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1.  Synergy between Proteasome Inhibitors and Imatinib Mesylate in Chronic Myeloid Leukemia 
PLoS ONE  2009;4(7):e6257.
Background
Resistance developed by leukemic cells, unsatisfactory efficacy on patients with chronic myeloid leukemia (CML) at accelerated and blastic phases, and potential cardiotoxity, have been limitations for imatinib mesylate (IM) in treating CML. Whether low dose IM in combination with agents of distinct but related mechanisms could be one of the strategies to overcome these concerns warrants careful investigation.
Methods and Findings
We tested the therapeutic efficacies as well as adverse effects of low dose IM in combination with proteasome inhibitor, Bortezomib (BOR) or proteasome inhibitor I (PSI), in two CML murine models, and investigated possible mechanisms of action on CML cells. Our results demonstrated that low dose IM in combination with BOR exerted satisfactory efficacy in prolongation of life span and inhibition of tumor growth in mice, and did not cause cardiotoxicity or body weight loss. Consistently, BOR and PSI enhanced IM-induced inhibition of long-term clonogenic activity and short-term cell growth of CML stem/progenitor cells, and potentiated IM-caused inhibition of proliferation and induction of apoptosis of BCR-ABL+ cells. IM/BOR and IM/PSI inhibited Bcl-2, increased cytoplasmic cytochrome C, and activated caspases. While exerting suppressive effects on BCR-ABL, E2F1, and β-catenin, IM/BOR and IM/PSI inhibited proteasomal degradation of protein phosphatase 2A (PP2A), leading to a re-activation of this important negative regulator of BCR-ABL. In addition, both combination therapties inhibited Bruton's tyrosine kinase via suppression of NFκB.
Conclusion
These data suggest that combined use of tyrosine kinase inhibitor and proteasome inhibitor might be helpful for optimizing CML treatment.
doi:10.1371/journal.pone.0006257
PMCID: PMC2705802  PMID: 19606213
2.  Prevalence of Cognitive Impairment No Dementia in a Rural Area of Northern China 
Neuroepidemiology  2014;42(4):197-203.
Objective
Few data are available on the prevalence of cognitive impairment no dementia (CIND) in rural China. The aim of this study was to estimate the prevalence of CIND in individuals aged 60 years and older in a large rural community, and to analyze the associated risk factors.
Methods
A two-phase, door-to-door epidemiological study was used for residents aged 60 years and older in Ji County, a rural county near Tianjin in Northern China. In phase 1 of the study, the Mini-Mental State Examination and Clinical Dementia Rating were administered for screening purposes. In phase 2, the subjects who screened positive were further examined by neurologists. A total of 5,744 individuals underwent the home visit interview, where demographic variables and comorbidities were recorded; 5,550 individuals completed the two phases. CIND was diagnosed by the Aging, Demographics and Memory Study on CIND criteria. The odds ratio (OR) for each risk factor was calculated by logistic regression analysis.
Results
The prevalence of CIND among those aged 60 years and older was 23.3%. The prevalence of CIND was lower among those with a higher level of education or social involvement. CIND was more prevalent in fe males, older individuals, those with a past history of stroke, and those living without a partner. Significant risk factors were found by multivariate analyses: past history of stroke (OR = 1.889; 95% CI: 1.437–2.483); being female (OR = 1.546; 95% CI: 1.305–1.832); and having no partner (divorced, widowed or single; OR = 1.250; 95% CI: 1.042–1.499). In turn, level of education (OR = 0.560; 95% CI: 0.460–0.681) and engagement in social activities (OR = 0.339; 95% CI: 0.258–0.404) were protective factors.
Conclusions
This is the first large-scale community-based epidemiological study assessing the prevalence of cognitive loss in the rural Chinese population. The total prevalence of CIND observed was 23.3%, which was higher than in other studies in Western and Asian countries. Living without a partner, female gender and previous stroke increased the risk of CIND, whereas a higher level of education and engagement in social activities reduced the risk of CIND.
doi:10.1159/000360138
PMCID: PMC4074439  PMID: 24751796
Cognitive impairment no dementia; China; Prevalence
3.  Ingredients of Huangqi decoction slow biliary fibrosis progression by inhibiting the activation of the transforming growth factor-beta signaling pathway 
Background
Huangqi decoction was first described in Prescriptions of the Bureau of Taiping People's Welfare Pharmacy in Song Dynasty (AD 1078), and it is an effective recipe that is usually used to treat consumptive disease, anorexia, and chronic liver diseases. Transforming growth factor beta 1 (TGFβ1) plays a key role in the progression of liver fibrosis, and Huangqi decoction and its ingredients (IHQD) markedly ameliorated hepatic fibrotic lesions induced by ligation of the common bile duct (BDL). However, the mechanism of IHQD on hepatic fibrotic lesions is not yet clear. The purpose of the present study is to elucidate the roles of TGFβ1 activation, Smad-signaling pathway, and extracellular signal-regulated kinase (ERK) in the pathogenesis of biliary fibrosis progression and the antifibrotic mechanism of IHQD.
Methods
A liver fibrosis model was induced by ligation of the common bile duct (BDL) in rats. Sham-operation was performed in control rats. The BDL rats were randomly divided into two groups: the BDL group and the IHQD group. IHQD was administrated intragastrically for 4 weeks. At the end of the fifth week after BDL, animals were sacrificed for sampling of blood serum and liver tissue. The effect of IHQD on the TGFβ1 signaling pathway was evaluated by western blotting and laser confocal microscopy.
