell lines and in GC tissues compared with adjacent normal tissues. Moreover, lower-level of miR-133b was also associated with venous invasion and a more aggressive tumor phenotype. Re-introduction of miR-133b in GC cells can inhibit cell proliferation, cell migration and invasion. In contrary, knockdown of miR-133b in GES cells can promote cell proliferation and invasion. Further investigation indicated that miR-133b targeted FSCN1 in GC cells and knockdown of FSCN1 can also inhibit GC cell growth and invasion.
Conclusion
Our findings demonstrated that miR-133b was significantly down-regulated in GC tissues and exerted its tumor suppressor role in GC cells. The investigation of the detailed mechanism showed that miR-133b directly targeted FSCN1 which functioned as an oncogenic gene in GC cells. These results suggested that miR-133b can be developed as a new diagnostic marker or therapeutic target for GC.
doi:10.1186/s13046-014-0099-0
PMCID: PMC4272783  PMID: 25433493
Gastric cancer; miR-133b; FSCN1; Tumor suppressor
5.  Niacin Activates the PI3K/Akt Cascade via PKC- and EGFR-Transactivation-Dependent Pathways through Hydroxyl-Carboxylic Acid Receptor 2 
PLoS ONE  2014;9(11):e112310.
Niacin has been demonstrated to activate a PI3K/Akt signaling cascade to prevent brain damage after stroke and UV-induced skin damage; however, the underlying molecular mechanisms for HCA2-induced Akt activation remain to be elucidated. Using CHO-K1 cells stably expressing HCA2 and A431 cells, a human epidermoid cell line with high levels of endogenous expression of functional HCA2 receptors, we first demonstrated that niacin induced a robust Akt phosphorylation at both Thr308 and Ser473 in a time-dependent fashion, with a maximal activation at 5 min and a subsequent reduction to baseline by 30 min through HCA2, and that the activation was significantly blocked by pertussis toxin. The HCA2-mediated activation of Akt was also significantly inhibited by the PKC inhibitors GF109203x and Go6983 in both cell lines, by the PDGFR-selective inhibitor tyrphostin A9 in CHO-HCA2 cells and by the MMP inhibitor GM6001 and EGFR-specific inhibitor AG1478 in A431 cells. These results suggest that the PKC pathway and PDGFR/EGFR transactivation pathway play important roles in HCA2-mediated Akt activation. Further investigation indicated that PI3K and the Gβγ subunit were likely to play an essential role in HCA2-induced Akt activation. Moreover, Immunobloting analyses using an antibody that recognizes p70S6K1 phosphorylated at Thr389 showed that niacin evoked p70S6K1 activation via the PI3K/Akt pathway. The results of our study provide new insight into the signaling pathways involved in HCA2 activation.
doi:10.1371/journal.pone.0112310
PMCID: PMC4223033  PMID: 25375133
6.  A ventilator strategy combining low tidal volume ventilation, recruitment maneuvers, and high positive end-expiratory pressure does not increase sedative, opioid, or neuromuscular blocker use in adults with acute respiratory distress syndrome and may improve patient comfort 
Background
The Lung Open Ventilation Study (LOV Study) compared a low tidal volume strategy with an experimental strategy combining low tidal volume, lung recruitment maneuvers, and higher plateau and positive end-expiratory pressures (PEEP) in adults with acute respiratory distress syndrome (ARDS). Herein, we compared sedative, opioid, and neuromuscular blocker (NMB) use among patients managed with the intervention and control strategies and clinicians' assessment of comfort in both groups.
Methods
This was an observational substudy of the LOV Study, a randomized trial conducted in 30 intensive care units in Canada, Australia, and Saudi Arabia. In 16 centers, we recorded daily doses of sedatives, opioids, and NMBs and surveyed bedside clinicians about their own comfort with the assigned ventilator strategy and their perceptions of patient comfort. We compared characteristics and outcomes of patients who did and did not receive NMBs.
Results
Study groups received similar sedative, opioid, and NMB dosing on days 1, 3, and 7. Patient comfort as assessed by clinicians was not different in the two groups: 93% perceived patients had no/minimal discomfort. In addition, 92% of clinicians were comfortable with the assigned ventilation strategy without significant differences between the two groups. When clinicians expressed discomfort, more expressed discomfort about PEEP levels in the intervention vs control group (2.9% vs 0.7%, P <0.0001), and more perceived patient discomfort among controls (6.0% vs 4.3%, P = 0.049). On multivariable analysis, the strongest associations with NMB use were higher plateau pressure (hazard ratio (HR) 1.15; 95% confidence interval (CI) 1.07 to 1.23; P = 0.0002) and higher daily sedative dose (HR 1.03; 95% CI 1.02 to 1.05; P <0.0001). Patients receiving NMBs had more barotrauma, longer durations of mechanical ventilation and hospital stay, and higher mortality.
