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Toxicology  2014;317:40-49.
Exposure to cigarette smoke during development is linked to neurodevelopmental delays and cognitive impairment including impulsivity, attention deficit disorder, and lower IQ. However, brain region specific biomolecular alterations induced by developmental cigarette smoke exposure (CSE) remain largely unexplored. In the current molecular phenotyping study, a mouse model of ‘active’ developmental CSE (serum cotinine>50 ng/mL) spanning pre-implantation through third trimester-equivalent brain development (gestational day (GD) 1 through postnatal day (PD) 21) was utilized. Hippocampus tissue collected at the time of cessation of exposure was processed for gel-based proteomic and non-targeted metabolomic profiling with Partial Least Squares-Discriminant Analysis (PLS-DA) for selection of features of interest. Ingenuity Pathway Analysis was utilized to identify candidate molecular and metabolic pathways impacted within the hippocampus. CSE impacted glycolysis, oxidative phosphorylation, fatty acid metabolism, and neurodevelopment pathways within the developing hippocampus.
PMCID: PMC4067966  PMID: 24486158
Development; cigarette smoke; tobacco; hippocampus; proteome; metabolome
2.  Reproducibility of Blood Pressure Responses to Dietary Sodium and Potassium Interventions: The GenSalt Study 
Hypertension  2013;62(3):499-505.
Blood pressure responses to dietary sodium and potassium interventions vary among individuals. We studied the long-term reproducibility of blood pressure responses to dietary sodium and potassium intake. We repeated the dietary sodium and potassium interventions among 487 Chinese adults 4.5 years after the original dietary intervention. The identical dietary intervention protocol, which included a 7-day low-sodium feeding (51.3 mmol/day), a 7-day high-sodium feeding (307.8 mmol/day), and a 7-day high-sodium feeding with oral potassium supplementation (60.0 mmol/day), was applied in both the initial and repeated studies. Three blood pressure measurements were obtained during each of the 3 days of baseline observation and on days 5, 6, and 7 of each intervention period. The results from the 24-hour urinary excretion of sodium and potassium showed excellent compliance with the study diet. Blood pressure responses to dietary intervention in the original and repeated studies were highly correlated. For example, the correlation coefficients (95% confidence interval) for systolic blood pressure levels were 0.77 (0.73, 0.80) at baseline, 0.79 (0.75, 0.82) during low-sodium, 0.80 (0.77, 0.83) during high-sodium, and 0.82 (0.79, 0.85) during high-sodium and potassium supplementation interventions (all P< 0.0001). The correlation coefficients for systolic blood pressure changes were 0.37 (0.29, 0.44) from baseline to low-sodium, 0.37 (0.29, 0.44) from low- to high-sodium, and 0.28 (0.20, 0.36) from high-sodium to high-sodium plus potassium supplementation (all P< 0.0001). These data indicate that blood pressure responses to dietary sodium and potassium interventions have long-term reproducibility and stable characteristics in the general population.
PMCID: PMC4364515  PMID: 23897070
blood pressure; potassium; dietary; reproducibility of results; sodium; dietary
3.  Association of obesity and biomarkers of inflammation and endothelial dysfunction in adults in Inner Mongolia, China 
International journal of cardiology  2010;150(3):247-252.
Recent studies suggest that central obesity is an important predictor of cardiovascular disease (CVD) in addition to overall obesity. Both inflammation and endothelial dysfunction are associated with increased risk of CVD. We examined the association between body mass index (BMI) and waist circumference (WC) with plasma concentrations of biomarkers of inflammation and endothelial dysfunction.
We conducted a cross-sectional study of 2589 lean, moderately active participants aged 20 years and older in Inner Mongolia, China. Overnight fasting blood samples were obtained to measure the biomarkers including C-reactive protein (CRP), soluble inter-cellular adhesion molecule-1 (sICAM-1), soluble E-selectin (sE-selectin), and angiotensin II. Height, body weight, and WC were measured by trained staff and BMI was calculated (kg/m2).
In univariate analysis, CRP, sICAM-1, and sE-selectin were all significantly higher among individuals with a higher BMI and WC. In multivariate analysis, each standard deviation (SD) increase in WC (9.6 cm) was associated with about 46% higher risk (odds ratio [OR] 1.46, 95% confidence interval [CI] 1.21–1.76) of elevated CRP but a 1 SD increase in BMI (3.5 kg/m2) was not associated with the risk of elevated CRP (OR 0.96, 95% CI 0.80–1.16). However, each SD increase in BMI was associated with about 30% higher risk of having elevated E-selectin (OR 1.30, 95% CI 1.08–1.55).
WC is a stronger predictor of inflammation while BMI is a stronger predictor for endothelial dysfunction. These results suggest measuring both BMI and WC will help to assess the risk of CVD in the Chinese population.
