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1.  Joint analysis of three genome-wide association studies of esophageal squamous cell carcinoma in Chinese populations 
Wu, Chen | Wang, Zhaoming | Song, Xin | Feng, Xiao-Shan | Abnet, Christian C. | He, Jie | Hu, Nan | Zuo, Xian-Bo | Tan, Wen | Zhan, Qimin | Hu, Zhibin | He, Zhonghu | Jia, Weihua | Zhou, Yifeng | Yu, Kai | Shu, Xiao-Ou | Yuan, Jian-Min | Zheng, Wei | Zhao, Xue-Ke | Gao, She-Gan | Yuan, Zhi-Qing | Zhou, Fu-You | Fan, Zong-Min | Cui, Ji-Li | Lin, Hong-Li | Han, Xue-Na | Li, Bei | Chen, Xi | Dawsey, Sanford M. | Liao, Linda | Lee, Maxwell P. | Ding, Ti | Qiao, You-Lin | Liu, Zhihua | Liu, Yu | Yu, Dianke | Chang, Jiang | Wei, Lixuan | Gao, Yu-Tang | Koh, Woon-Puay | Xiang, Yong-Bing | Tang, Ze-Zhong | Fan, Jin-Hu | Han, Jing-Jing | Zhou, Sheng-Li | Zhang, Peng | Zhang, Dong-Yun | Yuan, Yuan | Huang, Ying | Liu, Chunling | Zhai, Kan | Qiao, Yan | Jin, Guangfu | Guo, Chuanhai | Fu, Jianhua | Miao, Xiaoping | Lu, Changdong | Yang, Haijun | Wang, Chaoyu | Wheeler, William A. | Gail, Mitchell | Yeager, Meredith | Yuenger, Jeff | Guo, Er-Tao | Li, Ai-Li | Zhang, Wei | Li, Xue-Min | Sun, Liang-Dan | Ma, Bao-Gen | Li, Yan | Tang, Sa | Peng, Xiu-Qing | Liu, Jing | Hutchinson, Amy | Jacobs, Kevin | Giffen, Carol | Burdette, Laurie | Fraumeni, Joseph F. | Shen, Hongbing | Ke, Yang | Zeng, Yixin | Wu, Tangchun | Kraft, Peter | Chung, Charles C. | Tucker, Margaret A. | Hou, Zhi-Chao | Liu, Ya-Li | Hu, Yan-Long | Liu, Yu | Wang, Li | Yuan, Guo | Chen, Li-Sha | Liu, Xiao | Ma, Teng | Meng, Hui | Sun, Li | Li, Xin-Min | Li, Xiu-Min | Ku, Jian-Wei | Zhou, Ying-Fa | Yang, Liu-Qin | Wang, Zhou | Li, Yin | Qige, Qirenwang | Yang, Wen-Jun | Lei, Guang-Yan | Chen, Long-Qi | Li, En-Min | Yuan, Ling | Yue, Wen-Bin | Wang, Ran | Wang, Lu-Wen | Fan, Xue-Ping | Zhu, Fang-Heng | Zhao, Wei-Xing | Mao, Yi-Min | Zhang, Mei | Xing, Guo-Lan | Li, Ji-Lin | Han, Min | Ren, Jing-Li | Liu, Bin | Ren, Shu-Wei | Kong, Qing-Peng | Li, Feng | Sheyhidin, Ilyar | Wei, Wu | Zhang, Yan-Rui | Feng, Chang-Wei | Wang, Jin | Yang, Yu-Hua | Hao, Hong-Zhang | Bao, Qi-De | Liu, Bao-Chi | Wu, Ai-Qun | Xie, Dong | Yang, Wan-Cai | Wang, Liang | Zhao, Xiao-Hang | Chen, Shu-Qing | Hong, Jun-Yan | Zhang, Xue-Jun | Freedman, Neal D | Goldstein, Alisa M. | Lin, Dongxin | Taylor, Philip R. | Wang, Li-Dong | Chanock, Stephen J.