Conclusions
In the LOV Study, high PEEP, low tidal volume ventilation did not increase sedative, opioid, or NMB doses in adults with ARDS, compared with a lower PEEP strategy, and appeared at least as comfortable for patients. NMB use may reflect worse lung injury, as these patients had more barotrauma, longer durations of ventilation, and higher mortality.
Trial registration
ClinicalTrials.gov Identifier NCT00182195
doi:10.1186/s13613-014-0033-9
PMCID: PMC4273695  PMID: 25593749
ARDS; Neuromuscular blocker; Sedation; Opioid; Mechanical ventilation; Clinician comfort
7.  Critical behaviours of contact near phase transitions 
Nature Communications  2014;5:5140.
A central quantity of importance for ultracold atoms is contact, which measures two-body correlations at short distances in dilute systems. It appears in universal relations among thermodynamic quantities, such as large momentum tails, energy and dynamic structure factors, through the renowned Tan relations. However, a conceptual question remains open as to whether or not contact can signify phase transitions that are insensitive to short-range physics. Here we show that, near a continuous classical or quantum phase transition, contact exhibits a variety of critical behaviours, including scaling laws and critical exponents that are uniquely determined by the universality class of the phase transition, and a constant contact per particle. We also use a prototypical exactly solvable model to demonstrate these critical behaviours in one-dimensional strongly interacting fermions. Our work establishes an intrinsic connection between the universality of dilute many-body systems and universal critical phenomena near a phase transition.
Contact parameterises two-body correlations at short distances in dilute systems like ultracold atomic gases. Using a fundamental thermodynamic relation, Chen et al. study the contact near a continuous classical or quantum phase transition and find that it displays a number of critical behaviours.
doi:10.1038/ncomms6140
PMCID: PMC4220487  PMID: 25346226
8.  The Role of Apolipoprotein E as a Risk Factor for an Earlier Age at Onset for Machado-Joseph Disease Is Doubtful 
PLoS ONE  2014;9(11):e111356.
Machado-Joseph disease (MJD) is an inherited neurodegenerative disease caused by an expanded CAG repeat in the ATXN3 gene. Although the principal genetic determinant of the age at onset (AAO) is the length of the expanded CAG repeat, the additional genetic contribution of MJD toward the AAO has mostly not yet been clarified. It was recently suggested in two independent studies that apolipoprotein E (APOE) might be associated with AAO variability in MJD patients. To identify the potential modifier effect of APOE polymorphisms on the AAO of MJD patients, 403 patients with MJD (confirmed by molecular tests) from eastern and southeastern China were enrolled in the present study. CAG repeats in the ATXN3 and APOE polymorphisms were genotyped. Data were analyzed using a statistical package. No contribution of APOE polymorphisms to the variance in disease onset was observed using ANCOVA (F = 0.183, P = 0.947). However, significant effects on the AAO of MJD were found for the normal ATXN3 allele and for the interaction of mutant and normal ATXN3 alleles in a multiple linear regression model (P = 0.043 and P = 0.035, respectively). Our study does not support a role for APOE as a genetic modifier of the AAO of MJD. Additionally, our study presents evidence that the normal ATXN3 allele and its interaction with mutant alleles contribute toward AAO variance in MJD patients.
doi:10.1371/journal.pone.0111356
PMCID: PMC4219713  PMID: 25369462
9.  Nickel-Catalyzed Cross Couplings of Benzylic Pivalates with Arylboroxines: Stereospecific Formation of Diarylalkanes and Triarylmethanes 
We have developed a stereospecific, nickel-catalyzed cross coupling of benzylic pivalates with aryl boroxines. The success of this reaction relies on the use of Ni(cod)2 as catalyst and NaOMe as a uniquely effective base. This reaction has broad scope with respect to the aryl boroxine and benzylic pivalate, enabling the synthesis of a variety of diarylalkanes and triarylmethanes in good to excellent yields and ee's.
doi:10.1021/ja312087x
PMCID: PMC4218864  PMID: 23425080
11.  Optimized rapeseed oils rich in endogenous micronutrients ameliorate risk factors of atherosclerosis in high fat diet fed rats 
Background
Micronutrients in rapeseed such as polyphenols, tocopherols, phytosterols and phospholipids in rapeseed exert potential benefit to atherosclerosis. Some part of these healthy components substantially lost during the conventional refining processing. Thus some new processing technologies have been developed to produce various endogenous micronutrient-enriched optimized rapeseed oils. The aim of this study is to assess whether optimized rapeseed oils have positive effects on the atherosclerosis risk factors in rats fed a high-fat diet.
