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1.  Activated Scavenger Receptor A Promotes Glial Internalization of Aβ 
PLoS ONE  2014;9(4):e94197.
Beta-amyloid (Aβ) aggregates have a pivotal role in pathological processing of Alzheimer’s disease (AD). The clearance of Aβ monomer or aggregates is a causal strategy for AD treatment. Microglia and astrocytes are the main macrophages that exert critical neuroprotective roles in the brain. They may effectively clear the toxic accumulation of Aβ at the initial stage of AD, however, their functions are attenuated because of glial overactivation. In this study, we first showed that heptapeptide XD4 activates the class A scavenger receptor (SR-A) on the glia by increasing the binding of Aβ to SR-A, thereby promoting glial phagocytosis of Aβ oligomer in microglia and astrocytes and triggering intracellular mitogen-activated protein kinase (MAPK) signaling cascades. Moreover, XD4 enhances the internalization of Aβ monomers to microglia and astrocytes through macropinocytosis or SR-A-mediated phagocytosis. Furthermore, XD4 significantly inhibits Aβ oligomer-induced cytotoxicity to glial cells and decreases the production of proinflammatory cytokines, such as TNF-α and IL-1β, in vitro and in vivo. Our findings may provide a novel strategy for AD treatment by activating SR-A.
PMCID: PMC3981768  PMID: 24718459
2.  Spontaneous cortical activity alternates between motifs defined by regional axonal projections 
Nature neuroscience  2013;16(10):1426-1435.
In lightly anaesthetized or awake adult mice using millisecond timescale voltage sensitive dye imaging, we show that a palette of sensory-evoked and hemisphere-wide activity motifs are represented in spontaneous activity. These motifs can reflect multiple modes of sensory processing including vision, audition, and touch. Similar cortical networks were found with direct cortical activation using channelrhodopsin-2. Regional analysis of activity spread indicated modality specific sources such as primary sensory areas, and a common posterior-medial cortical sink where sensory activity was extinguished within the parietal association area, and a secondary anterior medial sink within the cingulate/secondary motor cortices for visual stimuli. Correlation analysis between functional circuits and intracortical axonal projections indicated a common framework corresponding to long-range mono-synaptic connections between cortical regions. Maps of intracortical mono-synaptic structural connections predicted hemisphere-wide patterns of spontaneous and sensory-evoked depolarization. We suggest that an intracortical monosynaptic connectome shapes the ebb and flow of spontaneous cortical activity.
PMCID: PMC3928052  PMID: 23974708 CAMSID: cams3906
3.  Genetic Variation in the OX40L/OX40 System and Plasma Lipid and Lipoprotein Levels in a Chinese Hypertriglyceridemic Population 
Aims: To investigate the variations of OX40 (tumor necrosis factor receptor superfamily, member 4) and its ligand OX40L genes and their relationships with serum lipids and apolipoproteins (apo) levels in Chinese healthy individuals and patients with endogenous hypertriglyceridemia (HTG) in the Chengdu area. Methods: The genotypes and allele frequencies of the rs3850641 and rs17568 polymorphisms in the OX40L and OX40 genes were assayed by polymerase chain reaction and restriction fragment length polymorphism. Results: In the case–control study, which included 126 HTG subjects and 206 normal control subjects, the frequencies of the G allele at the rs3850641 site and the G allele at the rs17568 site in the patients were similar to those observed in the controls. In the HTG group, subjects with G allele carriers of the rs3850641 site had lower serum high-density lipoprotein cholesterol and apo AI levels as compared to those of genotype AA. In the case group, subjects with G allele carriers of the rs17568 site had higher serum low-density lipoprotein cholesterol (LDL-C) levels, while controls had lower serum total serum cholesterol and LDL-C levels. Conclusion: These results suggest that the rs3850641 and rs17568 polymorphisms in the OX40L and OX40 genes are associated with some of the lipid and lipoprotein variations in subjects with endogenous HTG and/or in the general population of Han Chinese.
PMCID: PMC3582283  PMID: 23216302
4.  Left Atrial Volumes and Reservoir Function Are Associated With Subclinical Cerebrovascular Disease: The Cardiovascular Abnormalities and Brain Lesions (CABL) Study 
JACC. Cardiovascular imaging  2013;6(3):313-323.
To assess the relationship of left atrial (LA) phasic volumes and LA reservoir function with subclinical cerebrovascular disease in a stroke-free community-based cohort.
An increase in LA size is associated with cardiovascular events including stroke. However, it is not known whether LA phasic volumes and reservoir function are associated with subclinical cerebrovascular disease.