PMCID: PMC4364655  PMID: 20439121
Inflammation; Endothelial dysfunction; C-reactive protein; Body mass index; Waist circumference
4.  Spatio-temporal Model for Silencing of the Mitotic Spindle Assembly Checkpoint 
Nature communications  2014;5:4795.
The spindle assembly checkpoint arrests mitotic progression until each kinetochore secures a stable attachment to the spindle. Despite fluctuating noise, this checkpoint remains robust and remarkably sensitive to even a single unattached kinetochore among many attached kinetochores; moreover, the checkpoint is silenced only after the final kinetochore-spindle attachment. Experimental observations have shown that checkpoint components stream from attached kinetochores along microtubules toward spindle poles. Here, we incorporate this streaming behavior into a theoretical model that accounts for the robustness of checkpoint silencing. Poleward streams are integrated at spindle poles, but are diverted by any unattached kinetochore; consequently, accumulation of checkpoint components at spindle poles increases markedly only when every kinetochore is properly attached. This step-change robustly triggers checkpoint silencing after, and only after, the final kinetochore-spindle attachment. Our model offers a conceptual framework that highlights the role of spatiotemporal regulation in mitotic spindle checkpoint signaling and fidelity of chromosome segregation.
PMCID: PMC4163959  PMID: 25216458
mitosis; spindle assembly checkpoint; spatio-temporal regulation; SAC silencing; theoretical model
5.  The jasmonate-responsive GTR1 transporter is required for gibberellin-mediated stamen development in Arabidopsis 
Nature Communications  2015;6:6095.
Plant hormones are transported across cell membranes during various physiological events. Recent identification of abscisic acid and strigolactone transporters suggests that transport of various plant hormones across membranes does not occur by simple diffusion but requires transporter proteins that are strictly regulated during development. Here, we report that a major glucosinolate transporter, GTR1/NPF2.10, is multifunctional and may be involved in hormone transport in Arabidopsis thaliana. When heterologously expressed in oocytes, GTR1 transports jasmonoyl-isoleucine and gibberellin in addition to glucosinolates. gtr1 mutants are severely impaired in filament elongation and anther dehiscence resulting in reduced fertility, but these phenotypes can be rescued by gibberellin treatment. These results suggest that GTR1 may be a multifunctional transporter for the structurally distinct compounds glucosinolates, jasmonoyl-isoleucine and gibberellin, and may positively regulate stamen development by mediating gibberellin supply.
GTR1 is known to transport glucosinolates in Arabidopsis. Here, Saito et al. show that GTR1 also transports the plant hormones jasmonate and gibberellin when heterologously expressed in Xenopus oocytes, and that gtr1 mutant plants show a gibberellin-related fertility phenotype.
PMCID: PMC4347201  PMID: 25648767
6.  Long-term exposure to low-concentrations of Cr(VI) induce DNA damage and disrupt the transcriptional response to benzo[a]pyrene 
Toxicology  2013;316:14-24.
Living organisms are exposed on a daily basis to widespread mixtures of toxic compounds. Mixtures pose a major problem in the assessment of health effects because they often generate substance-specific effects that cannot be attributed to a single mechanism. Two compounds often found together in the environment are the heavy metal chromium and the polycyclic aromatic hydrocarbon benzo[a]pyrene (B[a]P). We have examined how long-term exposure to a low concentration of Cr(VI) affects the transcriptional response to B[a]P, a second toxicant with an unrelated mechanism of action. Growth of mouse hepatoma cells for 20 passages in medium with 0.1 or 0.5 μM Cr(VI) increases DNA damage and apoptosis while decreasing clonogenic ability. Treated cells also show transcriptome changes indicative of increased expression of DNA damage response and repair genes. In them, B[a]P activates cancer progression pathways, unlike in cells never exposed to Cr(VI), where B[a]P activates mostly xenobiotic metabolism pathways. Cells grown in Cr(VI) for 20 passages and then cultured for an additional 5 passages in the absence of Cr(VI) recover from some but not all the chromium effects. They show B[a]P-dependent transcriptome changes strongly weighted towards xenobiotic metabolism, similar to those in B[a]P-treated cells that had no previous Cr(VI) exposure, but retain a high level of Cr(VI)-induced DNA damage and silence the expression of DNA damage and cancer progression genes. We conclude that the combined effect of these two toxicants appears to be neither synergistic nor additive, generating a toxic/adaptive condition that cannot be predicted from the effect of each toxicant alone.
PMCID: PMC3945963  PMID: 24374135
Chromium; heavy metals; B[a]P; Gene expression; complex mixtures; transcriptome
7.  A New Domain in the Toll/IL-1R Domain-Containing Adaptor Inducing IFN-β Factor (TRIF) Protein Amino Terminus Is Important for TRAF3 Association, Protein Stabilization, and Interferon Signaling 
Journal of innate immunity  2014;6(3):377-393.