Nature genetics  2014;46(9):1001-1006.
We conducted a joint (pooled) analysis of three genome-wide association studies (GWAS) 1-3 of esophageal squamous cell carcinoma (ESCC) in ethnic Chinese (5,337 ESCC cases and 5,787 controls) with 9,654 ESCC cases and 10,058 controls for follow-up. In a logistic regression model adjusted for age, sex, study, and two eigenvectors, two new loci achieved genome-wide significance, marked by rs7447927 at 5q31.2 (per-allele odds ratio (OR) = 0.85, 95% CI 0.82-0.88; P=7.72x10−20) and rs1642764 at 17p13.1 (per-allele OR= 0.88, 95% CI 0.85-0.91; P=3.10x10−13). rs7447927 is a synonymous single nucleotide polymorphism (SNP) in TMEM173 and rs1642764 is an intronic SNP in ATP1B2, near TP53. Furthermore, a locus in the HLA class II region at 6p21.32 (rs35597309) achieved genome-wide significance in the two populations at highest risk for ESSC (OR=1.33, 95% CI 1.22-1.46; P=1.99x10−10). Our joint analysis identified new ESCC susceptibility loci overall as well as a new locus unique to the ESCC high risk Taihang Mountain region.
doi:10.1038/ng.3064
PMCID: PMC4212832  PMID: 25129146
2.  Ethanol extracts of Cinnamomum kanehirai Hayata leaves induce apoptosis in human hepatoma cell through caspase-3 cascade 
OncoTargets and therapy  2014;8:99-109.
Inducing apoptosis to susceptible cells is the major mechanism of most cytotoxic anticancer drugs in current use. Cinnamomum kanehirai Hayata (Lauraceae), a unique and native tree of Taiwan, is the major host for the medicinal fungus Antrodia cinnamomea which exhibits anti-cancer activity. Because of the scarcity of A. cinnamomea, C. kanehirai Hayata instead, is used as fork medicine in liver cancer. Here we observed the C. kanehirai Hayata ethanol extract could inhibit the cellular viability of both HepG2 and HA22T/VGH human hepatoma cell lines in a dose- and time-dependent manner. We found the mode of cell death was apoptosis according to cell morphological changes by Liu’s stain, oligonucleosomal DNA fragmentation by gel electrophoresis, externalization of phosphotidyl serine by detecting Annexin V and hypoploid population by cell cycle analysis. Our results showed that the extracts caused cleavage of caspase-3 and increased enzyme activity of caspase-8 and caspase-9. Caspase 3 inhibitor partially reversed the viability inhibition by the extract. Furthermore, the up-regulation of Bax and down-regulation of Bcl-2 were also noted by the extract treatment. In conclusion, C. kanehirai Hayata ethanol extract induced intrinsic pathway of apoptosis through caspase-3 cascade in human hepatoma HA22T/VGH and HepG2 cells, which might shed new light on hepatoma therapy.
doi:10.2147/OTT.S68765
PMCID: PMC4317145  PMID: 25678797
Antrodia cinnamomea; hepatoma; apoptosis; anticancer
3.  Medicinal Fungus Antrodia cinnamomea Inhibits Growth and Cancer Stem Cell Characteristics of Hepatocellular Carcinoma 
Background. Antrodia cinnamomea is an edible fungus commonly used in Asia as a well-known medicinal herb capable of treating drug intoxication and liver cancer. Methods. This study evaluated the anticancer activity of its biotechnological product, mycelial fermentation broth (AC-MFB) on hepatocellular carcinoma (HCC) by tetrazolium-based colorimetric assay in vitro and syngeneic Balb/c 1MEA.7R.1 tumor implantation model in vivo. Given that cancer stem cell characteristics, such as angiogenesis, invasiveness, and migration, are known to cause recurrence, we further evaluated the effect of AC-MFB on cellular viability inhibition of HCC cells, angiogenic activity and migration of endothelial cells, and the release of proangiogenic factors from HCC cells. Results. We found that AC-MFB markedly inhibited the growth of HCC without hepatic enzyme abnormality. This anti-HCC activity was validated by growth-inhibitory effects on both cultured murine 1MEA.7R.1 and human HA22T/VGH HCC cells. For cancer stem cell characteristics, AC-MFB inhibited the cellular viability, migration, and tube formation activity of EA. hy926 and SVEC4-10 endothelial cells. Production of extracellular vascular endothelial growth factor and intracellular hypoxia-inducible factor-1 alpha from HCC cells was suppressed by AC-MFB. Conclusion. Antrodia cinnamomea could inhibit the growth and cancer stem cell characteristics of HCC cells.