Results
Decreased content of hepatic hydroxyproline and improved liver function and histopathology were observed in IHQD rats. Hepatocytes, cholangiocytes, and myofibroblasts in the cholestatic liver injury released TGFβ1, and activated TGFβ1 receptors can accelerate liver fibrosis. IHQD markedly inhibited the protein expression of TGFβ1, TGFβ1 receptors, Smad3, and p-ERK1/2 expression with no change of Smad7 expression.
Conclusion
IHQD exert significant therapeutic effects on BDL-induced fibrosis in rats through inhibition of the activation of TGFβ1-Smad3 and TGFβ1-ERK1/2 signaling pathways.
doi:10.1186/1472-6882-12-33
PMCID: PMC3419610  PMID: 22471627
Ingredients of Huangqi decoction; Cholestatic liver fibrosis; Transforming growth factor beta 1; Smad-signaling pathway, Extracellular signal-regulated kinase
4.  Icotinib Is an Active Treatment of Non-Small-Cell Lung Cancer: A Retrospective Study 
PLoS ONE  2014;9(5):e95897.
Background
Icotinib hydrochloride is a novel epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) with preclinical and clinical activity in non-small cell lung cancer (NSCLC). This retrospective analysis was performed to assess the efficacy of icotinib on patients with non-small-cell lung cancer (NSCLC).
Methods
82 consecutive patients treated with icotinib as first (n = 24) or second/third line (n = 58) treatment at three hospitals in Nanjing were enrolled into our retrospective research. The Response Evaluation Criteria in Solid Tumors (RECIST) was used to evaluate the tumor responses and the progression-free survival (PFS) and overall survival (OS) was evaluated by the Kaplan-Meier method.
Results
Median PFS was 4.0 months (95% CI 2.311–5.689). Median OS was 11.0 months (95% CI 8.537–13.463) in this cohort. Median PFS for first and second/third line were 7.0 months (95% CI 2.151–11.8) and 3.0 months (95% CI 1.042–4.958), respectively. Median OS for first and second/third line were 13.0 months (95% CI 10.305–15.695) and 10.0 months (95% CI 7.295–12.70), respectively. In patients with EGFR mutation (n = 19), icotinib significantly reduced the risk of progression (HR 0.36, 95% CI 0.18–0.70, p = 0.003) and death (HR 0.10, 95% CI 0.02–0.42, p = 0.002) compared with those EGFR status unknown (n = 63). The most common adverse events were acne-like rash (39.0%) and diarrhea (20.7%).
Conclusions
Icotinib is active in the treatment of patients with NSCLC both in first or second/third line, especially in those patients harbouring EGFR mutations, with an acceptable adverse event profile.
doi:10.1371/journal.pone.0095897
PMCID: PMC4023939  PMID: 24836053
5.  Huangqi decoction inhibits apoptosis and fibrosis, but promotes Kupffer cell activation in dimethylnitrosamine-induced rat liver fibrosis 
Background
Previously, Huangqi decoction (HQD) has been found to have a potential therapeutic effect on DMN-induced liver cirrhosis. Here, the mechanisms of HQD action against liver fibrosis were investigated in relation to hepatocyte apoptosis and hepatic inflammation regulation.
Methods
Liver fibrosis was induced by DMN administration for 2 or 4 weeks. Hepatocyte apoptosis and of Kupffer cells (KC) and hepatic stellate cells (HSC) interaction were investigated using confocal microscopy. The principle cytokines, fibrogenic proteins and apoptotic factors were investigated using western blot analysis.
Results
Compared with the DMN-water group, HQD showed decreased hepatocyte apoptosis and reduced expression of apoptotic effectors, cleaved-caspase-3, and fibrotic factors, such as smooth muscle α-actin (α-SMA), transforming growth factor beta-1 (TGF-β1). However, the KC marker CD68 increased significantly in DMN-HQD liver. Confocal microscopy demonstrated widespread adhesion of KCs to HSCs in DMN-water and DMN-HQD rats liver.
Conclusions
HQD exhibited positive protective effects against liver fibrosis; its mechanism of action was associated with protection from hepatocyte apoptosis and the promotion of CD68 expression in the devolopment of liver fibrosis to cirrhosis development.
doi:10.1186/1472-6882-12-51
PMCID: PMC3495215  PMID: 22531084
6.  Resveratrol protects human lens epithelial cells against H2O2-induced oxidative stress by increasing catalase, SOD-1, and HO-1 expression 
Molecular Vision  2010;16:1467-1474.
Purpose
Oxidative damage induced by H2O2 treatment can irreversibly damage the lens epithelium, resulting in cell death and cataract. Whether the effects of oxidative stress could be attenuated in cultured human lens epithelial cells by incubation with resveratrol (RES) is still unknown. In the present study, we examined the function of resveratrol in protecting human lens epithelial B-3 (HLEB-3) cells against H2O2 induced cell death and cell apoptosis, its role in reducing H2O2 induced intracellular reactive oxygen species (ROS) accumulation, and investigated the mechanism by which resveratrol underlies the effect.
Methods
HLEB-3 cells, a human lens epithelial cell line, were exposed to 100 μM H2O2 with or without RES pre-treatment at different concentrations for different time duration. Cell viabilities were monitored by 4-[3-[4-iodophenyl]-2-4(4-nitrophenyl)-2H-5-tetrazolio-1,3-benzene disulfonate] (WST-1) assay. The apoptosis rate and ROS generation were detected by flow cytometric analysis. Expression levels of superoxide dismutases-1 (SOD-1), catalase, and heme oxygenase-1 (HO-1) proteins were measured by western-blotting analysis. p38 and c-jun N terminal kinase (JNK) activation was also evaluated by western-blotting analysis.