Toll/IL-1R domain-containing adaptor inducing IFN-β factor (TRIF) is a key adapter for Toll-like receptor (TLR) 3 and 4 signaling. Using a novel cDNA isolate encoding a TRIF protein with a 21-residue deletion (Δ160-181) from its amino-terminal half, we investigated the impact of this deletion on TRIF functions. Transfection studies consistently showed higher expression levels of the (Δ160-181) TRIF compared to wild-type (wt) TRIF, an effect unrelated to apoptosis, cell lines, or plasmid amplification. Colocalization of wt and (Δ160-181) TRIF proteins led to a dramatic reduction of their respective expressions, suggesting that wt/(Δ160-181) TRIF heterocomplexes are targeted for degradation. We demonstrated that wt TRIF associates with TRAF3 better than (Δ160-181) TRIF, culminating in its greater ubiquitination and proteolysis. This explains, in part, the differential expression levels of the two TRIF proteins. Despite higher expression levels in transfected cells, (Δ160-181) TRIF inefficiently transactivated the interferon pathway, whereas the NF-κB pathway activation remained similar to that by wt TRIF. In co-expression studies, (Δ160-181) TRIF marginally contributed to the interferon pathway activation, but still enhanced NF-κB signaling with wt TRIF. Therefore, this 21 amino acid sequence is crucial for TRAF3 association, modulation of TRIF stability and activation of the interferon pathway.
PMCID: PMC4058787  PMID: 24577058
Innate Immunity; Interferon Signaling; Protein Stability; TRAF3; TRIF; Ubiquitination
8.  Home-based tele-supervising rehabilitation for brain infarction patients (HTRBIP): study protocol for a randomized controlled trial 
Trials  2015;16:61.
With high morbidity, mortality and disability rate, brain infarction brings a huge economic and health burden to the whole society in China. Although some previous studies suggested that telerehabilitation may facilitate rehabilitation for stroke survivors at home, the evidence is insufficient for clinical application; additionally, as yet no trial evaluates efficacy of telerehabilitation for brain infarction patients. Therefore, more high quality trials are needed to provide practice evidence for this novel rehabilitation strategy.
Based on recruitment criteria, this assessor blinded, paralleled randomized controlled trial will recruit 210 brain infarction patients. After being randomly allocated into two groups, participants will receive home-based tele-supervising rehabilitation or conventional rehabilitation. Outcome measurement will be conducted at the end of intervention and 90-day follow-up. Among which, Barthel index assessment will be considered as primary outcome measurement, secondary outcome measurements include NIHSS score, mRS score, 3-oz water swallow test and surface electromyography. Adverse events will also be recorded during the whole process of the trial for safety assessment.
The HTRBIP trial will evaluate efficacy and safety of home-based tele-supervising rehabilitation for brain infarction patients. It is expected to provide new evidence for telerehabilitation application.
Trial registration
Registration date: 17 September 2014; Registration number: ChiCTR-TRC-14005233
PMCID: PMC4346119  PMID: 25888520
Brain infarction; Stroke; Rehabilitation; Telemedicine; Telerehabilitation
9.  Tyr-phosphorylation of PDP1 toggles recruitment between ACAT1 and SIRT3 to regulate pyruvate dehydrogenase complex 
Molecular cell  2014;53(4):534-548.
Mitochondrial pyruvate dehydrogenase complex (PDC) is crucial for glucose homoeostasis in mammalian cells. The current understanding of PDC regulation involves inhibitory serine phosphorylation of pyruvate dehydrogenase (PDH) by PDH kinase (PDK), whereas dephosphorylation of PDH by PDH phosphatase (PDP) activates PDC. Here we report that lysine acetylation of PDHA1 and PDP1 is common in EGF-stimulated cells and diverse human cancer cells. K321 acetylation inhibits PDHA1 by recruiting PDK1 and K202 acetylation inhibits PDP1 by dissociating its substrate PDHA1, both of which are important to promote glycolysis in cancer cells and consequent tumor growth. Moreover, we identified mitochondrial ACAT1 and SIRT3 as the upstream acetyltransferase and deacetylase, respectively, of PDHA1 and PDP1, while knockdown of ACAT1 attenuates tumor growth. Furthermore, Y381 phosphorylation of PDP1 dissociates SIRT3 and recruits ACAT1 to PDC. Together, hierarchical, distinct post-translational modifications act in concert to control molecular composition of PDC and contribute to the Warburg effect.
PMCID: PMC3943932  PMID: 24486017
10.  Bacteria that glide with helical tracks 
Current biology : CB  2014;24(4):R169-R173.
Many bacteria glide smoothly on surfaces, but with no discernable propulsive organelles on their surface. Recent experiments with Myxococcus xanthus and Flavobacterium johnsoniae show that both distantly related bacterial species glide utilizing proteins that move in helical tracks, albeit with significantly different motility mechanisms. Both species utilize proton motive force for movement. However, the motors that power gliding in M. xanthus have been identified, while the F. johnsoniae motors remain to be discovered.