LA minimum (LAVmin) and maximum (LAVmax) volumes, and LA reservoir function, measured as total emptying volume (LAEV) and total emptying fraction (LAEF), were assessed by real-time three-dimensional echocardiography in 455 stroke-free participants from the community-based Cardiovascular Abnormalities and Brain Lesions (CABL) study. Subclinical cerebrovascular disease was assessed as silent brain infarcts (SBI) and white matter hyperintensity volume (WMHV) by brain magnetic resonance imaging (MRI).
SBI prevalence was 15.4%; mean WMHV was 0.66±0.92%. Participants with SBI showed greater LAVmin (17.1±9.3 vs. 12.5±5.6 ml/m2, p<0.01) and LAVmax (26.6±8.8 vs. 23.3±7.0 ml/m2, p<0.01) compared to those without SBI. LAEV (9.5±3.4 vs. 10.8±3.9 ml/m2, p<0.01) and LAEF (38.7±14.7% vs. 47.0±11.9%, p<0.01) were also reduced in participants with SBI. In univariate analyses, greater LA volumes and smaller reservoir function were significantly associated with greater WMHV. In multivariate analyses, LAVmin remained significantly associated with SBI [adjusted odds ratio (OR) per SD increase: 1.37, 95% confidence intervals (CI) 1.04–1.80, p<0.05] and with WMHV (β=0.12, p<0.01), whereas LAVmax was not independently associated with either. Smaller LAEF was independently associated with SBI (adjusted OR=0.67, 95% CI 0.50–0.90, p<0.01) and WMHV (β=−0.09, p<0.05).
Greater LA volumes and reduced LA reservoir function are associated with subclinical cerebrovascular disease detected by brain MRI in subjects without history of stroke. LAVmin and LAEF, in particular, are more strongly associated with SBI and WMHV than the more commonly measured LAVmax, and their relationship with subclinical brain lesions is independent of other cardiovascular risk factors.
PMCID: PMC3600634  PMID: 23473112
Left atrial volume; Silent brain infarct; White matter hyperintensity volume; Magnetic resonance imaging; Three-dimensional echocardiography
5.  In Vivo Suppression of MiR-24 Prevents the Transition toward Decompensated Hypertrophy in Aortic-constricted Mice 
Circulation research  2013;112(4):601-605.
During the transition from compensated hypertrophy to heart failure, the signaling between L-type Ca2+ channels (LCCs) in the cell membrane/T-tubules (TTs) and ryanodine receptors (RyRs) in the sarcoplasmic reticulum (SR) becomes defective, partially due to the decreased expression of a TT-SR anchoring protein, junctophilin-2 (JP2). MiR-24, a JP2 suppressing microRNA, is up-regulated in hypertrophied and failing cardiomyocytes.
To test whether miR-24 suppression can protect the structural and functional integrity of LCC-RyR signaling in hypertrophied cardiomyocytes.
Methods and Results
In vivo silencing of miR-24 by a specific antagomir in an aorta-constricted mouse model effectively prevented the degradation of heart contraction but not ventricular hypertrophy. Electrophysiology and confocal imaging studies showed that antagomir treatment prevented the decreases in LCC-RyR signaling fidelity/efficiency and whole-cell Ca2+ transients. Further studies showed that antagomir treatment stabilized JP2 expression and protected the ultrastructure of TT-SR junctions from disruption.
MiR-24 suppression prevented the transition from compensated hypertrophy to decompensated hypertrophy, providing a potential strategy for early treatment against heart failure.
PMCID: PMC3622206  PMID: 23307820
Hypertrophy; remodeling heart failure; myocardial contraction; Ca2+ signaling; hypertrophic cardiomyopathy
6.  Midkine, a Potential Link between Obesity and Insulin Resistance 
PLoS ONE  2014;9(2):e88299.
Obesity is associated with increased production of inflammatory mediators in adipose tissue, which contributes to chronic inflammation and insulin resistance. Midkine (MK) is a heparin-binding growth factor with potent proinflammatory activities. We aimed to test whether MK is associated with obesity and has a role in insulin resistance. It was found that MK was expressed in adipocytes and regulated by inflammatory modulators (TNF-α and rosiglitazone). In addition, a significant increase in MK levels was observed in adipose tissue of obese ob/ob mice as well as in serum of overweight/obese subjects when compared with their respective controls. In vitro studies further revealed that MK impaired insulin signaling in 3T3-L1 adipocytes, as indicated by reduced phosphorylation of Akt and IRS-1 and decreased translocation of glucose transporter 4 (GLUT4) to the plasma membrane in response to insulin stimulation. Moreover, MK activated the STAT3-suppressor of cytokine signaling 3 (SOCS3) pathway in adipocytes. Thus, MK is a novel adipocyte-secreted factor associated with obesity and inhibition of insulin signaling in adipocytes. It may provide a potential link between obesity and insulin resistance.
PMCID: PMC3917881  PMID: 24516630
7.  The Identification and Characteristics of Immune-Related MicroRNAs in Haemocytes of Oyster Crassostrea gigas 
PLoS ONE  2014;9(2):e88397.