Results
Resveratrol clearly reduced H2O2 induced cell apoptosis and ROS accumulation; protected HLEB-3 cells from H2O2 induced oxidative damage, and increased the expression levels of SOD-1, catalase, and HO-1. Further studies showed that RES also inhibited H2O2 induced p38 and JNK phosphorylation.
Conclusions
These findings suggested that RES protected HLEB-3 cells from H2O2 induced oxidative damage, presumably by inducing three antioxidative enzymes including catalase, SOD-1, and HO-1.
PMCID: PMC2925910  PMID: 20806083
7.  Effect of Fuzheng Huayu formula and its actions against liver fibrosis 
Chinese Medicine  2009;4:12.
Liver fibrosis is a common histological process to develop into cirrhosis in various chronic liver diseases including chronic hepatitis and fatty liver. Therefore anti-liver fibrosis is very important strategy to treat chronic liver diseases. Fuzheng Huayu (FZHY), a preparation containing herbs such as Radix Salvia Miltiorrhizae, Cordyceps, Semen Persicae, was formulated on the basis of Chinese medicine theory in treating liver fibrosis and was approved. Pharmacological studies and clinical trials demonstrate that FZHY has a significant effect against liver fibrosis and that many of the pharmacological actions are attributable to the effect. This article reviews the effects and actions of FZHY, in particular the effects observed from clinical trials in treating liver fibrosis caused by chronic hepatitis B and the actions on inhibition of hepatic stellate cell activation, protection of hepatocytes and inhibition of hepatic sinusoidal capillarization. This article also reviews the coordinated effects of the constituent herbs of FZHY and the actions of their active compounds such as salvianonic acid B (SA-B) on liver fibrosis.
doi:10.1186/1749-8546-4-12
PMCID: PMC2720970  PMID: 19558726
8.  Effects of Yinchenhao Tang and related decoctions on DMN-induced cirrhosis/fibrosis in rats 
Chinese Medicine  2008;3:1.
Background
Chinese medicine decoctions such as Yinchenhao Tang (YCHT), Xiayuxue Tang (XYXT), Huangqi Tang (HQT), Yiguan Jian (YGJ) and Xiaochaihu Tang (XCHT)) were used to treat liver cirrhosis. The present study evaluates the effects of these decoctions on fibrosis in rats induced by dimethylnitrosamine (DMN).
Methods
DMN solution (0.5%) was injected to rats for three consecutive days per week for four weeks. At the beginning of week 3, rats were randomly divided into 4-week DMN control group, YCHT, XYXT, HQT, YGJ, XCHT and vehicle groups. Each group was orally administered with specific decoctions daily for two weeks. Rats in the vehicle group were orally administered with only water.
Results
Liver fibrosis and cirrhosis were observed in weeks 2 and 4 in DMN-intoxicated rats. Compared with normal rats, alanine transaminase (ALT), aspartate transaminase (AST), alkaline phosphatase (ALP) activities and level of total bilirubin acid (TBA) in serum and content of Hydroxyproline (Hyp) in liver tissue of model group rats rose significantly. However, the albumin (Alb) level in serum decreased significantly. Compared with the 4-week DMN group, the pathological conditions and functions of the liver in the YCHT group improved significantly, and the content of Hyp decreased remarkably: only one rat in this group developed liver cirrhosis and the ratio of cirrhosis was only 8.3%. On the other hand, the other decoctions did not show remarkable effects. YCHT inhibited α-SMA activation, including its gene expression into mRNA and protein.
Conclusion
Among the five Chinese medicine decoctions, YCHT exerted the most significant therapeutic effects on DMN-induced cirrhosis/fibrosis in rats.
doi:10.1186/1749-8546-3-1
PMCID: PMC2267793  PMID: 18237412
9.  Promotion of water-mediated carbon removal by nanostructured barium oxide/nickel interfaces in solid oxide fuel cells 
Nature Communications  2011;2:357-.
The existing Ni-yttria-stabilized zirconia anodes in solid oxide fuel cells (SOFCs) perform poorly in carbon-containing fuels because of coking and deactivation at desired operating temperatures. Here we report a new anode with nanostructured barium oxide/nickel (BaO/Ni) interfaces for low-cost SOFCs, demonstrating high power density and stability in C3H8, CO and gasified carbon fuels at 750°C. Synchrotron-based X-ray analyses and microscopy reveal that nanosized BaO islands grow on the Ni surface, creating numerous nanostructured BaO/Ni interfaces that readily adsorb water and facilitate water-mediated carbon removal reactions. Density functional theory calculations predict that the dissociated OH from H2O on BaO reacts with C on Ni near the BaO/Ni interface to produce CO and H species, which are then electrochemically oxidized at the triple-phase boundaries of the anode. This anode offers potential for ushering in a new generation of SOFCs for efficient, low-emission conversion of readily available fuels to electricity.
Anodes composed of nickel/yttria-stabilized zirconia in solid oxide fuel cells are known to suffer from coking, which reduces their performance. Here, Yang and colleagues report a new barium oxide/nickel anode, which efficiently oxidizes fuel with minimum carbon buildup.
doi:10.1038/ncomms1359
PMCID: PMC3157151  PMID: 21694705
10.  Genetic polymorphisms of HSP70 in age-related cataract 
Cell Stress & Chaperones  2013;18(6):703-709.