PMCID: PMC3964879  PMID: 24556443
11.  Analysis of methane-producing and metabolizing archaeal and bacterial communities in sediments of the northern South China Sea and coastal Mai Po Nature Reserve revealed by PCR amplification of mcrA and pmoA genes 
Communities of methanogens, anaerobic methanotrophic archaea and aerobic methanotrophic bacteria (MOB) were compared by profiling polymerase chain reaction (PCR)-amplified products of mcrA and pmoA genes encoded by methyl-coenzyme M reductase alpha subunit and particulate methane monooxygenase alpha subunit, respectively, in sediments of northern South China Sea (nSCS) and Mai Po mangrove wetland. Community structures representing by mcrA gene based on 12 clone libraries from nSCS showed separate clusters indicating niche specificity, while, Methanomicrobiales, Methanosarcinales clades 1,2, and Methanomassiliicoccus-like groups of methanogens were the most abundant groups in nSCS sediment samples. Novel clusters specific to the SCS were identified and the phylogeny of mcrA gene-harboring archaea was updated. Quantitative polymerase chain reaction was used to detect mcrA gene abundance in all samples: similar abundance of mcrA gene in the surface layers of mangrove (3.4∼3.9 × 106 copies per gram dry weight) and of intertidal mudflat (5.5∼5.8 × 106 copies per gram dry weight) was observed, but higher abundance (6.9 × 106 to 1.02 × 108 copies per gram dry weight) was found in subsurface samples of both sediment types. Aerobic MOB were more abundant in surface layers (6.7∼11.1 × 105 copies per gram dry weight) than the subsurface layers (1.2∼5.9 × 105 copies per gram dry weight) based on pmoA gene. Mangrove surface layers harbored more abundant pmoA gene than intertidal mudflat, but less pmoA genes in the subsurface layers. Meanwhile, it is also noted that in surface layers of all samples, more pmoA gene copies were detected than the subsurface layers. Reedbed rhizosphere exhibited the highest gene abundance of mcrA gene (8.51 × 108 copies per gram dry weight) and pmoA gene (1.56 × 107 copies per gram dry weight). This study investigated the prokaryotic communities responsible for methane cycling in both marine and coastal wetland ecosystems, showing the distribution characteristics of mcrA gene-harboring communities in nSCS and stratification of mcrA and pmoA gene diversity and abundance in the Mai Po Nature Reserve.
PMCID: PMC4343527  PMID: 25774150
methanotrophs; anaerobic methane oxidation; carbon cycle; mcrA gene; pmoA gene
12.  CsrA impacts survival of Yersinia enterocolitica by affecting a myriad of physiological activities 
BMC Microbiology  2015;15:31.
A previous study identified a Yersinia enterocolitica transposon mutant, GY448, that was unable to export the flagellar type three secretion system (T3SS)-dependent phospholipase, YplA. This strain was also deficient for motility and unable to form colonies on Lauria-Bertani agar medium. Preliminary analysis suggested it carried a mutation in csrA. CsrA in Escherichia coli is an RNA-binding protein that is involved in specific post-transcriptional regulation of a myriad of physiological activities. This study investigated how CsrA affects expression of the flagellar regulatory cascade that controls YplA export and motility. It also explored the effect of csrA mutation on Y. enterocolitica in response to conditions that cue physiological changes important for growth in environments found both in nature and the laboratory.
The precise location of the transposon insertion in GMY448 was mapped within csrA. Genetic complementation restored disruptions in motility and the YplA export phenotype (Yex), which confirmed this mutation disrupted CsrA function. Mutation of csrA affected expression of yplA and flagellar genes involved in flagellar T3SS dependent export and motility by altering expression of the master regulators flhDC. Mutation of csrA also resulted in increased sensitivity of Y. enterocolitica to various osmolytes, temperatures and antibiotics.
The results of this study reveal unique aspects of how CsrA functions in Y. enterocolitica to control its physiology. This provides perspective on how the Csr system is susceptible to adaptation to particular environments and bacterial lifestyles.
PMCID: PMC4336687  PMID: 25885058
Yersinia; CsrA; Csr system; Motility; Salt sensitivity; Antibiotic sensitivity; Temperature sensitivity; Psychrotroph; Mutant selection
13.  Activation of TRPV1 channel by dietary capsaicin improves visceral fat remodeling through connexin43-mediated Ca2+ Influx 
The prevalence of obesity has dramatically increased worldwide and has attracted rising attention, but the mechanism is still unclear. Previous studies revealed that transient receptor potential vanilloid 1 (TRPV1) channels take part in weight loss by enhancing intracellular Ca2+ levels. However, the potential mechanism of the effect of dietary capsaicin on obesity is not completely understood. Ca2+ transfer induced by connexin43 (Cx43) molecules between coupled cells takes part in adipocyte differentiation. Whether TRPV1-evoked alterations in Cx43-mediated adipocyte-to-adipocyte communication play a role in obesity is unknown.