MicroRNAs (miRNAs) represent a class of small ncRNAs that repress gene expression on the post-transcriptional level by the degradation or translation inhibition of target mRNA.
Three small RNA libraries from oyster haemocytes were sequenced on the Illumina platform to investigate the latent immunomodulation of miRNAs after bacteria challenge and heat stress. Totally, 10,498,663, 8,588,606 and 9,679,663 high-quality reads were obtained in the control, bacteria and bacteria+heat library, respectively, from which 199 oyster miRNAs including 71 known and 128 novel ones were identified. Among these miRNAs, 6 known and 23 novel ones were predicted to possess more than one precursor-coding region, and cgi-miR-10a, cgi-miR-184b, cgi-miR-100, cgi-miR-1984 and cgi-miR-67a were observed to be the most abundant miRNAs in the control library. The expression levels of 22 miRNAs in the bacteria library were significantly higher than those in the control library, while there were another 33 miRNAs whose expression levels were significantly lower than that in the control library. Meanwhile, the expression levels of 65 miRNAs in the bacteria+heat library changed significantly compared to those in the bacteria library. The target genes of these differentially expressed miRNAs were annotated, and they fell in immune and stress-related GO terms including antioxidant, cell killing, death, immune system process, and response to stimulus. Furthermore, there were 42 differentially expressed miRNAs detected in both control/bacteria and bacteria/bacteria+heat comparisons, among which 9 miRNAs displayed the identical pattern in the two comparisons, and the expression alterations of 8 miRNAs were confirmed using quantitative RT-PCR.
These results indicated collectively that immune challenge could induce the expression of immune-related miRNAs, which might modulate the immune response such as redox reaction, phagocytosis and apoptosis, and the expression of some immune-related miRNAs could be also regulated by heat stress to improve the environmental adaption of oyster.
PMCID: PMC3916443  PMID: 24516648
8.  Cardiorespiratory Fitness as a Predictor of Dementia Mortality in Men and Women 
There is evidence that physical activity may reduce the risk of developing Alzheimer’s disease and dementia. However, few reports have examined the physical activity-dementia association with objective measures of physical activity. Cardiorespiratory fitness (hereafter called fitness) is an objective reproducible measure of recent physical activity habits.
We sought to determine whether fitness is associated with lower risk for dementia mortality in women and men.
We followed 14,811 women and 45,078 men, ages 20-88 at baseline, for an average of 17 years. All participants completed a preventive health examination at the Cooper Clinic in Dallas, Texas during 1970-2001. Fitness was measured with a maximal treadmill exercise test, with results expressed in maximal metabolic equivalents (METs). The National Death Index identified deaths through 2003. Cox proportional hazards models were used to examine the association between baseline fitness and dementia mortality, adjusting for age, sex, examination year, body mass index, smoking, alcohol use, abnormal ECGs, and health status.
There were 164 deaths with dementia listed as the cause during 1,012,125 person-years of exposure. Each 1-MET increase in fitness was associated with a 14% lower adjusted risk of dementia mortality (95% confidence interval, CI 6%-22%). With fitness expressed in tertiles, adjusted hazard ratios (HRs) for those in the middle and high fitness groups suggest their risk of dementia mortality was less than half that of those in the lowest fitness group (respectively: HR 0.44, CI 0.26-0.74; HR 0.49, CI 0.26-0.90).
Greater fitness was associated with lower risk of mortality from dementia in a large cohort of men and women.
PMCID: PMC3908779  PMID: 21796048
physical fitness; cognitive function; Alzheimer’s disease; vascular dementia; metabolic equivalents (METs)
9.  Bilateral telovelar approach: A safe route revisited for resections of various large fourth ventricle tumors 
Tumors located in the posterior fossa and especially in the middle and upper fourth ventricle are comparatively rare and technically very challenging. For some lesions, the telovelar approach has been shown to be a suitable approach. The unilateral approach is sufficient in most cases of small lesions. However, large fourth ventricle tumors are more problematic since they distort the normal anatomy with both vermis and cerebellar peduncles thinned and stretched out. This puts the patient at increased risk for a neurological deficit, which is minimized with a bilateral telovelar approach. By illustrating the adequacy of this technique, we emphasize the suitability of a rather unusual bilateral approach, which will provide excellent panoramic visualization of entire fourth ventricle and thus avoids complications usually associated with resections of large fourth ventricle tumors.
Case Description:
Here we present three cases of benign intraventricular tumors (meningioma, solitary fibrous tumor and ependymoma) in patients with site specific symptoms from local mass effect. Typical symptoms of posterior fossa lesions were present preoperatively and resolved after surgery. The bilateral telovelar approach was used to remove these tumors completely and the pertinent intraoperative steps are described for each case. All three patients had excellent postoperative outcome and could be discharged after short hospital stays.