doi:10.1155/2013/569737
PMCID: PMC3606723  PMID: 23533499
4.  Stomatal development and movement 
Plant Signaling & Behavior  2010;5(10):1176-1180.
Stomata are epidermal pores on plant surface used for gas exchange with the atmosphere. Stomatal development and movement are regulated by environmental and internal signals. Mitogen-activated protein kinase (MAPK) cascades are universal transducers of extracellular signals among all eukaryotes. In plant, MAPK cascades regulate diverse cellular processes occurring during the whole ontogenetic plant life and ranging from normal cell proliferation to stress-inducing plant-to-environment interactions. Recent reports reveal that MAPK signaling is involved in both stomatal development and movement. This mini-review summarizes the roles of MAPK signaling in stomatal development and movement. How MAPK specificity is maintained in stomatal development and movement is also discussed.
doi:10.4161/psb.5.10.12757
PMCID: PMC3115344  PMID: 20855958
stomatal development; stomatal movement; mitogen-activated protein kinase; signaling specificity
5.  Incorporation of quantum dots on virus in polycationic solution 
Developing methods to label viruses with fluorescent moieties has its merits in elucidating viral infection mechanisms and exploring novel antiviral therapeutics. Fluorescent quantum dots (QDs), an emerging probe for biological imaging and medical diagnostics, were employed in this study to tag retrovirus encoding enhanced green fluorescent protein (EGFP) genes. Electrostatic repulsion forces generated from both negatively charged retrovirus and QDs were neutralized by cationic Polybrene®, forming colloidal complexes of QDs–virus. By examining the level of EGFP expression in 3T3 fibroblast cells treated with QDs-tagged retroviruses for 24 hours, the infectivity of retrovirus incorporated with QDs was shown to be only slightly decreased. Moreover, the imaging of QDs can be detected in the cellular milieu. In summary, the mild method developed here makes QDs-tagged virus a potential imaging probe for direct tracking the infection process and monitoring distribution of viral particles in infected cells.
PMCID: PMC2426762  PMID: 17722262
endocytosis; infection; envelope protein; Polybrene®; quantum dots; retroviral transduction
7.  A Standardized Precipitation Evapotranspiration Index Reconstruction in the Taihe Mountains Using Tree-Ring Widths for the Last 283 Years 
PLoS ONE  2015;10(7):e0133605.
Tree-ring samples from Chinese Pine (Pinus tabulaeformis Carr.) that were collected in the Taihe Mountains on the western Loess Plateau, China, were used to analyze the effects of climate and drought on radial growth and to reconstruct the mean April-June Standardized Precipitation Evapotranspiration Index (SPEI) during the period 1730–2012 AD. Precipitation positively affected tree growth primarily during wet seasons, while temperature negatively affected tree growth during dry seasons. Tree growth responded positively to SPEI at long time scales most likely because the trees were able to withstand water deficits but lacked a rapid response to drought. The 10-month scale SPEI was chosen for further drought reconstruction. A calibration model for the period 1951–2011 explained 51% of the variance in the modeled SPEI data. Our SPEI reconstruction revealed long-term patterns of drought variability and captured some significant drought events, including the severe drought of 1928–1930 and the clear drying trend since the 1950s which were widespread across northern China. The reconstruction was also consistent with two other reconstructions on the western Loess Plateau at both interannual and decadal scales. The reconstructed SPEI series showed synchronous variations with the drought/wetness indices and spatial correlation analyses indicated that this reconstruction could be representative of large-scale SPEI variability in northern China. Period analysis discovered 128-year, 25-year, 2.62-year, 2.36-year, and 2.04-year cycles in this reconstruction. The time-dependency of the growth response to drought should be considered in further studies of the community dynamics. The SPEI reconstruction improves the sparse network of long-term climate records for an enhanced understanding of climatic variability on the western Loess Plateau, China.