Materials and methods
We investigated whether Cx43 participated in TRPV1-mediated adipocyte lipolysis in cultured 3T3-L1 preadipocytes and visceral adipose tissues from humans and wild-type (WT) and TRPV1-deficient (TRPV1-/-) mice.
TRPV1 and Cx43 co-expressed in mesenteric adipose tissue. TRPV1 activation by capsaicin increased the influx of Ca2+ in 3T3-L1 preadipocytes and promoted cell lipolysis, as shown by Oil-red O staining. These effects were deficient when capsazepine, a TRPV1 antagonist, and 18 alpha-glycyrrhetinic acid (18α-GA), a gap-junction inhibitor, were administered. Long-term chronic dietary capsaicin reduced the weights of perirenal, mesenteric and testicular adipose tissues in WT mice fed a high-fat diet. Capsaicin increased the expression levels of p-CaM, Cx43, CaMKII, PPARδ and HSL in mesenteric adipose tissues from WT mice fed a high-fat diet, db/db mice, as well as obese humans, but these effects of capsaicin were absent in TRPV1-/- mice. Long-term chronic dietary capsaicin decreased the body weights and serum lipids of WT mice, but not TRPV1-/- mice, fed a high-fat diet.
This study demonstrated that capsaicin activation of TRPV1-evoked increased Ca2+ influx in Cx43-mediated adipocyte-to-adipocyte communication promotes lipolysis in both vitro and vivo. TRPV1 activation by dietary capsaicin improves visceral fat remodeling through the up-regulation of Cx43.
PMCID: PMC4340344  PMID: 25849380
TRPV1; Cx43; Obesity; Ca2+; Visceral fat remodeling
14.  Detection of Hepatitis B Virus Genotypic Resistance Mutations by Coamplification at Lower Denaturation Temperature-PCR Coupled with Sanger Sequencing 
Journal of Clinical Microbiology  2014;52(8):2933-2939.
Mutations in the reverse transcriptase (rt) region of the DNA polymerase gene are the primary cause of hepatitis B virus (HBV) drug resistance. In this study, we established a novel method that couples coamplification at lower denaturation temperature (COLD)-PCR and Sanger sequencing, and we applied it to the detection of known and unknown HBV mutations. Primers were designed based on the common mutations in the HBV rt sequence at positions 180 to 215. The critical denaturation temperature (Tc) was established as a denaturing temperature for both fast and full COLD-PCR procedures. For single mutations, when a melting temperature (Tm)-reducing mutation occurred (e.g., C-G→T-A), the sensitivities of fast and full COLD-PCR for mutant detection were 1% and 2%, respectively; when the mutation caused no change in Tm (e.g., C-G→G-C) or raised Tm (e.g., T-A→C-G), only full COLD-PCR improved the sensitivity for mutant detection (2%). For combination mutations, the sensitivities of both full and fast COLD-PCR were increased to 0.5%. The limits of detection for fast and full COLD-PCR were 50 IU/ml and 100 IU/ml, respectively. In 30 chronic hepatitis B (CHB) cases, no mutations were detected by conventional PCR, whereas 18 mutations were successfully detected by COLD-PCR, including low-prevalence mutations (<10%), as confirmed by ultradeep pyrosequencing. In conclusion, COLD-PCR provides a highly sensitive, simple, inexpensive, and practical tool for significantly improving amplification efficacy and detecting low-level mutations in clinical CHB cases.
PMCID: PMC4136161  PMID: 24899029
15.  NVP-BEZ235 overcomes gefitinib-acquired resistance by down-regulating PI3K/AKT/mTOR phosphorylation 
OncoTargets and therapy  2015;8:269-277.
Patients harboring activating mutations in epidermal growth factor receptors (EGFR) are particularly sensitive to EGFR tyrosine kinase inhibitors (TKIs). However, most patients develop an acquired resistance after a period of about 10 months. This study focuses on the therapeutic effect of NVP-BEZ235, a dual inhibitor of phosphatidylinositol-3-kinase/mammalian target of rapamycin (PI3K/mTOR), in gefitinib-resistant non-small cell lung cancer.
H1975 cell line was validated as a gefitinib-resistant cell model by the nucleotide-sequence analysis. We used the 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay to detect the growth of H1975 cell line in vitro. H1975 cells’ migration was detected by the migration assay. Xenograft models were used to investigate the growth of gefitinib-resistant non-small cell lung cancer in vivo. Western blot and immunohistochemical analysis were used to investigate the level of PI3K/protein kinase B(AKT)/mTOR signaling pathway proteins.
We show that NVP-BEZ235 effectively inhibited the growth of H1975 cells in vivo as well as in vitro. Similarly, H1975 cell migration was reduced by NVP-BEZ235. Further experiments revealed that NVP-BEZ235 attenuated the phosphorylation of PI3K/AKT/mTOR signaling pathway proteins.
Taken together, we suggest that NVP-BEZ235 inhibits gefitinib-resistant tumor growth by downregulating PI3K/AKT/mTOR phosphorylation.