Methods
Rats received experiment diets containing 20% fat and refined rapeseed oil or optimized rapeseed oils obtained with various processing technologies as lipid source. After 10 weeks of treatment, plasma was assayed for oxidative stress, lipid profiles and imflammation.
Results
Micronutrients enhancement in optimized rapeseed oils significantly reduced plasma oxidative stress, as evaluated by the significant elevation in the activities of CAT and GPx as well as the level of GSH, and the significant decline in lipid peroxidation. Optimized rapeseed oil with the highest micronutrient contents obtained by microwave pretreatment-cold pressing reduced the levels of TG, TC and LDL-C as well as IL-6 and CRP in plasma.
Conclusions
These results suggest that optimized rapeseed oils may contribute to prevent atherogenesis and make them very promising functional food in cardiovascular health promotion.
doi:10.1186/1476-511X-13-166
PMCID: PMC4232689  PMID: 25358951
Optimized rapeseed oils; Micronutrients; Atherosclerosis; Oxidant stress; Plasma lipids; Inflammation
12.  Synergistic Antibiotic Combination Powders of Colistin and Rifampicin Provide High Aerosolization Efficiency and Moisture Protection 
The AAPS Journal  2013;16(1):37-47.
For many respiratory infections caused by multidrug-resistant Gram-negative bacteria, colistin is the only effective antibiotic despite its nephrotoxicity. A novel inhaled combination formulation of colistin with a synergistic antimicrobial component of rifampicin was prepared via co-spray drying, aiming to deliver the drug directly to the respiratory tract and minimize drug resistance and adverse effects. Synergistic antibacterial activity against Acinetobacter baumannii was demonstrated for the combination formulation with high emitted doses (96%) and fine particle fraction total (FPFtotal; 92%). Storage of the spray-dried colistin alone formulation in the elevated relative humidity (RH) of 75% resulted in a substantial deterioration in the aerosolization performance because the amorphous colistin powders absorbed significant amount of water up to 30% by weight. In contrast, the FPFtotal values of the combination formulation stored at various RH were unchanged, which was similar to the aerosolization behavior of the spray-dried rifampicin-alone formulation. Advanced surface chemistry measurements by XPS and ToF-SIMS demonstrated a dominance of rifampicin on the combination particle surfaces, which contributed to the moisture protection at the elevated RH. This study shows a novel inhalable powder formulation of antibiotic combination with the combined beneficial properties of synergistic antibacterial activity, high aerosolization efficiency, and moisture protection.
Electronic supplementary material
The online version of this article (doi:10.1208/s12248-013-9537-8) contains supplementary material, which is available to authorized users.
doi:10.1208/s12248-013-9537-8
PMCID: PMC3889531  PMID: 24129586
combination antibiotics; dry powder inhaler; moisture protection; respiratory infection; synergistic antibacterial activity
13.  Association of GSTP1 Ile105Val polymorphism with risk of esophageal cancer: a meta-analysis of 21 case-control studies 
Background: The association of glutathione s-transferase P1 (GSTP1) Ile105Val polymorphism with risk of esophageal cancer (EC) has been evaluated in many studies; however, the results from these studies are controversial. Thus, further analysis on association between GSTP1 Ile105Val polymorphism and risk of EC is needed among a larger study population. Method: We searched the relevant electronic databases and performed a meta-analysis based on 21 published case-control studies. The Chi-square based I2-statistic test was performed to evaluate possible heterogeneity across the studies. Additionally, random-effects models were used to calculate crude pooled odds ratios (ORs) with 95% confidence intervals (CIs). Results: Overall, this meta-analysis did support a significant association between GSTP1 Ile105Val polymorphism and risk of EC (pooled OR 1.25, 95% CI, 1.05-1.49). Furthermore, the stratified analysis showed that, in comparison to GSTP1 Ile105Val Ile/Ile genotype, the Val/Val genotype was significantly associated with risk of esophageal squamous cell carcinoma (ESCC) (pooled OR 1.45, 95% CI, 1.07-1.96), particularly in the Caucasian population (pooled OR 1.41, 95% CI, 1.01-1.95). Such a significant association was not observed for esophageal adenocarcinoma (EAC) patients or subjects of an Asian ethnicity. Moreover, substantial evidence of heterogeneity among the studies was not observed. Conclusion: The results from this meta-analysis support a significant association between the GSTP1 Ile105Val polymorphism and risk of EC, particularly in a subgroup with ESCC and in the Caucasian population. Further studies with larger sample sizes are needed to validate our findings.