doi:10.1371/journal.pone.0133605
PMCID: PMC4514737  PMID: 26207621
8.  Primary cutaneous malignant granular cell tumor: a case report in China and review of the literature 
Diagnostic Pathology  2015;10:113.
Granular cell tumor is rare and accounts for approximately 0.5 % of all soft tissue tumors. The malignant granular cell tumor, especially cutaneous malignant granular cell tumor is extremely rare. The present case is the first patient of primary cutaneous malignant granular cell tumor reported from China in English. A review of the literature is performed, and the presentation, position, pathological diagnosis, treatment and prognosis of the patients with cutaneous malignant granular cell tumor of the reported cases before is analysed.
doi:10.1186/s13000-015-0357-2
PMCID: PMC4506611  PMID: 26187381
Malignant granular cell tumor; Cutaneous
9.  Mechanically selflocked chiral gemini-catenanes 
Nature Communications  2015;6:7590.
Mechanically interlocked and entangled molecular architectures represent one of the elaborate topological superstructures engineered at a molecular resolution. Here we report a methodology for fabricating mechanically selflocked molecules (MSMs) through highly efficient one-step amidation of a pseudorotaxane derived from dual functionalized pillar[5]arene (P[5]A) threaded by α,ω-diaminoalkane (DA-n; n=3–12). The monomeric and dimeric pseudo[1]catenanes thus obtained, which are inherently chiral due to the topology of P[5]A used, were isolated and fully characterized by NMR and circular dichroism spectroscopy, X-ray crystallography and DFT calculations. Of particular interest, the dimeric pseudo[1]catenane, named ‘gemini-catenane', contained stereoisomeric meso-erythro and dl-threo isomers, in which two P[5]A moieties are threaded by two DA-n chains in topologically different patterns. This access to chiral pseudo[1]catenanes and gemini-catenanes will greatly promote the practical use of such sophisticated chiral architectures in supramolecular and materials science and technology.
Mechanically locked molecules provide interesting topological structures and can present challenging synthetic targets. Here the authors report the synthesis of mechanically self-locked molecules, including chiral endo-spirobicyclics containing multiply interlocked rings within a single molecule.
doi:10.1038/ncomms8590
PMCID: PMC4506498  PMID: 26126502
10.  Diurnal and circadian expression profiles of glycerolipid biosynthetic genes in Arabidopsis 
Plant Signaling & Behavior  2014;9:e29715.
Glycerolipid composition in plant membranes oscillates in response to diurnal change. However, its functional significance remained unclear. A recent discovery that Arabidopsis florigen FT binds diurnally oscillating phosphatidylcholine molecules to promote flowering suggests that diurnal oscillation of glycerolipid composition is an important input in flowering time control. Taking advantage of public microarray data, we globally analyzed the expression pattern of glycerolipid biosynthetic genes in Arabidopsis under long-day, short-day, and continuous light conditions. The results revealed that 12 genes associated with glycerolipid metabolism showed significant oscillatory profiles. Interestingly, expression of most of these genes followed circadian profiles, suggesting that glycerolipid biosynthesis is partially under clock regulation. The oscillating expression profile of one representative gene, PECT1, was analyzed in detail. Expression of PECT1 showed a circadian pattern highly correlated with that of the clock-regulated gene GIGANTEA. Thus, our study suggests that a considerable number of glycerolipid biosynthetic genes are under circadian control.
doi:10.4161/psb.29715
PMCID: PMC4205134  PMID: 25763705
Diurnal/circadian oscillation; gene expression; glycerolipid; Arabidopsis thaliana
11.  Andrographolide sodium bisulphite-induced inactivation of urease: inhibitory potency, kinetics and mechanism 
Background
The inhibitory effect of andrographolide sodium bisulphite (ASB) on jack bean urease (JBU) and Helicobacter pylori urease (HPU) was performed to elucidate the inhibitory potency, kinetics and mechanism of inhibition in 20 mM phosphate buffer, pH 7.0, 2 mM EDTA, 25 °C.