PMCID: PMC4321659  PMID: 25674002
gefitinib-acquired resistance; PI3K kinase; mTOR; NVP-BEZ235
16.  New substitute name for the genus Poliocoris Slater, 1994 (Hemiptera, Heteroptera, Rhyparochromidae) 
ZooKeys  2015;147-148.
Neopoliocoris nom. n., a new substitute name is proposed for Poliocoris Slater, 1994 (Hemiptera: Heteroptera: Rhyparochromidae), preoccupied by Poliocoris Kirkaldy, 1910 (Hemiptera: Heteroptera: Pentatomidae). A new combination, Neopoliocoris umbrosus (Slater, 1994), comb. n. is proposed for Poliocoris umbrosus Slater, 1994.
PMCID: PMC4319055  PMID: 25685013
Hemiptera; Heteroptera; bugs; homonym; replacement name
17.  Prognostic and clinical significance of STAT3 and MMP9 in patients with gastric cancer: a meta-analysis of a Chinese cohort 
As signal transducer and activator of transcription 3 (STAT3)-mediated signaling cascade directly contributes to tumor metastasis, numerous agents targeting STAT3 are in clinical development. However, reported data on the prognostic impact of STAT3 expression vary considerably. We aim to quantitatively summarize available evidences for evaluating the association between STAT3 and STAT3-regulated target gene, matrix metalloproteinase 9 (MMP9), and the prognosis of Chinese patients with gastric cancer. Searches were applied to PubMed and the Chinese National Knowledge Infrastructure database without any language restriction. A total of 5,757 patients were included in the final analyses. All results favored an association between high STAT3 expression and poor 5-year overall survival (risk ratio = 1.845, 95% confidence interval [CI] = 1.027-3.315). The reduced survival was heavily influenced by advanced tumor invasion (OR = 2.885, 95% CI = 2.034-4.094), lymph node metastasis (OR = 5.349, 95% CI = 3.807-7.516), distant metastasis (OR = 5.873, 95% CI = 2.641-13.062), dedifferentiation (OR = 2.516, 95% CI = 1.814-3.491), tumor size (OR = 1.918, 95% CI = 1.246-2.954), and higher TNM stage (OR = 4.171, 95% CI = 2.840-6.126). Similar results were observed in the meta-analyses of MMP9, with the magnitude of effect OR > 2. Our findings indicate that STAT3 and MMP9, as measured by IHC, are associated with worse survival and potentially mark invasion and metastasis in gastric cancer, especially in Chinese patients. More significantly, these two biomarkers may be converted from candidates to the routine clinical evaluation to help predict the outcome of gastric carcinoma patients.
PMCID: PMC4358484  PMID: 25785029
Gastric cancer; STAT3; MMP9; prognostic factor
18.  Liver Damage Associated with Polygonum multiflorum Thunb.: A Systematic Review of Case Reports and Case Series 
Objective. To summarize the characteristics and analysis of relevant factors and to give references for prevention and further study of liver damage associated with Polygonum multiflorum Thunb. (HSW), we provide a systematic review of case reports and case series about liver damage associated with HSW. Methods. An extensive search of 6 medical databases was performed up to June 2014. Case reports and case series involving liver damage associated with HSW were included. Results. This review covers a total of 450 cases in 76 articles. HSW types included raw and processed HSW decoction pieces and many Chinese patent medicines that contain HSW. Symptoms of liver damage occur mostly a month or so after taking the medicine, mainly including jaundice, fatigue, anorexia, and yellow or tawny urine. Of the 450 patients, two cases who received liver transplantation and seven who died, the remaining 441 cases recovered or had liver function improvement after discontinuing HSW products and conservative care. Conclusion. HSW causes liver toxicity and may cause liver damage in different degrees and even lead to death; most of them are much related to long-term and overdose of drugs. Liver damage associated with HSW is reversible, and, after active treatment, the majority can be cured. People should be alert to liver damage when taking HSW preparations.
PMCID: PMC4306360  PMID: 25648693
19.  Vav1 as a Central Regulator of Invadopodia Assembly 
Current biology : CB  2013;24(1):86-93.
Invadopodia are protrusive structures used by tumor cells for degradation of the extracellular matrix to promote invasion [1]. Invadopodia formation and function are regulated by cytoskeletal remodeling pathways and the oncogenic kinase Src. The guanine nucleotide exchange factor Vav1, which is an activator of Rho family GTPases, is ectopically expressed in many pancreatic cancers, where it promotes tumor cell survival and migration [2, 3]. We have now determined that Vav1 is also a potent regulator of matrix degradation by pancreatic tumor cells, as depletion of Vav1 by siRNA-mediated knockdown inhibits the formation of invadopodia. This requires the exchange function of Vav1 toward the GTPase Cdc42, which is required for invadopodia assembly [4, 5]. In addition, we have determined that Src-mediated phosphorylation and activation of Vav1 is both required for, and, unexpectedly, sufficient for, invadopodia formation. Expression of Vav1 Y174F, which mimics its activated state, is a potent inducer of invadopodia formation through Cdc42, even in the absence of Src activation and phosphorylation of other Src substrates, such as cortactin. Thus, these data identify a novel mechanism by which Vav1 can enhance the tumorigenicity and invasive potential of cancer cells. These data suggest that Vav1 promotes the matrix-degrading processes underlying tumor cell migration, and further, under conditions of ectopic Vav1 expression, that Vav1 is a central regulator and major driver of invasive matrix remodeling by pancreatic tumor cells.