The different pathological entities could be completely resected without added neurological deficit employing a bilateral approach. In cases of large or giant fourth ventricle tumors, the bilateral telovelar approach provides excellent intraoperative visibility allowing complete excision of extensive tumors with minimal morbidity.
PMCID: PMC3942613  PMID: 24678432
Cerebellomedullary fissure; fourth ventricle; microsurgery; telovelar approach
10.  Lactuside B decreases aquaporin-4 and caspase-3 mRNA expression in the hippocampus and striatum following cerebral ischaemia-reperfusion injury in rats 
This study aimed to investigate the effects of lactuside B (LB) on aquaporin-4 (AQP4) and caspase-3 mRNA expression in the hippocampus and the striatum following cerebral ischaemia-reperfusion (I/R) injury in rats. Cerebral I/R injury was established in Sprague-Dawley rats by occluding the middle cerebral artery for 2 h and then inducing reperfusion. Rats in the I/R + LB groups were treated with various doses of LB following reperfusion. Neurological deficit scores and brain water content were obtained to determine the pharmacodynamics of LB. Reverse transcription polymerase chain reaction was performed to determine the expression levels of AQP4 and caspase-3 mRNA in the hippocampus and the striatum. The results of the present study indicate that LB decreased the neurological deficit scores and the brain water content. In the hippocampus, AQP4 and caspase-3 mRNA expression levels were significantly downregulated in the I/R + LB groups at 24 and 72 h following drug administration, compared with those in the I/R group (P<0.05). In the striatum, LB was also shown to significantly reduce AQP4 and caspase-3 mRNA expression levels at 24 and 72 h following drug administration, compared with those in the I/R group (P<0.05). The effects became stronger as the LB dose was increased. The most significant reductions in AQP4 and caspase-3 mRNA expression were noted in the I/R + LB 25 mg/kg and I/R + LB 50 mg/kg groups at 72 h following drug administration. The results of the present study show that LB is capable of significantly downregulating AQP4 and caspase-3 mRNA expression in the hippocampus and striatum following cerebral I/R injury in rats. The mechanism by which LB improved ischaemic brain injury may be associated with changes in AQP4 and caspase-3 mRNA expression in the hippocampus and the striatum.
PMCID: PMC3919888  PMID: 24520266
lactuside B; cerebral I/R injury; brain edema; AQP4; caspase-3; apoptosis; hippocampus; striatum
11.  Follistatin-Like 1: A Potential Mediator of Inflammation in Obesity 
Mediators of Inflammation  2013;2013:752519.
Obesity is associated with a state of chronic low-grade inflammation, which contributes to insulin resistance and type 2 diabetes. However, the molecular mechanisms that link obesity to inflammation are not fully understood. Follistatin-like 1 (FSTL1) is a novel proinflammatory cytokine that is expressed in adipose tissue and secreted by preadipocytes/adipocytes. We aimed to test whether FSTL1 could have a role in obesity-induced inflammation and insulin resistance. It was found that FSTL1 expression was markedly decreased during differentiation of 3T3-L1 preadipocytes but reinduced by TNF-α. Furthermore, a significant increase in FSTL1 levels was observed in adipose tissue of obese ob/ob mice, as well as in serum of overweight/obese subjects. Mechanistic studies revealed that FSTL1 induced inflammatory responses in both 3T3-L1 adipocytes and RAW264.7 macrophages. The expression of proinflammatory mediators including IL-6, TNF-α, and MCP-1 was upregulated by recombinant FSTL1 in a dose-dependent manner, paralleled with activation of the IKKβ-NFκB and JNK signaling pathways in the two cell lines. Moreover, FSTL1 impaired insulin signaling in 3T3-L1 adipocytes, as revealed by attenuated phosphorylation of both Akt and IRS-1 in response to insulin stimulation. Together, our results suggest that FSTL1 is a potential mediator of inflammation and insulin resistance in obesity.
PMCID: PMC3857907  PMID: 24347831
12.  Effect of 15-hydroxyprostaglandin dehydrogenase gene on the proliferation of gastric cancer cell murine forestomach carcinoma 
The aim of the present study was to construct the eukaryotic expression vector pcDNA3.1/15-PGDH. The vector was used to transfect mouse murine forestomach carcinoma (MFC) cancer cells and observe the effects of 15-hydroxyprostaglandin dehydrogenase (15-PGDH) on the proliferation of MFC. pcDNA3.1/15-PGDH was constructed using gene recombination technology and the vector was used to transfect MFC cells to build a stable transfected cell strain. The expression levels of 15-PGDH in the transfected cells were detected using reverse transcription polymerase chain reaction. Optical Density (OD) values were determined using an MTT assay and used to draw cell growth curves. The effects of 15-PGDH on the proliferation of MFC were observed using a clone formation experiment. Following successful transfection by 15-PGDH, the relative expression levels of 15-PGDH in the MFC/15-PGDH cells were significantly higher (1.06±0.08) (P<0.01) compared with the empty plasmid-transfected group (0.22±0.01) and the untransfected group (0.21±0.01). Following transfection by 15-PGDH, cell growth was markedly inhibited. The MTT results showed that on days 4, 6 and 8, the 15-PGDH-transfected group had a low OD on average, which was significantly different (P<0.05) from the empty plasmid-transfected group or the untransfected group. The 15-PGDH-transfected group had a plating efficiency of 18%, and compared with the untransfected group (63%) and the empty plasmid-transfected group (59%), clone formation was significantly inhibited (P<0.01). Results of the present study indicate that transfection by 15-PGDH may significantly inhibit the proliferation and clone formation of MFC cells.