Methods
The ammonia formations, indicator of urease activity, were examined using modified spectrophotometric Berthelot (phenol-hypochlorite) method. The inhibitory effect of ASB was characterized with IC50 values. Lineweaver-Burk and Dixon plots for JBU inhibition of ASB was constructed from the kinetic data. SH-blocking reagents and competitive active site Ni2+ binding inhibitors were employed for mechanism study. Molecular docking technique was used to provide some information on binding conformations as well as confirm the inhibition mode.
Results
The IC50 of ASB against JBU and HPU was 3.28 ± 0.13 mM and 3.17 ± 0.34 mM, respectively. The inhibition proved to be competitive and concentration- dependent in a slow-binding progress. The rapid formation of initial ASB-JBU complex with an inhibition constant of Ki = 2.86 × 10−3 mM was followed by a slow isomerization into the final complex with an overall inhibition constant of Ki* = 1.33 × 10−4 mM. The protective experiment proved that the urease active site is involved in the binding of ASB. Thiol reagents (L-cysteine and dithiothreithol) strongly protect the enzyme from the loss of enzymatic activity, while boric acid and fluoride show weaker protection, indicating that the active-site sulfhydryl group of JBU was potentially involved in the blocking process. Moreover, inhibition of ASB proved to be reversible since ASB-inactivated JBU could be reactivated by dithiothreitol application. Molecular docking assay suggested that ASB made contacts with the important sulfhydryl group Cys-592 residue and restricted the mobility of the active-site flap.
Conclusions
ASB was a competitive inhibitor targeting thiol groups of urease in a slow-binding manner both reversibly and concentration-dependently, serving as a promising urease inhibitor for the treatment of urease-related diseases.
doi:10.1186/s12906-015-0775-4
PMCID: PMC4504079  PMID: 26179287
Andrographolide sodium bisulphite; Urease; Inhibition; Slow-binding; Sulfhydryl group; Molecular docking
12.  Conjugation of toll-like receptor-7 agonist to gastric cancer antigen MG7-Ag exerts antitumor effects 
AIM: To investigate the effects of our tumor vaccines on reversing immune tolerance and generating therapeutic response.
METHODS: Vaccines were synthesized by solid phase using an Fmoc strategy, where a small molecule toll-like receptor-7 agonist (T7) was conjugated to a monoclonal gastric cancer 7 antigen mono-epitope (T7-MG1) or tri-epitope (T7-MG3). Cytokines were measured in both mouse bone marrow dendritic cells and mouse spleen lymphocytes after exposed to the vaccines. BALB/c mice were intraperitoneally immunized with the vaccines every 2 wk for a total of three times, and then subcutaneously challenged with Ehrlich ascites carcinoma (EAC) cells. Three weeks later, the mice were killed, and the tumors were surgically removed and weighed. Serum samples were collected from the mice, and antibody titers were determined by ELISA using an alkaline phosphate-conjugated detection antibody for total IgG. Antibody-dependent cell-mediated cytotoxicity was detected by the lactate dehydrogenase method using natural killer cells as effectors and antibody-labeled EAC cells as targets. Cytotoxic T lymphocyte activities were also detected by the lactate dehydrogenase method using lymphocytes as effectors and EAC cells as targets.