Polymorphisms have been identified in several HSP70 genes, which may affect HSP70 repair efficiency. We investigated the association of the polymorphisms in HSPA1A, HSPA1B, and HSPA1L genes in the HSPs repair pathway with the risk of cataract in a Chinese population. The study included 415 cataract patients and 386 controls. Genotyping was done by the polymerase chain reaction-restriction fragment length polymorphism method. HSPA1B 1267 A/A genotype seems to have a protective role against cataract (p = 0.014, odds ratio (OR) = 0.664, 95 % confidence intervals (CI) = 0.480–0.919), and the G allele (p = 0.057, OR = 1.216, 95 % CI = 0.999–1.479) does not seem to have a deleterious role in the development of cataract. Haplotypes with frequencies of GAT were significantly different than those of controls (p = 0.005). In HSPA1A G190C and HSPA1L T2437C polymorphisms, there were no significant differences in frequencies of the variant homozygous in patients compared to controls. We conclude that the A/A genotype of HSPA1B A1267G polymorphism seem to have a protective role against age-related cataract.
doi:10.1007/s12192-013-0420-4
PMCID: PMC3789879  PMID: 23666708
Oxidative stress; Reactive oxygen species; Polymorphisms; Cataract; Heat shock proteins
11.  Identification of Transcriptome-Derived Microsatellite Markers and Their Association with the Growth Performance of the Mud Crab (Scylla paramamosain) 
PLoS ONE  2014;9(2):e89134.
Microsatellite markers from a transcriptome sequence library were initially isolated, and their genetic variation was characterized in a wild population of the mud crab (Scylla paramamosain). We then tested the association between these microsatellite markers and the growth performance of S. paramamosain. A total of 129 polymorphic microsatellite markers were identified, with an observed heterozygosity ranging from 0.19 to 1.00 per locus, an expected heterozygosity ranging from 0.23 to 0.96 per locus, and a polymorphism information content (PIC) ranging from 0.21 to 0.95 per locus. Of these microsatellite markers, 30 showed polymorphism in 96 full-sib individuals of a first generation family. Statistical analysis indicated that three microsatellite markers were significantly associated with 12 growth traits of S. paramamosain. Of these three markers, locus Scpa36 was significantly associated with eight growth traits, namely, carapace length, abdomen width (AW), body height (BH), fixed finger length of the claw, fixed finger width of the claw, fixed finger height of the claw, meropodite length of pereiopod 2, and meropodite length of pereiopod 3 (MLP3) (P<0.05). Locus Scpa75 was significantly associated with five growth traits, namely, internal carapace width, AW, carapace width at spine 8, distance between lateral spine 2 (DLS2), and MLP3 (P<0.05). Locus Spm30 was significantly associated with BH, DLS2, and body weight (P<0.05). Further analysis suggested a set of genotypes (BC at Scpa36, BC and BD at Scpa75, and AC at Spm30) that have great potential in the selection of S. paramamosain for growth traits. These findings will facilitate the development of population conservation genetics and molecular marker-assisted selective breeding of S. paramamosain and other closely related species.
doi:10.1371/journal.pone.0089134
PMCID: PMC3923883  PMID: 24551232
12.  History and Experience: A Survey of Traditional Chinese Medicine Treatment for Alzheimer's Disease 
Traditional Chinese medicine (TCM) is practiced in the Chinese health care system for more than 2,000 years. In recent years, herbal medicines, which are used to treat Alzheimer's disease (AD) in China based on TCM or modern pharmacological theories have attracted considerable attention. In this paper, we discuss etiology and pathogenesis of AD, TCM therapy, and herbal extracts for the treatment of AD. There is evidence to suggest that TCM therapy may offer certain complementary cognitive benefits for the treatment of AD. Chinese herb may have advantages with multiple target regulation compared with the single-target antagonist in view of TCM.
doi:10.1155/2014/642128
PMCID: PMC3927560  PMID: 24624220
13.  Metabolic heterogeneity of follicular amino acids in polycystic ovary syndrome is affected by obesity and related to pregnancy outcome 
Background
Polycystic ovary syndrome (PCOS) is a heterogeneous endocrine disorder frequently accompanied by obesity and by insulin resistance, and patients with this syndrome suffer from infertility and poor pregnancy outcome. Disturbances in plasma amino acid (AA) metabolism have been implicated in women with PCOS. However, direct evidence on follicular AA metabolic profiles in PCOS patients and their relationship with pregnancy outcome is sparse.
Methods
We conducted a prospective study in 63 PCOS patients and 48 controls in the Division of Reproductive Center, Peking University Third Hospital. Follicular AA levels were measured by the liquid chromatography-tandem mass spectrometric method, and the results were analyzed based on different grouping criteria.
Results
The levels of aromatic amino acid (AAA) increased in PCOS patients independent of obesity (P < 0.05), whereas the levels of branched-chain amino acid (BCAA), glutamic acid, phenylalanine, alanine, and arginine increased with body mass index irrespective of the PCOS status (all P < 0.05). In addition, compared with non insulin resistant-PCOS patients and controls, insulin resistant-PCOS group had higher levels of leucine, valine and glutamic acid (all P < 0.05). In PCOS group, aspartic acid and serine levels were elevated in pregnant patients compared with the non-pregnant subjects (both P < 0.05). Moreover, the levels of BCAA and valine were higher in the non-pregnant group than in the pregnant group (both P < 0.05). The pregnancy rate (45.00%) of subjects with elevated BCAA level was significantly lower than that (66.67%) in control subjects (P = 0.036) at a BCAA cutoff value of 239.10 μM, while the abortion rate was much higher (33.33% versus 2.78%, P = 0.004).