PMCID: PMC3861248  PMID: 24348808
15-hydroxyprostaglandin dehydrogenase; gastric; transfection; proliferation; inhibition
13.  Research on the Premotor Symptoms of Parkinson’s Disease: Clinical and Etiological Implications 
Environmental Health Perspectives  2013;121(11-12):1245-1252.
Background: The etiology and natural history of Parkinson’s disease (PD) are not well understood. Some non-motor symptoms such as hyposmia, rapid eye movement sleep behavior disorder, and constipation may develop during the prodromal stage of PD and precede PD diagnosis by years.
Objectives: We examined the promise and pitfalls of research on premotor symptoms of PD and developed priorities and strategies to understand their clinical and etiological implications.
Methods: This review was based on a workshop, Parkinson’s Disease Premotor Symptom Symposium, held 7–8 June 2012 at the National Institute of Environmental Health Sciences in Research Triangle Park, North Carolina.
Discussion: Research on premotor symptoms of PD may offer an excellent opportunity to characterize high-risk populations and to better understand PD etiology. Such research may lead to evaluation of novel etiological hypotheses such as the possibility that environmental toxicants or viruses may initiate PD pathogenesis in the gastrointestinal tract or olfactory bulb. At present, our understanding of premotor symptoms of PD is in its infancy and faces many obstacles. These symptoms are often not specific to PD and have low positive predictive value for early PD diagnosis. Further, the pathological bases and biological mechanisms of these premotor symptoms and their relevance to PD pathogenesis are poorly understood.
Conclusion: This is an emerging research area with important data gaps to be filled. Future research is needed to understand the prevalence of multiple premotor symptoms and their etiological relevance to PD. Animal experiments and mechanistic studies will further understanding of the biology of these premotor symptoms and test novel etiological hypothesis.
Citation: Chen H, Burton EA, Ross GW, Huang X, Savica R, Abbott RD, Ascherio A, Caviness JN, Gao X, Gray KA, Hong JS, Kamel F, Jennings D, Kirshner A, Lawler C, Liu R, Miller GW, Nussbaum R, Peddada SD, Comstock Rick A, Ritz B, Siderowf AD, Tanner CM, Tröster AI, Zhang J. 2013. Research on the premotor symptoms of Parkinson’s Disease: clinical and etiological implications. Environ Health Perspect 121:1245–1252;
PMCID: PMC3855519  PMID: 23933572
14.  Circulating microRNA-101 as a potential biomarker for hepatitis B virus-related hepatocellular carcinoma 
Oncology Letters  2013;6(6):1811-1815.
Circulating microRNAs (miRNAs) are emerging as promising biomarkers for cancer; however, the significance of circulating miRNAs in hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) remains largely unknown. Based on our prior observations that miRNA-101 (miR-101) is downregulated by HBV and induces epigenetic modification, we sought to test whether circulating miR-101 may serve as a potential biomarker for HCC. The expression of miR-101 in HCCs and serum was evaluated by real-time polymerase chain reaction. Tissue and serum miR-101 levels were assessed in samples from patients with HBV-related HCC and healthy controls. A potential correlation was also evaluated between miR-101 expression and the clinicopathological features and prognosis of HCC patients. miR-101 was downregulated in HBV-related HCC tissues compared with adjacent noncancerous tissues. Furthermore, the miR-101 levels in these tissues from HCC patients were significantly lower than those in tissues from control subjects. Notably, serum miR-101 levels were found to have an inverse correlation with tissue miR-101 expression levels. The expression of serum miR-101 in patients with HBV-related HCC was significantly higher than that in the healthy controls, and this increase correlated with hepatitis B surface antigen positivity, HBV DNA levels and tumor size. These results indicate that different factors govern the levels of miR-101 in the tissue and serum of HCC patients. Given the marked and consistent increase in serum miR-101 levels in HCC patients, circulating miR-101 may serve as a promising biochemical marker for monitoring the progression of tumor development in HBV-related HCC.