RESULTS: Vaccines were successfully synthesized and validated by analytical high performance liquid chromatography and electrospray mass spectrometry, including T7, T7-MG1, and T7-MG3. Rapid inductions of tumor necrosis factor-α and interleukin-12 in bone marrow dendritic cells and interferon γ and interleukin-12 in lymphocytes occurred in vitro after T7, T7-MG1, and T7-MG3 treatment. Immunization with T7-MG3 reduced the EAC tumor burden in BALB/c mice to 62.64% ± 5.55% compared with PBS control (P < 0.01). Six or nine weeks after the first immunization, the monoclonal gastric cancer 7 antigen antibody increased significantly in the T7-MG3 group compared with the PBS control (P < 0.01). As for antibody-dependent cell-mediated cytotoxicity, antisera obtained by immunization with T7-MG3 were able to markedly enhance cell lysis compared to PBS control (31.58% ± 2.94% vs 18.02% ± 2.26%; P < 0.01). As for cytotoxic T lymphocytes, T7-MG3 exhibited obviously greater cytotoxicity compared with PBS control (40.92% ± 4.38% vs 16.29% ± 1.90%; P < 0.01).
CONCLUSION: A successful method is confirmed for the design of gastric cancer vaccines by chemical conjugation of T7 and multi-repeat-epitope of monoclonal gastric cancer 7 antigen.
doi:10.3748/wjg.v21.i26.8052
PMCID: PMC4499347  PMID: 26185376
Gastric cancer; Immunotherapy; Monoclonal gastric cancer 7 antigen; Toll-like receptor-7; Vaccine
13.  Digestion of Nucleic Acids Starts in the Stomach 
Scientific Reports  2015;5:11936.
The ingestion of nucleic acids (NAs) as a nutritional supplement or in genetically modified food has attracted the attention of researchers in recent years. Discussions over the fate of NAs led us to study their digestion in the stomach. Interestingly, we found that NAs are digested efficiently by human gastric juice. By performing digests with commercial, recombinant and mutant pepsin, a protein-specific enzyme, we learned that the digestion of NAs could be attributed to pepsin rather than to the acidity of the stomach. Further study showed that pepsin cleaved NAs in a moderately site-specific manner to yield 3′-phosphorylated fragments and the active site to digest NAs is probably the same as that used to digest protein. Our results rectify the misunderstandings that the digestion of NAs in the gastric tract begins in the intestine and that pepsin can only digest protein, shedding new light on NA metabolism and pepsin enzymology.
doi:10.1038/srep11936
PMCID: PMC4500949  PMID: 26168909
14.  Public Health Responses to Reemergence of Animal Rabies, Taiwan, July 16–December 28, 2013 
PLoS ONE  2015;10(7):e0132160.
Taiwan had been free of indigenous human and animal rabies case since canine rabies was eliminated in 1961. In July 2013, rabies was confirmed among three wild ferret-badgers, prompting public health response to prevent human rabies cases. This descriptive study reports the immediate response to the reemergence of rabies in Taiwan. Response included enhanced surveillance for human rabies cases by testing stored cerebrospinal fluids (CSF) from patients with encephalitides of unknown cause by RT-PCR, prioritizing vaccine use for postexposure prophylaxis (PEP) during periods of vaccine shortage and subsequent expansion of PEP, surveillance of animal bites using information obtained from vaccine application, roll out of preexposure prophylaxis (PrEP) with vaccine stock restoration, surveillance for adverse events following immunization (AEFI), and ensuring surge capacity to respond to general public inquiries by phone and training for healthcare professionals. Enhanced surveillance for human rabies found no cases after testing 205 stored CSF specimens collected during January 2010–July 2013. During July 16 to December 28, 2013, we received 8,241 rabies PEP application; 6,634 (80.5%) were consistent with recommendations. Among the 6,501persons who received at least one dose of rabies vaccine postexposure, 4,953 (76.2%) persons who were bitten by dogs; only 59 (0.9%) persons were bitten by ferret-badgers. During the study period, 6,247 persons received preexposure prophylaxis. There were 23 reports of AEFI; but no anaphylaxis, Guillain-Barré syndrome, or acute disseminated encephalomyelitis were found. During the study period, there were 40,312 calls to the Taiwan Centers for Disease Control hotline, of which, 8,692 (22%) were related to rabies. Recent identification of rabies among ferret-badgers in a previously rabies-free country prompted rapid response. To date, no human rabies has been identified. Continued multifaceted surveillance and interministerial collaboration are crucial to achieve the goal of rabies-free status in Taiwan.