Conclusions
Both PCOS and obesity were accompanied by follicular AA metabolic disturbances, with obesity exerting a more pronounced effect on AA metabolic profiles. The disruptions in specific AAs in the follicular fluid might account for the inferior pregnancy outcome in obese patients and increased risk of abortion in PCOS patients.
doi:10.1186/1471-2393-14-11
PMCID: PMC3897995  PMID: 24410809
PCOS; Amino acid; Obesity; Follicular fluid
14.  Detection of Fusobacterium Nucleatum and fadA Adhesin Gene in Patients with Orthodontic Gingivitis and Non-Orthodontic Periodontal Inflammation 
PLoS ONE  2014;9(1):e85280.
Fusobacterium nucleatum is one of the most abundant gram-negative bacilli colonizing the subgingival plaque and closely associated with periodontal disease. However it is unclear whether F. nucleatum is involved in gingival inflammation under orthodontic appliance. A novel adhesin, FadA, which is unique to oral Fusobacteria, is required for F. nucleatum binding and invasion to epithelial cells and thus may play an important role in colonization of Fusobacterium in the host. In this study, we evaluated the prevalence of F. nucleatum and its virulence factor FadA adhesion gene (fadA) in 169 subgingival biofilm samples from 55 cases of gingivitis patients with orthodontic appliances, 49 cases of gingivitis patients without orthodontic treatment, 35 cases of periodontitis patients and 30 cases of periodontally healthy people via PCR. The correlations between the F. nucleatum/fadA and gingivitis index(GI)was also analyzed. The detection rate of F. nucleatum/fadA in periodontitis group and non-orthodontic gingivitis group was higher than the other two groups (p<0.01) while it was higher in orthodontic gingivitis group than in health people (p<0.05). An obviously positive correlation was observed between the prevalence of F. nucleatum/fadA and GI. F. nucleatum carrying fadA may be more closely related to the development of gingivitis and periodontal disease compared with orthodontic gingivitis.
doi:10.1371/journal.pone.0085280
PMCID: PMC3887018  PMID: 24416378
15.  New understanding of hardening mechanism of TiN/SiNx-based nanocomposite films 
Nanoscale Research Letters  2013;8(1):427.
In order to clarify the controversies of hardening mechanism for TiN/SiNx-based nanocomposite films, the microstructure and hardness for TiN/SiNx and TiAlN/SiNx nanocomposite films with different Si content were studied. With the increase of Si content, the crystallization degree for two series of films firstly increases and then decreases. The microstructural observations suggest that when SiNx interfacial phase reaches to a proper thickness, it can be crystallized between adjacent TiN or TiAlN nanocrystallites, which can coordinate misorientations between nanocrystallites and grow coherently with them, resulting in blocking of the dislocation motions and hardening of the film. The microstructure of TiN/SiNx-based nanocomposite film can be characterized as the nanocomposite structure with TiN-based nanocrystallites surrounded by crystallized SiNx interfacial phase, which can be denoted by nc-TiN/c-SiNx model ('c’ before SiNx means crystallized) and well explain the coexistence between nanocomposite structure and columnar growth structure within the TiN/SiNx-based film.
doi:10.1186/1556-276X-8-427
PMCID: PMC3856532  PMID: 24134611
TiN/SiNx film; Nanocomposite; Hardening mechanism; Microstructure
16.  Genetic Variation in a MicroRNA-502 Minding Site in SET8 Gene Confers Clinical Outcome of Non-Small Cell Lung Cancer in a Chinese Population 
PLoS ONE  2013;8(10):e77024.
Background
Genetic variants may influence microRNA-target interaction through modulate their binding affinity, creating or destroying miRNA-binding sites. SET8, a member of the SET domain-containing methyltransferase, has been implicated in a variety array of biological processes.
Methods
Using Taqman assay, we genotyped a polymorphism rs16917496 T>C within the miR-502 binding site in the 3′-untranslated region of the SET8 gene in 576 non-small cell lung cancer (NSCLC) patients. Functions of rs16917496 were investigated using luciferase activity assay and validated by immunostaining.
Results
Log-rank test and cox regression indicated that the CC genotype was associated with a longer survival and a reduced risk of death for NSCLC [58.0 vs. 41.0 months, P = 0.031; hazard ratio = 0.44, 95% confidential interval: 0.26–0.74]. Further stepwise regression analysis suggested rs16917496 was an independently favorable factor for prognosis and the protective effect more prominent in never smokers, patients without diabetes and patients who received chemotherapy. A significant interaction was observed between rs16917496 and smoking status in relation to NSCLC survival (P<0.001). Luciferase activity assay showed a lower expression level for C allele as compared with T allele, and the miR-502 had an effect on modulation of SET8 gene in vitro. The CC genotype was associated with reduced SET8 protein expression based on immunostaining of 192 NSCLC tissue sample (P = 0.007). Lower levels of SET8 were associated with a non-significantly longer survival (55.0 vs. 43.1 months).
Conclusion
Our data suggested that the rs16917496 T>C located at miR-502 binding site contributes to NSCLC survival by altering SET8 expression through modulating miRNA-target interaction.
doi:10.1371/journal.pone.0077024
PMCID: PMC3795636  PMID: 24146953
17.  Baicalin Attenuates Brain Edema in a Rat Model of Intracerebral Hemorrhage 
Inflammation  2013;37:107-115.