PMCID: PMC3834113  PMID: 24260081
miR-101; serum; monitor; HBV-related HCC
15.  Prognosis of the intrahepatic cholangiocarcinoma after resection: hepatitis B virus infection and adjuvant chemotherapy are favorable prognosis factors 
The incidence and mortality associated with intrahepatic cholangiocarcinoma is increasing in many countries and documentation of disease outcome is sparse. The present study was undertaken to investigate the prognostic factors for intrahepatic cholangiocarcinoma (ICC) following surgical resection. The impact of pre-existing HBV virus infection and adjuvant chemotherapy on the overall survival was also evaluated.
Clinical and pathological data were collected retrospectively from 81 patients undergoing surgery for ICC between 2005 and 2011, at The Henan Province Tumor Hospital and the First Affiliated Hospital of Zheng Zhou University. Survival and prognosis were analyzed using the Kaplan-Meier method and COX regression model.
The population included 37 patients who were HBsAg + or anti-HBc+, 21 patients who were anti-HBs + positive and 18 patients who received adjuvant chemotherapy. The overall 1- and 3-year survival rates were 51% and 20%, respectively. The median survival was 12.2 months. Univariate analysis identified the following prognostic factors: HBV virus infection or HBV vaccine prior to resection (P = 0.017); adjuvant chemotherapy (P = 0.001); preoperative serum CA19-9 (> 200 U/mL; P = 0.015); GGT (> 64 U/L; P = 0.008), ALP (> 119 U/L; P = 0.01); lymph node metastasis (P = 0.005); radical resection (P = 0.021); intrahepatic metastasis (P = 0.015) and diabetes (P = 0.07). Multivariate analysis identified chronic HBV infection (RR = 0.583; P = 0.041), anti-HBs positivity (RR = 0.680; P = 0.050), adjuvant chemotherapy (RR = 0.227; P < 0.001), lymph node metastasis (RR = 2.320; P = 0.001), and intrahepatic duct stones (RR = 0.473; P = 0.032) as independent prognostic factors.
HBV virus infection or HBV vaccination prior to resection, together with adjuvant chemotherapy, were independently associated with improved survival in patients undergoing surgery for ICC.
PMCID: PMC3852727  PMID: 24139471
Intrahepatic cholangiocarcinoma; Hepatitis B virus; Adjuvant chemotherapy; Survival; Prognosis
16.  Effects of hypoxia on the proliferation, mineralization and ultrastructure of human periodontal ligament fibroblasts in vitro 
This study aimed to investigate the effects of hypoxia on the proliferation, mineralization and ultrastructure of human periodontal ligament fibroblasts (HPLFs) at various times in vitro in order to further study plateau-hypoxia-induced periodontal disease. HPLFs (fifth passage) cultured by the tissue culture method were assigned to the slight (5% O2), middle (2% O2), and severe hypoxia (1% O2) groups and the control (21% O2) group, respectively. At 12, 24, 48 and 72 h, the proliferation and alkaline phosphatase (ALP) activities were detected. The ultrastructure of the severe hypoxia group was observed. HPLFs grew more rapidly with an increase in the degree of hypoxia at 12 and 24 h, and significant levels of proliferation (P<0.05) were observed in the severe hypoxia group at 24 h. Cell growth was restrained with an increase in the degree of hypoxia at 48 and 72 h, and the restrictions were clear (P<0.05) in the middle and severe hypoxia groups. ALP activity was restrained with increasing hypoxia at each time point. The restrictions were marked (P<0.05) in the severe hypoxia group at 24 h and in the middle and severe hypoxia groups at 48 and 72 h. However, the restriction was more marked (P<0.05) in the severe hypoxia group at 72 h. An increase was observed in the number of mitochondria and rough endoplasmic reticula (RER), with slightly expanded but complete membrane structures, in the severe hypoxia group at 24 h. At 48 h, the number of mitochondria and RER decreased as the mitochondria increased in size. Furthermore, mitochondrial cristae appeared to be vague, and a RER structural disorder was observed. At 72 h, the number of mitochondria and RER decreased further when the mitochondrial cristae were broken, vacuolar degeneration occurred, and the RER particles were reduced while the number of lysosomes increased. HPLF proliferation and mineralization was restrained. Additionally, HPLF structure was broken for a relatively long period of time in the middle and severe hypoxia groups. This finding demonstrated that hypoxia was capable of damaging the metabolism, reconstruction and recovery of HPLFs. The poor state of HPLFs under hypoxic conditions may therefore initiate or aggravate periodontal disease.
PMCID: PMC3829746  PMID: 24255690
periodontal disease; hypoxia; human periodontal ligament fibroblasts; proliferation; mineralization; ultrastructure
17.  Light-harvesting chlorophyll a/b-binding proteins, positively involved in abscisic acid signalling, require a transcription repressor, WRKY40, to balance their function 
Journal of Experimental Botany  2013;64(18):5443-5456.