PMCID: PMC4238532  PMID: 25419352
Esophageal cancer; GSTP1; polymorphism; meta-analysis; cancer risk
14.  Rosa26 Locus Supports Tissue-Specific Promoter Driving Transgene Expression Specifically in Pig 
PLoS ONE  2014;9(9):e107945.
Genetically modified pigs have become a popular model system in fundamental research, agricultural and biomedical applications. However, random integration often result in unstable expression of transgene and unpredictable phenotypes. The Rosa26 locus has been widely used to produce genetic modified animals with high and consistent expressing of transgene in mouse, human and rat, as it can be targeted efficiently and is not subject to gene-silencing effects. Recently, the first case of reporter gene targeting pigs in porcine Rosa26 (pRosa26) locus was reported. In the study, full sequence of pRosa26 locus was further characterized, and the pRosa26 promoter (pR26) was cloned and we evidenced that the new porcine endogenous promoter is suitable for driving transgene expression in a high and stable manner by avoiding DNA methylation. Furthermore, elongation factor 1a promoter (EF1a) -driven GFP reporter and Myostatin promoter (MyoP)-driven Follistatin (Fst) were successfully targeted into the pRosa26 locusby traditional homologous recombination (HR) strategy. EF1a showed high activity and hypomethylation at the locus. And, muscle-specific promoter MyoP was activated strictly in muscle of the pRosa26 targeted pigs, indicating Rosa26 locus supports tissue-specific promoter driving transgene expression in its own manner. The study provided further demonstration on biomedical and agricultural applications of porcine Rosa26 promoter and locus.
doi:10.1371/journal.pone.0107945
PMCID: PMC4169413  PMID: 25232950
15.  Antidiabetic Effect of Methanolic Extract from Berberis julianae Schneid. via Activation of AMP-Activated Protein Kinase in Type 2 Diabetic Mice 
We have investigated the antidiabetic effect and mechanism of methanolic extract of Berberis julianae Schneid. (BJSME) in STZ induced Type 2 diabetes mellitus mice. T2DM mice were induced by high fat diet and low dose streptozotocin (STZ). BJSME was orally administrated at the doses of 60, 120, and 240 mg/kg/d, for 21 days. Metformin was used as positive control drug. Food intake, body weight, plasma glucose, oral glucose tolerance test, insulin tolerance test, insulin, and blood-lipid content were measured. The effects of BJSME on the glucose transporter 4 (GLUT4) translocation in L6 myotubes and the GLUT4 protein expression in skeletal muscle as well as phosphorylation of the AMP-activated protein kinase (AMPK) in liver and muscle were examined. In vitro and in vivo results indicate that BJSME increased GLUT4 translocation by 1.8-fold and BJSME significantly improved the oral glucose tolerance and low density lipoprotein cholesterol (LDL-C) of serum and reduced body weight, glucose, and other related blood-lipid contents. The BJSME treatment also stimulated the phosphorylation of AMPK. Thus, BJSME seems to possess promising beneficial effects for the treatment of T2DM with the possible mechanism via stimulating AMPK activity.