PMCID: PMC3917499  PMID: 24332539
20.  Blood Pressure Responses to Dietary Sodium and Potassium Interventions and the Cold Pressor Test: The GenSalt Replication Study in Rural North China 
In the Genetic Epidemiology Network of Salt Sensitivity (GenSalt) study, we observed that blood pressure (BP) responses to dietary sodium and potassium interventions and the cold pressor test (CPT) varied greatly among individuals. We conducted a replication study to confirm our previous findings among 695 study participants.
The dietary intervention included a 7-day low sodium (51.3 mmol/day), a 7-day high sodium (307.8 mmol/day), and a 7-day high sodium with potassium supplementation (307.8 mmol sodium and 60 mmol potassium/day). BP measurements were obtained during the baseline and each intervention phase. During the CPT, BP was measured before and at 0, 1, 2, and 4 minutes after the participants immersed their right hand in ice water for 1 minute.
Systolic and diastolic BP responses (mean ± SD (range), mm Hg) were 8.1±8.4 (−39.1 to 18.2) and −3.5±5.1 (−25.1 to 11.1) to low sodium, 9.1±8.4 (−13.3 to 33.1) and 4.0±5.4 (−16.0 to 20.7) to high sodium, and −4.6±5.8 (−31.8 to 11.6) and −1.9±4.3 (−16.9 to 14.2) to potassium supplementation, respectively (all P < 0.0001 for comparison with each former phase). The mean maximum systolic and diastolic BP responses to the CPT were 16.5±10.5 (−15.3 to 63.3) and 7.6±6.1 (−8.7 to 39.3), respectively (all P < 0.0001).
Our study indicates that there are large variations in BP responses to dietary sodium and potassium interventions and to the CPT among individuals.
PMCID: PMC3848630  PMID: 24004934
blood pressure; cold pressor test; dietary potassium; hypertension; salt sensitivity; sodium.
21.  Application of the Protection Motivation Theory in Predicting Cigarette Smoking Among Adolescents in China 
Addictive behaviors  2013;39(1):181-188.
Reducing tobacco use among adolescents in China represents a significant challenge for global tobacco control. Existing behavioral theories developed in the West – such as the Protection Motivation Theory (PMT) – may be useful tools to help tackle this challenge. We examined the relationships between PMT factors and self-reported cigarette smoking behavior and intention among a random sample of vocational high school students (N = 553) in Wuhan, China. Tobacco-related perceptions were assessed using the PMT Scale for Adolescent Smoking. Among the total sample, 45% had initiated cigarette smoking, and 25% smoked in the past month. Among those who never smoked, 15% indicated being likely or very likely to smoke in a year. Multiple regression modeling analysis indicated the significance of the seven PMT constructs, the four PMT perceptions and the two PMT pathways in predicting intention to smoke and actual smoking behavior. Overall, perceived rewards of smoking, especially intrinsic rewards, were consistently positively related to smoking intentions and behavior, and self-efficacy to avoid smoking was negatively related to smoking. The current study suggests the utility of PMT for further research examining adolescent smoking. PMT-based smoking prevention and clinical smoking cessation intervention programs should focus more on adolescents’ perceived rewards from smoking and perceived efficacy of not smoking to reduce their intention to and actual use of tobacco.
PMCID: PMC3966196  PMID: 24157424
Protection Motivation Theory; Adolescents; Cigarette smoking; China
22.  Single-Sample Face Recognition Based on Intra-Class Differences in a Variation Model 
Sensors (Basel, Switzerland)  2015;15(1):1071-1087.
In this paper, a novel random facial variation modeling system for sparse representation face recognition is presented. Although recently Sparse Representation-Based Classification (SRC) has represented a breakthrough in the field of face recognition due to its good performance and robustness, there is the critical problem that SRC needs sufficiently large training samples to achieve good performance. To address these issues, we challenge the single-sample face recognition problem with intra-class differences of variation in a facial image model based on random projection and sparse representation. In this paper, we present a developed facial variation modeling systems composed only of various facial variations. We further propose a novel facial random noise dictionary learning method that is invariant to different faces. The experiment results on the AR, Yale B, Extended Yale B, MIT and FEI databases validate that our method leads to substantial improvements, particularly in single-sample face recognition problems.