Baicalin is a flavonoid compound purified from the roots of Scutellaria baicalensis, which possesses multiple biological activities. Previous studies have shown that baicalin is protective in ischemic cerebral diseases. The aim of the present study was to examine the effects of baicalin on brain injury in a rat model of intracerebral hemorrhage (ICH) and to explore the possible mechanisms. Intracerebral hemorrhage was induced in male Wistar rats by injection of 0.5 U collagenaseVII to the caudate nucleus. Sham operation rats were injected with equal volume of saline. After the induction of ICH, the rats were randomly divided into four groups and administered with different dose of baicalin (0, 25, 50, or 100 mg/kg in saline) through peritoneal injection. The brain tissues around the hemorrhage areas were collected on days 1, 3, and 5 after treatment. Brain edema was analyzed by desiccation method; the metalloproteinase-9 (MMP-9) protein and mRNA expression were determined by western blotting and real time RT-PCR, respectively. Nuclear factor-κB (NF-κB) protein expression was analyzed by western blotting. IL-1β and IL-6 levels were determined by enzyme-linked immunosorbent assay. Blood–brain barrier permeability was determined by Evans blue leakage method. The results showed that baicalin reduced brain edema following ICH in a dose-dependent manner, with concomitant inhibition of NF-κB activation and suppression of MMP-9 expression. In addition, baicalin also reduced IL-1β and IL-6 production, as well as blood–brain barrier permeability. The above results indicated that baicalin prevents against perihematomal edema development after intracerebral hemorrhage possibly through an anti-inflammatory mechanism.
doi:10.1007/s10753-013-9717-9
PMCID: PMC3929027  PMID: 23974988
baicalin; intracerebral hemorrhage; brain edema; nuclear factor-κB; metalloproteinase-9
18.  Molecular hydrogen regulates the expression of miR-9, miR-21 and miR-199 in LPS-activated retinal microglia cells 
AIM
To explore the potential mechanism of molecular hydrogen in the regulation of miRNA expression and signal-modulating activities.
METHODS
Retinal microglia cells were activated by Lipopolysaccharides (LPS) and then treated with hydrogen-saturated medium or normal medium without hydrogen. qRT-PCR was used to detect the expression difference in miR-9, miR-21 and miR-199 between these two groups. Moreover, the expression of LPS-induced signaling proteins, including Myd88, IKK-β, NF-κB, and PDCD4, were detected by Western blotting.
RESULTS
The results demonstrated a marked down-regulation of miR-9 and miR-21 and up-regulation of miR-199 by hydrogen treatment; the expression of Myd88 and IKK-β was decreased after hydrogen treatment, whereas PDCD4 was increased, and there was no significant change in NF-κB expression.
CONCLUSION
The results in the present study indicate that miR-9, miR-199 and miR-21 play an important role in the anti-inflammatory regulation of LPS-activated microglia cells by molecular hydrogen, which will help to explain the protective mechanism of molecular hydrogen against inflammatory injury.
doi:10.3980/j.issn.2222-3959.2013.03.05
PMCID: PMC3693006  PMID: 23826519
hydrogen; Lipopolysaccharides; miR-9; miR-21; miR-199; Toll-like receptor 4
19.  Association of a Rare Haplotype in Kinesin Light Chain 1 Gene with Age-Related Cataract in a Han Chinese Population 
PLoS ONE  2013;8(6):e64052.
Purpose
The causal genes for congenital cataract are good candidates for the genetic susceptibility for age-related cataract (ARC). The aim of this study was to investigate association between the polymorphisms in the causal genes for congenital cataract and ARC in a Chinese population. Meanwhile, we performed the replication study for previous identified risk genes for ARC.
Methods
We recruited 212 sporadic Han Chinese patients with age-related cataracts (ARC) and 172 normal controls in this study. We analyzed 31 SNPs from 13 genes which mostly possible contributes the progress of ARC in a Chinese population, comprising 212 cataract patients and 172 controls. Polymorphism-spanning fragments were amplified by using the multiplex polymerase chain reaction (PCR) and genotyped using primer extension method in MassARRAY platform. Allelic and haplotypic difference in the frequencies were estimated using the SHEsis software platform. P-value was adjusted by the Bonferroni correction.
Results
There was no difference in the frequencies of the genotype and allele of the all SNPs between the patients with ARC and the controls. In the haplotypic analysis, the haplotypes consisting of rs7154572, rs7150141 and rs12432994 in Kinesin Light Chain 1 Gene (KLC1) showed significant association with ARC (p = 0.000878). A rare haplotype CGT was more frequent in patients (p = 0.000106, and p = 0.00795 after corrected for 75 tests).
Conclusions
Our study provides evidence that the combined effect of three variants within the KLC1 gene may predispose to ARC, but the precise mechanism needs further investigating.
doi:10.1371/journal.pone.0064052
PMCID: PMC3679130  PMID: 23776437
20.  Systematic Review and Meta-Analysis on the Association between IL-1B Polymorphisms and Cancer Risk 
PLoS ONE  2013;8(5):e63654.
Background
Interleukin-1 beta (IL-1β), a pro-inflammatory cytokine, is emerging as a key mediator of carcinogenesis that characterizes host-environment interactions. Epidemiological studies investigating the association between two polymorphisms of IL-1B (−511C/T and +3954C/T) and cancer susceptibility have shown conflicting results. The aim of this study is to derive a more precise estimation of the relationship.
Methods
Related studies were identified through a systematic literature search of PubMed and Web of Science from their inception to September 15, 2012. Summary odds ratios (ORs) and 95% confidence intervals (CIs) for the IL-1B −511C/T and +3954C/T polymorphisms and cancer risk were calculated. Heterogeneity among studies and publication bias were also tested.