doi:10.1155/2014/106206
PMCID: PMC4167208  PMID: 25258641
16.  Tumour necrosis factor-α promotes liver ischaemia-reperfusion injury through the PGC-1α/Mfn2 pathway 
Tumour necrosis factor (TNF)-α has been considered to induce ischaemia-reperfusion injury (IRI) of liver which is characterized by energy dysmetabolism. Peroxisome proliferator–activated receptor-γ co-activator (PGC)-1α and mitofusion2 (Mfn2) are reported to be involved in the regulation of mitochondrial function. However, whether PGC-1α and Mfn2 form a pathway that mediates liver IRI, and if so, what the underlying involvement is in that pathway remain unclear. In this study, L02 cells administered recombinant human TNF-α had increased TNF-α levels and resulted in down-regulation of PGC-1α and Mfn2 in a rat liver IRI model. This was associated with hepatic mitochondrial swelling, decreased adenosine triphosphate (ATP) production, and increased levels of reactive oxygen species (ROS) and alanine aminotransferase (ALT) activity as well as cell apoptosis. Inhibition of TNF-α by neutralizing antibody reversed PGC-1α and Mfn2 expression, and decreased hepatic injury and cell apoptosis both in cell culture and in animals. Treatment by rosiglitazone sustained PGC-1α and Mfn2 expression both in IR livers, and L02 cells treated with TNF-α as indicated by increased hepatic mitochondrial integrity and ATP production, reduced ROS and ALT activity as well as decreased cell apoptosis. Overexpression of Mfn2 by lentiviral-Mfn2 transfection decreased hepatic injury in IR livers and L02 cells treated with TNF-α. However, there was no up-regulation of PGC-1α. These findings suggest that PGC-1α and Mfn2 constitute a regulatory pathway, and play a critical role in TNF-α-induced hepatic IRI. Inhibition of the TNF-α or PGC-1α/Mfn2 pathways may represent novel therapeutic interventions for hepatic IRI.
doi:10.1111/jcmm.12320
PMCID: PMC4196661  PMID: 24898700
liver; tumour necrosis factor alpha; ischaemia-reperfusion injury; peroxisome proliferator–activated receptor-γ co-activator-1α; mitofusion2
17.  Sodium ferulate lowers portal pressure in rats with secondary biliary cirrhosis through the RhoA/Rho-kinase signaling pathway: A preliminary study 
Cirrhotic rats show higher expression levels of hepatic RhoA and Rho-kinase than normal healthy rats, and the activation of this signaling pathway leads to portal hypertension. Sodium ferulate (SF) has been shown to decrease the production of geranylgeranyl pyrophosphate (GGPP), a substance essential for RhoA activation. In the present study, to investigate the effects of SF on fibrosis, portal hypertension and the RhoA/Rho-kinase pathway, hepatic cirrhosis was induced in rats by bile duct ligation. Liver function and fibrogenesis-related biochemical parameters, the hepatic hydroxyproline content, the pathological characteristics of the liver sections and the levels of hepatic α-smooth muscle actin (α-SMA; by immunohistochemistry) were analyzed to assess effects of SF on hepatic fibrosis. In addition, hepatic RhoA, Rho-kinase and endothelial nitric oxide synthase (eNOS) expression was examined by immunohistochemistry. Apoptosis in the SF-treated and SF + GGPP-treated rat primary hepatic stellate cells (HSCs) and a human stellate cell line (LX-2) was examined by flow cytometry. Intrahepatic resistance and responsiveness to the α1-adrenoceptor agonist, methoxamine, were investigated by in situ liver perfusion. Treatment with SF did not affect fibrosis-related biochemical parameters or the hydroxyproline content; however, SF reduced the histological evidence of fibrosis and hepatocyte damage. The SF-treated rats had a significantly lower expression of α-SMA and Rho-kinase, as well as an increased hepatic eNOS content; however, SF did not affect RhoA expression. The SF-treated HSCs had a significantly increased apoptotic rate compared to the untreated rats. Following the addition of GGPP, the rate apoptotic rate decreased. SF reduced basal intrahepatic resistance and the responsiveness of hepatic vascular smooth muscle to methoxamine. Therefore, our data demonstrate that SF reduces fibrogenesis, decreases portal pressure in cirrhotic rats and inhibits the activation of the RhoA/Rho-kinase signaling pathway.
doi:10.3892/ijmm.2014.1905
PMCID: PMC4199412  PMID: 25174394
portal hypertension; sodium ferulate; cirrhosis; bile duct ligation; RhoA; Rho-kinase; methoxamine; endothelial nitric oxide synthase; fibrosis
18.  Sex-specific adaptation drives early sex chromosome evolution in Drosophila 
Science (New York, N.Y.)  2012;337(6092):341-345.