The light-harvesting chlorophyll a/b-binding (LHCB) proteins are the apoproteins of the light-harvesting complex of photosystem II. In the present study, we observed that downregulation of any of the six LHCB genes resulted in abscisic acid (ABA)-insensitive phenotypes in seed germination and post-germination growth, demonstrating that LHCB proteins are positively involved in these developmental processes in response to ABA. ABA was required for full expression of different LHCB members and physiologically high levels of ABA enhanced LHCB expression. The LHCB members were shown to be targets of an ABA-responsive WRKY-domain transcription factor, WRKY40, which represses LHCB expression to balance the positive function of the LHCBs in ABA signalling. These findings revealed that ABA is an inducer that fine-tunes LHCB expression at least partly through repressing the WRKY40 transcription repressor in stressful conditions in co-operation with light, which allows plants to adapt to environmental challenges.
PMCID: PMC3871805  PMID: 24078667
Abscisic acid signalling; Arabidopsis thaliana; light-harvesting chlorophyll a/b-binding protein; post-germination growth; seed germination; WRKY40 transcription factor.
18.  Correction: Differential Regulation of MAPK Phosphorylation in the Dorsal Hippocampus in Response to Prolonged Morphine Withdrawal-Induced Depressive-Like Symptoms in Mice 
PLoS ONE  2013;8(9):10.1371/annotation/99966397-acf2-41ca-ad92-69dbd87cc9f9.
PMCID: PMC3796587  PMID: 24137507
19.  Tramadol and Propentofylline Coadministration Exerted Synergistic Effects on Rat Spinal Nerve Ligation-Induced Neuropathic Pain 
PLoS ONE  2013;8(8):e72943.
Neuropathic pain is an intractable clinical problem. Drug treatments such as tramadol have been reported to effectively decrease neuropathic pain by inhibiting the activity of nociceptive neurons. It has also been reported that modulating glial activation could also prevent or reverse neuropathic pain via the administration of a glial modulator or inhibitor, such as propentofylline. Thus far, there has been no clinical strategy incorporating both neuronal and glial participation for treating neuropathic pain. Therefore, the present research study was designed to assess whether coadministration of tramadol and propentofylline, as neuronal and glial activation inhibitors, respectively, would exert a synergistic effect on the reduction of rat spinal nerve ligation (SNL)-induced neuropathic pain. Rats underwent SNL surgery to induce neuropathic pain. Pain behavioral tests were conducted to ascertain the effect of drugs on SNL-induced mechanical allodynia with von-Frey hairs. Proinflammatory factor interleukin-1β (IL-1β) expression was also detected by Real-time RT-PCR. Intrathecal tramadol and propentofylline administered alone relieved SNL-induced mechanical allodynia in a dose-dependent manner. Tramadol and propentofylline coadministration exerted a more potent effect in a synergistic and dose dependent manner than the intrathecal administration of either drug alone. Real-time RT-PCR demonstrated IL-1β up-expression in the ipsilateral spinal dorsal horn after the lesion, which was significantly decreased by tramadol and propentofylline coadministration. Inhibiting proinflammatory factor IL-1β contributed to the synergistic effects of tramadol and propentofylline coadministration on rat peripheral nerve injury-induced neuropathic pain. Thus, our study provided a rationale for utilizing a novel strategy for treating neuropathic pain by blocking the proinflammatory factor related pathways in the central nervous system.
PMCID: PMC3756942  PMID: 24009718
22.  The identification of novel targets of miR-16 and characterization of their biological functions in cancer cells 
Molecular Cancer  2013;12:92.
In eukaryotes, miR-16 is an important microRNA (miRNA) that is involved in numerous biological processes. However, it is not fully understood how miR-16 executes its physiological functions. In the present study, we aimed to identify novel miR-16 targets and study their biological functions.
Candidate target genes of miR-16 were screened by microarray analysis of mRNA levels in several cancer cell lines with enhanced miR-16. Three bioinformatics algorithms, including TargetScan, PicTar, and miRanda, were used in combination to calculate the miR-16 targets. The expression levels of miR-16 and target mRNA were examined by relative quantification RT-PCR, and the expression levels of target protein were detected by Western blot. Luciferase reporter plasmids were constructed to confirm direct targeting. The effect of miR-16 and target gene on cell viability was evaluated using MTT assays. The effects of miR-16 and target gene on apoptosis and cell cycle distribution were evaluated by flow cytometry analysis.