Results
The meta-analysis included 91 case-control studies in 85 publications, 81 studies for the −511C/T (19547 cases and 23935 controls) and 26 studies for the +3954C/T polymorphisms (8083 cases and 9183). The pooled results indicated that IL-1B +3954C/T (dominant model: OR = 1.15, 95% CI: 1.01–1.30) was significantly associated with increased overall cancer risk, especially among hospital-based case-control studies (dominant model: OR = 1.30, 95% CI: 1.02–1.66). As for −511C/T, we observed an inverse relationship in cervical cancer (dominant model: OR = 1.74, 95% CI: 1.35–2.23) and hepatocellular carcinoma (dominant model: OR = 0.68, 95% CI: 0.47–0.99). Moreover, −511C/T was associated with risk of specific subtypes of gastric carcinoma.
Conclusion
This meta-analysis suggested that both the IL-1B –511C/T and +3954C/T polymorphisms might modulate cancer susceptibility. Further well-designed studies based on larger sample sizes should be performed to confirm the findings.
doi:10.1371/journal.pone.0063654
PMCID: PMC3660576  PMID: 23704929
21.  Comparative proteomic and metabolomic profiling of citrus fruit with enhancement of disease resistance by postharvest heat treatment 
BMC Plant Biology  2013;13:44.
Background
From field harvest to the consumer’s table, fresh citrus fruit spends a considerable amount of time in shipment and storage. During these processes, physiological disorders and pathological diseases are the main causes of fruit loss. Heat treatment (HT) has been widely used to maintain fruit quality during postharvest storage; however, limited molecular information related to this treatment is currently available at a systemic biological level.
Results
Mature ‘Kamei’ Satsuma mandarin (Citrus unshiu Marc.) fruits were selected for exploring the disease resistance mechanisms induced by HT during postharvest storage. Proteomic analyses based on two-dimensional gel electrophoresis (2-DE), and metabolomic research based on gas chromatography coupled to mass spectrometry (GC-MS), and liquid chromatography quadrupole time-of-flight mass spectrometry (LC-QToF-MS) were conducted. The results show resistance associated proteins were up-regulated in heat treated pericarp, such as beta-1, 3-glucanase, Class III chitinase, 17.7 kDa heat shock protein and low molecular weight heat-shock protein. Also, redox metabolism enzymes were down-regulated in heat treated pericarp, including isoflavone reductase, oxidoreductase and superoxide dismutase. Primary metabolic profiling revealed organic acids and amino acids were down-regulated in heat treated pericarp; but significant accumulation of metabolites, including tetradecanoic acid, oleic acid, ornithine, 2-keto-d-gluconic acid, succinic acid, turanose, sucrose, galactose, myo-inositol, glucose and fructose were detected. Noticeably, H2O2 content decreased, while, lignin content increased in heat treated pericarp compared to the control, which might increase fruit resistibility in response to external stress. Also, flavonoids, substances which are well-known to be effective in reducing external stress, were up-regulated in heat treated pericarp.
Conclusions
This study provides a broad picture of differential accumulation of proteins and metabolites in postharvest citrus fruit, and gives new insights into HT improved fruit disease resistance during subsequent storage of ‘Kamei’ Satsuma mandarin. Interpretation of the data for the proteins and metabolites revealed reactive oxygen species (ROS) and lignin play important roles in heat treatment induced fruit resistance to pathogens and physiological disorders.
doi:10.1186/1471-2229-13-44
PMCID: PMC3668225  PMID: 23497220
Disease resistance; H2O2; Heat treatment; Lignin postharvest storage; Metabolomics; Proteomics
22.  Detection and Genetic Diversity of Human Metapneumovirus in Hospitalized Children with Acute Respiratory Infections in Southwest China 
Journal of Clinical Microbiology  2012;50(8):2714-2719.
Human metapneumovirus (hMPV) is the main pathogen causing respiratory tract infection in susceptible populations, particularly in children and the elderly. Specimens were collected from hospitalized children with acute lower respiratory tract infections (ALRTI), and the hMPV was detected by using real-time reverse transcription-PCR (RT-PCR). The full-length G gene of hMPV was amplified by RT-PCR. A total of 1,410 nasopharyngeal aspirates (NPAs) were collected from April 2008 to March 2011, and 114 (10.2%) were positive for hMPV. Most hMPV-positive children were <5 years of age. The hMPV infection rate peaked in the spring-summer season of 2008 to 2009 and 2009 to 2010, while hMPV circulated predominantly during the winter-spring season of 2010 to 2011. The full-length G gene of 23 hMPV strains was amplified, and group A and B viruses accounted for 95.7% (22/23) and 4.3% (1/23), respectively. Genotype A2b of hMPV appeared to be predominant during the study period. Three genotypes (A2b, A1, and B1) were prevalent in the epidemic season of 2008 to 2009, and only genotype A2b was identified in the other two seasons (2009 to 2010 and 2010 to 2011). The G gene of hMPV was predicted to encode proteins with four different lengths, in which one with 210 amino acids was first identified in China. These findings suggest that hMPV was an important pathogen of ALRTI in pediatric patients, especially those <5 years of age. Genotype A2b of hMPV likely predominates in Southwest China, where other genotypes also circulate.