Most species’ sex chromosomes are derived from ancient autosomes and show few signatures of their origins. We studied the sex chromosomes of Drosophila miranda, where a neo-Y chromosome originated only about 1 million years (MY) ago. Whole genome and transcriptome analysis reveals massive degeneration of the neo-Y, that male-beneficial genes on the neo-Y are more likely to undergo accelerated protein-evolution, and that neo-Y genes evolve biased expression towards male-specific tissues, i.e. the shrinking gene content of the neo-Y becomes masculinized. In contrast, while older X chromosomes show a paucity of genes expressed in male tissues, neo-X genes highly expressed in male-specific tissues undergo increased rates of protein evolution if haploid in males. Thus, the response to sex-specific selection can shift at different stages of X differentiation, resulting in masculinization or demasculinization of the X-chromosomal gene content.
doi:10.1126/science.1225385
PMCID: PMC4107656  PMID: 22822149
19.  The Associations between Two Vital GSTs Genetic Polymorphisms and Lung Cancer Risk in the Chinese Population: Evidence from 71 Studies 
PLoS ONE  2014;9(7):e102372.
Background
The genetic polymorphisms of glutathione S-transferase (GSTs) have been suspected to be related to the development of lung cancer while the current results are conflicting, especially in the Chinese population.
Methods
Data on genetic polymorphisms of glutathione S-transferase Mu 1 (GSTM1) from 68 studies, glutathione S-transferase theta 1 (GSTT1) from 17 studies and GSTM1-GSTT1 from 8 studies in the Chinese population were reanalyzed on their association with lung cancer risk. Odds ratios (OR) were pooled using forest plots. 9 subgroups were all or partly performed in the subgroup analyses. The Galbraith plot was used to identify the heterogeneous records. Potential publication biases were detected by Begg's and Egger's tests.
Results
71 eligible studies were identified after screening of 1608 articles. The increased association between two vital GSTs genetic polymorphisms and lung cancer risk was detected by random-effects model based on a comparable heterogeneity. Subgroup analysis showed a significant relationship between squamous carcinoma (SC), adenocarcinoma (AC) or small cell lung carcinoma (SCLC) and GSTM1 null genotype, as well as SC or AC and GSTT1 null genotype. Additionally, smokers with GSTM1 null genotype had a higher lung cancer risk than non-smokers. Our cumulative meta-analysis demonstrated a stable and reliable result of the relationship between GSTM1 null genotype and lung cancer risk. After the possible heterogeneous articles were omitted, the adjusted risk of GSTs and lung cancer susceptibility increased (fixed-effects model: ORGSTM1 = 1.23, 95% CI: 1.19 to 1.27, P<0.001; ORGSTT1 = 1.18, 95% CI: 1.10 to 1.26, P<0.001; ORGSTM1-GSTT1 = 1.33, 95% CI: 1.10 to 1.61, P = 0.004).
Conclusions
An increased risk of lung cancer with GSTM1 and GSTT1 null genotype, especially with dual null genotype, was found in the Chinese population. In addition, special histopathological classification of lung cancers and a wide range of gene-environment and gene-gene interaction analysis should be taken into consideration in future studies.
doi:10.1371/journal.pone.0102372
PMCID: PMC4103841  PMID: 25036724
20.  Induced Effects of Transcranial Magnetic Stimulation on the Autonomic Nervous System and the Cardiac Rhythm 
The Scientific World Journal  2014;2014:349718.
Several standard protocols based on repetitive transcranial magnetic stimulation (rTMS) have been employed for treatment of a variety of neurological disorders. Despite their advantages in patients that are retractable to medication, there is a lack of knowledge about the effects of rTMS on the autonomic nervous system that controls the cardiovascular system. Current understanding suggests that the shape of the so-called QRS complex together with the size of the different segments and intervals between the PQRST deflections of the heart could predict the nature of the different arrhythmias and ailments affecting the heart. This preliminary study involving 10 normal subjects from 20 to 30 years of age demonstrated that rTMS can induce changes in the heart rhythm. The autonomic activity that controls the cardiac rhythm was indeed altered by an rTMS session targeting the motor cortex using intensity below the subject's motor threshold and lasting no more than 5 minutes. The rTMS activation resulted in a reduction of the RR intervals (cardioacceleration) in most cases. Most of these cases also showed significant changes in the Poincare plot descriptor SD2 (long-term variability), the area under the low frequency (LF) power spectrum density curve, and the low frequency to high frequency (LF/HF) ratio. The RR intervals changed significantly in specific instants of time during rTMS activation showing either heart rate acceleration or heart rate deceleration.
doi:10.1155/2014/349718
PMCID: PMC4127210  PMID: 25136660
21.  Serum B7-H4 expression is a significant prognostic indicator for patients with gastric cancer 
Background
B7-H4 is a novel B7 ligand that plays an important role in the T cell-mediated immune response as a negative regulator. Previous studies have suggested the aberrant expression of membrane B7-H4 in tumor cells. The aim of this study is to determine the expression levels of preoperative soluble B7-H4 (sB7-H4) in circulation and to investigate the correlations between sB7-H4 levels and clinicopathological parameters as well as the survival rate of patients with gastric cancer.