By overexpressing miR-16 in several cancer cell lines and measuring global mRNA levels using microarray analysis, we identified 27 genes that may be regulated by miR-16. After the bioinformatics filtering process, 18 genes were selected as candidate miR-16 targets. Furthermore, we experimentally validated three of these candidates, MAP7 (microtubule-associated protein 7), PRDM4 (PR domain containing 4) and CDS2 (CDP-diacylglycerol synthase 2), as direct targets of miR-16. Finally, we demonstrated that miR-16 targeting MAP7 played a critical role in regulating proliferation but not apoptosis and cell cycle progression in cancer cells.
In summary, the present study identifies several novel miR-16 targets and illustrates a novel function of miR-16 targeting MAP7 in modulating proliferation in cancer cells.
PMCID: PMC3751425  PMID: 23941513
microRNA; miR-16; MAP7; PRDM4; CDS2
23.  Reducing TDP-43 aggregation does not prevent its cytotoxicity 
TAR DNA-binding protein 43 (TDP-43) is a protein that is involved in the pathology of Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Lobar Degeneration (FTLD). In patients with these neurodegenerative diseases, TDP-43 does not remain in its normal nuclear location, but instead forms insoluble aggregates in both the nucleus and cytoplasm of affected neurons.
We used high density peptide array analysis to identify regions in TDP-43 that are bound by TDP-43 itself and designed candidate peptides that might be able to reduce TDP-43 aggregation. We found that two of the synthetic peptides identified with this approach could effectively inhibit the formation of TDP-43 protein aggregates in a concentration-dependent manner in HeLa cells in which a mutated human TDP-43 gene was overexpressed. However, despite reducing aggregation, these peptides did not reduce or prevent cell death. Similar results were observed in HeLa cells treated with arsenite. Again we found reduced aggregation, in this case of wild type TDP-43, but no difference in cell death.
Our results suggest that TDP-43 aggregation is associated with the cell death process rather than being a direct cause.
PMCID: PMC3893365  PMID: 24252504
TDP-43; Aggregation; Peptides; Cell death
24.  Transforming growth factor beta suppresses glutamate cysteine ligase gene expression and induces oxidative stress in a lung fibrosis model 
Free radical biology & medicine  2012;53(3):554-563.
The concentration of glutathione (GSH), the most abundant intracellular free thiol and an important antioxidant, is decreased in the lung in both fibrotic diseases and experimental fibrosis models. The underlying mechanisms and biological significance of GSH depletion, however, remain unclear. Transforming growth factor beta (TGF-β) is the most potent and ubiquitous profibrogenic cytokine and its expression is increased in almost all fibrotic diseases. In this study, we show that increasing TGF-β1 expression in mouse lung to a level comparable to those found in lung fibrotic diseases by intranasal instillation of AdTGF-β1223/225, an adenovirus expressing constitutively active TGF-β1, suppressed the expression of both catalytic and modifier subunits of glutamate cysteine ligase (GCL), the rate-limiting enzyme in de novo GSH synthesis, decreased GSH concentration, and increased protein and lipid peroxidation in mouse lung. Furthermore, we show that increasing TGF-β1 expression activated JNK and induced activating transcription factor 3 (ATF3), a transcriptional repressor involved in the regulation of the catalytic subunit of GCL (GCLC), in mouse lung. Control virus (AdDL70-3) had no significant effect on any of these parameters, compared to saline treated control. Concurrent with GSH depletion, TGF-β1 induced lung epithelial apoptosis and robust pulmonary fibrosis. Importantly, lung GSH levels returned to the normal whereas fibrosis persisted at least 21 days after TGF-β1 instillation. Together, the data suggest that increased TGF-β1 expression may contribute to the GSH depletion observed in pulmonary fibrosis diseases and that GSH depletion may be an early event in, rather than a consequence of, fibrosis development.
PMCID: PMC3432394  PMID: 22634145
GSH depletion; lung fibrosis; transforming growth factor beta 1; glutamate cysteine ligase; oxidative stress
25.  Tenascin-C Produced by Oxidized LDL-Stimulated Macrophages Increases Foam Cell Formation through Toll-like Receptor-4 
Molecules and Cells  2012;34(1):35-41.
Atherosclerosis is a chronic inflammatory disease in which both innate and adaptive immunity are involved. Although there have been major advances in the involvement of toll-like receptor 4 (TLR4) and CD36 in the initiation and development of this disease, detailed mechanisms remain unknown. Here, we show that tenascin-C (TN-C) can stimulate foam cell formation and this can be inhibited by a TLR4-blocking antibody or CD36 gene silencing. Our results identify TN-C-TLR4 activation as a common molecular mechanism in oxLDL-stimulated foam cell formation and atherosclerosis. In addition, CD36 is the major scavenger receptor responsible for the TN-C-mediated foam cell formation. Taken together, we have identified that TN-C produced by oxLDL-stimulated macrophages increases foam cell formation through TLR4 and scavenger receptor CD36.
PMCID: PMC3887780  PMID: 22699754
atherosclerosis; CD36; foam cell formation; tenascin-c; toll-like receptor 4

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