doi:10.1128/JCM.00809-12
PMCID: PMC3421497  PMID: 22692746
23.  Proteomic Analysis of the Effect of Fuzheng Huayu Recipe on Fibrotic Liver in Rats 
Hepatic fibrosis is a common pathological process of chronic liver diseases and would lead to cirrhosis, and Fuzheng Huayu (FZHY) is an effective Chinese herbal product against liver fibrosis. This study observes FZHY influence on proteome of fibrotic liver with differential proteomic approach and aims to understand FZHY multiple action mechanisms on liver fibrosis. The liver fibrosis models were induced with intraperitoneal injection of dimethylnitrosamine for 4 weeks in rats and divided into model control (model) and FZHY-treated (FZHY) groups, while normal rats were used as normal control (normal). After model establishment, rats in FZHY groups were administered 4 g/kg wt of FZHY for 4 weeks, and normal and model groups were given the same volume of saline. The liver proteins in the above 3 groups were separated by two-dimensional gel electrophoresis (2-DE), the differentially expressed spots were analyzed and compared between normal and model or model and FZHY groups, and then the proteins were identified with mass spectrum analysis and validated partially with western blot and real-time PCR. 1000~1200 spots were displayed on each 2D gel, and a total of 61 protein spots were found with significant intensity difference between normal control or FZHY and model control. 23 most obviously differential spots were excised, and in-gel digestion and 21 peptide mass fingerprints (PMF) were obtained with MALDI-TOF MS analysis, and 14 proteins were identified through protein database searching. Among 14 differentially expressed proteins, 8 proteins in normal and FZHY groups had the same tendency of differential expression compared with the ones in model group. And one of them, vimentin, was validated by western blot and real-time PCR analyses. Our study reveals 12 proteins responsible for fibrogenesis induced by DMN in rats, and among them, 8 proteins in fibrotic liver were regulated by FZHY, including aldehyde dehydrogenase, vimentin isoform (CRA_b), gamma-actin, vimentin, fructose-bisphosphate aldolase B, aldo-keto reductase, S-adenosylhomocysteine hydrolase isoform, and HSP90. It indicates that the action mechanism of FZHY antiliver fibrosis may be associated with modulation of proteins associated with metabolism and stress response, as well as myofibroblast activation. The study provides new insights and data for exploring the liver fibrogenesis pathophysiology and FZHY action mechanism against liver fibrosis.
doi:10.1155/2013/972863
PMCID: PMC3569931  PMID: 23431353
24.  Metabolic profiles characterizing different phenotypes of polycystic ovary syndrome: plasma metabolomics analysis 
BMC Medicine  2012;10:153.
Background
Polycystic ovary syndrome (PCOS) is a heterogeneous endocrine disorder accompanied with an increased risk of developing type 2 diabetes mellitus and cardiovascular disease; despite being a common condition, the pathogenesis of PCOS remains unclear. Our aim was to investigate the potential metabolic profiles for different phenotypes of PCOS, as well as for the early prognosis of complications.
Methods
A total of 217 women with PCOS and 48 healthy women as normal controls were studied. Plasma samples of subjects were tested using two different analytical platforms of metabolomics: 1H nuclear magnetic resonance (NMR) and gas chromatography/time-of-flight mass spectrometry (GC/TOF-MS).
Results
Our results showed that carbohydrate, lipid and amino acid metabolisms were influenced in PCOS. The levels of lactate, long-chain fatty acids, triglyceride and very low-density lipoprotein were elevated, while glucose, phosphatidylcholine and high-density lipoprotein (HDL) concentrations were reduced in PCOS patients as compared with controls. Additionally, the levels of alanine, valine, serine, threonine, ornithine, phenylalanine, tyrosine and tryptophan were generally increased, whereas the levels of glycine and proline were significantly reduced in PCOS samples compared to controls. Furthermore, the ratio of branched-chain amino acid to aromatic amino acid concentrations (BCAA/AAA) in PCOS plasma was significantly reduced in PCOS patients and was insusceptible to obesity and insulin sensitivity.
Conclusions
Our results suggested that the enhanced glycolysis and inhibited tricarboxylic acid cycle (TAC) in women with PCOS. Decrease of BCAA/AAA ratio was directly correlated with the development of PCOS. Ovulatory dysfunction of PCOS patients was associated with raised production of serine, threonine, phenylalanine, tyrosine and ornithine. Elevated levels of valine and leucine, and decreased concentrations of glycine in PCOS plasma could contribute to insulin sensitivity and could be considered as the potential biomarkers for long-term risk assessment of diabetes mellitus.
doi:10.1186/1741-7015-10-153
PMCID: PMC3599233  PMID: 23198915
polycystic ovary syndrome; amino acid metabolism; carbohydrate and lipid metabolism; insulin resistance; inflammation
25.  Salvianolic Acid B Attenuates Rat Hepatic Fibrosis via Downregulating Angiotensin II Signaling 
The renin-angiotensin system (RAS) plays an important role in hepatic fibrosis. Salvianolic acid B (Sal B), one of the water-soluble components from Radix Salviae miltiorrhizae, has been used to treat hepatic fibrosis, but it is still not clear whether the effect of Sal B is related to angiotensin II (Ang II) signaling pathway. In the present study, we studied Sal B effect on rat liver fibrosis and Ang-II related signaling mediators in dimethylnitrosamine-(DMN-) induced rat fibrotic model in vivo and Ang-II stimulated hepatic stellate cells (HSCs) in vitro, with perindopril or losartan as control drug, respectively. The results showed that Sal B and perindopril inhibited rat hepatic fibrosis and reduced expression of Ang II receptor type 1 (AT1R) and ERK activation in fibrotic liver. Sal B and losartan also inhibited Ang II-stimulated HSC activation including cell proliferation and expression of type I collagen I (Col-I) and α-smooth muscle actin (α-SMA) production in vitro, reduced the gene expression of transforming growth factor beta (TGF-β), and downregulated AT1R expression and ERK and c-Jun phosphorylation. In conclusion, our results indicate that Sal B may exert an antihepatic fibrosis effect via downregulating Ang II signaling in HSC activation.
doi:10.1155/2012/160726
PMCID: PMC3518291  PMID: 23243430

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