Methods
Blood specimens from 132 patients with gastric cancer and 63 healthy volunteers were analyzed by sandwich enzyme-linked immunosorbent assay.
Results
Median concentrations of sB7-H4 in patients with gastric cancer were significantly higher than those in healthy volunteers (16.85 versus 10.46 ng/mL; P = 0.008). Median levels of sB7-H4 were significantly correlated with tumor size, lymph node metastasis, the depth of tumor invasion and tumor-node-metastasis classification (P = 0.002, P = 0.001, P = 0.041 and P <0.001, respectively), but not with sex, age, tumor location or histological subtype (all P >0.05). Additionally, the overall survival rate was significantly lower in patients with high sB7-H4 levels when compared with low sB7-H4 levels (50.0% versus 77.3%, χ2 = 10.78, P = 0.001). Moreover, multivariate analysis demonstrated that the risk of death was significantly higher in patients with high sB7-H4 levels than in those with low sB7-H4 levels (P = 0.039).
Conclusions
sB7-H4 is a valuable blood marker for predicting the progression and prognosis of patients with gastric cancer.
doi:10.1186/1477-7819-12-188
PMCID: PMC4076248  PMID: 24947047
Gastric cancer; sB7-H4; Prognosis; ELISA
22.  Time-course changes in left ventricular myocardial deformation in STZ-induced rabbits on velocity vector imaging 
Objectives
To clarify the time-course changes in left ventricular myocardial deformation using velocity vector imaging and to provide insights into our understanding of the cardiac pathophysiology in diabetes mellitus.
Methods
Thirty New Zealand white rabbits were randomly divided into either the control group (n = 10) or the diabetes mellitus (DM) group (induced with STZ, n = 20). For the myocardial deformation studies, echocardiography and syngo-vector velocity imaging (VVI) were performed at baseline and after 2, 4, 8, and 12 weeks in all of the rabbits. The left ventricular (LV) global longitudinal and circumferential strain and strain rate were measured. For histomorphological study of the heart structure, 2 of the STZ-induced rabbits were killed at 2, 4, 8, and 12 weeks. Routine hematoxylin and eosin staining was performed.
Results
At 2 weeks, the global longitudinal strain (GLS), systolic strain rate (GLSRs), and diastolic strain rate (GLSRd) were significantly lower in the DM group compared with the control group (-18.16% versus -24.00%, -1.86 s-1 versus -2.49 s-1, 1.93 s-1 versus 2.42 s-1, respectively, P < 0.05), while, compared with the control group, the global circumferential strain (GCS), systolic strain rate (GCSRs), and diastolic strain rate (GCSRd) in the DM group were significantly decreased (-12.77% versus -23.31%, -1.31 s-1 versus -2.20 s-1, 1.41 s-1 versus 2.15 s-1, respectively, P < 0.05) at 8 weeks. With the progression of untreated diabetes, the histoanatomical alterations intensified gradually beginning at 2 weeks.
Conclusions
The progressive impairments in LV myocardial deformation and structure occurred early in diabetic rabbits with normal LV ejection fraction (EF), FS, and E/A. VVI could be used to evaluate subtle cardiac dysfunction in the early phase of DM.
doi:10.1186/1476-7120-12-17
PMCID: PMC4065093  PMID: 24885095
DM; Myocardial deformation; VVI; STZ-induced rabbits
23.  The Different Roles of Glucocorticoids in the Hippocampus and Hypothalamus in Chronic Stress-Induced HPA Axis Hyperactivity 
PLoS ONE  2014;9(5):e97689.