PMCID: PMC4327065  PMID: 25580904
intra-class variation model differences; face recognition; sparse representation
23.  Proteomic analyses reveal differences in cold acclimation mechanisms in freezing-tolerant and freezing-sensitive cultivars of alfalfa 
Cold acclimation in alfalfa (Medicago sativa L.) plays a crucial role in cold tolerance to harsh winters. To examine the cold acclimation mechanisms in freezing-tolerant alfalfa (ZD) and freezing-sensitive alfalfa (W5), holoproteins, and low-abundance proteins (after the removal of RuBisCO) from leaves were extracted to analyze differences at the protein level. A total of 84 spots were selected, and 67 spots were identified. Of these, the abundance of 49 spots and 24 spots in ZD and W5, respectively, were altered during adaptation to chilling stress. Proteomic results revealed that proteins involved in photosynthesis, protein metabolism, energy metabolism, stress and redox and other proteins were mobilized in adaptation to chilling stress. In ZD, a greater number of changes were observed in proteins, and autologous metabolism and biosynthesis were slowed in response to chilling stress, thereby reducing consumption, allowing for homeostasis. The capability for protein folding and protein biosynthesis in W5 was enhanced, which allows protection against chilling stress. The ability to perceive low temperatures was more sensitive in freezing-tolerant alfalfa compared to freezing-sensitive alfalfa. This proteomics study provides new insights into the cold acclimation mechanism in alfalfa.
PMCID: PMC4343008  PMID: 25774161
proteomics; cold acclimation; RuBisCO; metabolism; homeostasis; alfalfa
24.  Induction of H2AX phosphorylation in tumor cells by gossypol acetic acid is mediated by phosphatidylinositol 3-kinase (PI3K) family 
H2AX is phosphorylated (γH2AX) by members of the phosphatidylinositol 3-kinase (PI3K) family, including Ataxia telangiectasia-mutated (ATM), ATM- and Rad3-related (ATR) and DNA-PK in response to DNA damage. Our study shows that gossypol acetic acid (GAA) alone can induce γH2AX in Human mucoepidermoid carcinoma cell line (MEC-1) in vitro. Thus, we further examined the possible mechanisms of GAA to induce γH2AX in tumor cells.
Materials and methods
The PI3K inhibitors caffeine and wortmannin were used in an effort to identify the kinase(s) responsible for GAA -induced γH2AX in MEC-1 cells. DNA dependent protein kinase (DNA-PK) - proficient and –deficient cells, human glioma cell lines M059K and M059J, were also used to evaluate the kinases responsible for GAA induced H2AX phosphorylation. γH2AX expression was detected by immunofluorescent microscopy. Flow cytometry assay was used to assay γH2AX and cell cycle.
GAA induced H2AX phosphorylation in a cell cycle-dependent manner and a significant G0/G1 phase arrest in MEC-1 cells was shown. Caffeine and wortmannin significantly inhibited GAA-induced H2AX phosphorylation in MEC-1 cells. GAA induced H2AX phosphorylation in M059K, but not in M059J. Taken together, these data suggested that GAA treatment alone could induce H2AX phosphorylation in a cell cycle dependent manner in MEC-1 and M059K, but not in M059J cells. A significant G0/G1 phase arrest was shown in MEC-1.
The member of PI3K family, DNA-PK, ATM and ATR are involved in the H2AX phosphorylation of MEC-1 cells.
PMCID: PMC4272777  PMID: 25530717
Gossypol acetic acid; H2AX phosphorylation; DNA-PK; ATM; ATR
25.  Identification of several hub-genes associated with periodontitis using integrated microarray analysis 
Molecular Medicine Reports  2014;11(4):2541-2547.
The aim of the present study was to identify differentially expressed genes and biological processes associated with periodontitis. In this study, the most significant 200 differentially expressed genes associated with periodontitis were identified using integrated analysis of multiple microarray data in combination with screening for genome-wide relative significance and genome-wide global significance. Gene Ontology (GO) enrichment analysis and pathway analysis were performed using the GO website and Kyoto Encyclopedia of Genes and Genomes (KEGG). A protein-protein interaction (PPI) network was constructed based on the Search Tool for the Retrieval of Interacting Genes/Proteins. The top 200 differentially expressed genes were found to be highly associated with periodontitis. GO enrichment analyses revealed that the identified genes were significantly enriched in terms of response to organic substance, response to wounding and cell migration. The most common term of the KEGG pathway was cytokine-cytokine receptor interaction. PPI network analysis indicated that interleukin (IL)8, IL1β, vascular endothelial growth factor A, intercellular adhesion molecule 1, PTGS2 and CXCL10 were hub genes, which formed numerous interactions with several genes. In conclusion, the present study identified numerous genes that were differentially expressed in periodontitis, as well as determined the biological pathways and PPI network associated with those genes.
PMCID: PMC4337736  PMID: 25483140
periodontitis; differentially expressed genes; bioinformatics

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