Hypothalamus-pituitary-adrenal (HPA) hyperactivity is observed in many patients suffering from depression and the mechanism underling the dysfunction of HPA axis is not well understood. Chronic stress has a causal relationship with the hyperactivity of HPA axis. Stress induces the over-synthesis of glucocorticoids, which will arrive at all the body containing the brain. It is still complicated whether glucocorticoids account for chronic stress-induced HPA axis hyperactivity and in which part of the brain the glucocorticoids account for chronic stress-induced HPA axis hyperactivity. Here, we demonstrated that glucocorticoids were indispensable and sufficient for chronic stress-induced hyperactivity of HPA axis. Although acute glucocorticoids elevation in the hippocampus and hypothalamus exerted a negative regulation of HPA axis, we found that chronic glucocorticoids elevation in the hippocampus but not in the hypothalamus accounted for chronic stress-induced hyperactivity of HPA axis. Chronic glucocorticoids exposure in the hypothalamus still exerted a negative regulation of HPA axis activity. More importantly, we found mineralocorticoid receptor (MR) - neuronal nitric oxide synthesis enzyme (nNOS) - nitric oxide (NO) pathway mediated the different roles of glucocorticoids in the hippocampus and hypothalamus in regulating HPA axis activity. This study suggests that the glucocorticoids in the hippocampus play an important role in the development of HPA axis hyperactivity and the glucocorticoids in the hypothalamus can't induce hyperactivity of HPA axis, revealing new insights into understanding the mechanism of depression.
doi:10.1371/journal.pone.0097689
PMCID: PMC4022669  PMID: 24831808
24.  MT2-MMP expression associates with tumor progression and angiogenesis in human lung cancer 
Matrix metalloproteinases (MMPs) are a family of important proteolytic enzymes that play an important role in the remodeling of the tumor microenvironment and associate with tumorigenesis and metastasis. We previously reported that membrane type-2 MMP (MT2-MMP) is highly expressed in human esophageal cancer tissues, and its expression level is positively correlated to tumor size and intratumoral angiogenesis. In order to reveal whether MT2-MMP expression is operative in human lung cancer and its underlying physio-pathological role, in the present study, we examined both mRNA and protein expression levels of MT2-MMP in non-small cell lung caner (NSCLC) tissues and in adjacent normal tissues by using real-time RT-PCR and immunohistochemistry respectively, which showed that both MT2-MMP mRNA (P=0.0359) and protein (P<0.0001) expression levels were significantly increased in cancer tissues in contrast to adjacent normal tissues. Moreover, we also found that the MT2-MMP protein level in cancer tissues positively correlated to lymph node metastasis (P=0.0483), tumor stage (P=0.0483), intra-tumoral microvessel density (MVD) (P=0.0445). We have not found statistically significant correlation between MT2-MMP expression and patients’ prognoses, but we found that the patients with both higher MT2-MMP protein expression and higher intra-tumoral microvessel density showed better prognoses than that of the patients with either higher MT2-MMP protein expression or higher intra-tumoral microvessel density (P=0.0311). Thus, our data suggest that MT2-MMP expression positively involves in NSCLC, and might play an important role in promoting the tumor progression and intra-tumoral angiogenesis in NSCLC.
PMCID: PMC4097292  PMID: 25031779
MT2-MMP; NSCLC; intratumoral angiogenesis; prognosis
25.  Metallic Nickel Nanoparticles May Exhibit Higher Carcinogenic Potential than Fine Particles in JB6 Cells 
PLoS ONE  2014;9(4):e92418.
While numerous studies have described the pathogenic and carcinogenic effects of nickel compounds, little has been done on the biological effects of metallic nickel. Moreover, the carcinogenetic potential of metallic nickel nanoparticles is unknown. Activator protein-1 (AP-1) and nuclear factor-κB (NF-κB) have been shown to play pivotal roles in tumor initiation, promotion, and progression. Mutation of the p53 tumor suppressor gene is considered to be one of the steps leading to the neoplastic state. The present study examines effects of metallic nickel fine and nanoparticles on tumor promoter or suppressor gene expressions as well as on cell transformation in JB6 cells. Our results demonstrate that metallic nickel nanoparticles caused higher activation of AP-1 and NF-κB, and a greater decrease of p53 transcription activity than fine particles. Western blot indicates that metallic nickel nanoparticles induced a higher level of protein expressions for R-Ras, c-myc, C-Jun, p65, and p50 in a time-dependent manner. In addition, both metallic nickel nano- and fine particles increased anchorage-independent colony formation in JB6 P+ cells in the soft agar assay. These results imply that metallic nickel fine and nanoparticles are both carcinogenetic in vitro in JB6 cells. Moreover, metallic nickel nanoparticles may exhibit higher carcinogenic potential, which suggests that precautionary measures should be taken in the use of nickel nanoparticles or its compounds in nanomedicine.
doi:10.1371/journal.pone.0092418
PMCID: PMC3972196  PMID: 24691273

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