doi:10.1371/journal.pone.0132160
PMCID: PMC4498755  PMID: 26162074
15.  QiShenYiQi Pills, a compound in Chinese medicine, protects against pressure overload-induced cardiac hypertrophy through a multi-component and multi-target mode 
Scientific Reports  2015;5:11802.
The present study aimed to explore the holistic mechanism for the antihypertrophic effect of a compound in Chinese medicine, QiShenYiQi Pills (QSYQ) and the contributions of its components to the effect in rats with cardiac hypertrophy (CH). After induction of CH by ascending aortic stenosis, rats were treated with QSYQ, each identified active ingredient (astragaloside IV, 3, 4-dihydroxy-phenyl lactic acid or notoginsenoside R1) from its 3 major herb components or dalbergia odorifera, either alone or combinations, for 1 month. QSYQ markedly attenuated CH, as evidenced by echocardiography, morphology and biochemistry. Proteomic analysis and western blot showed that the majority of differentially expressed proteins in the heart of QSYQ-treated rats were associated with energy metabolism or oxidative stress. Each ingredient alone or their combinations exhibited similar effects as QSYQ but to a lesser extent and differently with astragaloside IV and notoginsenoside R1 being more effective for enhancing energy metabolism, 3, 4-dihydroxy-phenyl lactic acid more effective for counteracting oxidative stress while dalbergia odorifera having little effect on the variables evaluated. In conclusion, QSYQ exerts a more potent antihypertrophic effect than any of its ingredients or their combinations, due to the interaction of its active components through a multi-component and multi-target mode.
doi:10.1038/srep11802
PMCID: PMC4488877  PMID: 26136154
16.  Balsalazide Potentiates Parthenolide-Mediated Inhibition of Nuclear Factor-κB Signaling in HCT116 Human Colorectal Cancer Cells 
Intestinal Research  2015;13(3):233-241.
Background/Aims
Balsalazide is an anti-inflammatory drug used in the treatment of inflammatory bowel disease. Balsalazide can reduce inflammatory responses via several mechanisms, including inhibition of nuclear factor-κB (NF-κB) activity. Parthenolide (PT) inhibits NF-κB and exerts promising anticancer effects by promoting apoptosis. The present investigated the antitumor effects of balsalazide, combined with PT, on NF-κB in a representative human colorectal carcinoma cell line, HCT116.
Methods
We counted cells and conducted annexin-V assays and cell cycle analysis to measure apoptotic cell death. Western blotting was used investigate the levels of proteins involved in apoptosis.
Results
PT and balsalazide produced synergistic anti-proliferative effects and induced apoptotic cell death. The combination of balsalazide and PT markedly suppressed nuclear translocation of the NF-κB p65 subunit and the phosphorylation of inhibitor of NF-κB. Moreover, PT and balsalazide dramatically enhanced NF-κB p65 phosphorylation. Apoptosis, through the mitochondrial pathway, was confirmed by detecting effects on Bcl-2 family members, cytochrome c release, and activation of caspase-3 and -8.
Conclusions
Combination treatment with PT and balsalazide may offer an effective strategy for the induction of apoptosis in HCT116 cells.
doi:10.5217/ir.2015.13.3.233
PMCID: PMC4479738  PMID: 26130998
Balsalazide; Parthenolide; NF-κB; Apoptosis; Colorectal neoplasms
17.  Improving neurovascular outcomes with bilateral forepaw stimulation in a rat photothrombotic ischemic stroke model 
Neurophotonics  2014;1(1):011007.
Abstract.
Restoring perfusion to the penumbra during the hyperacute phase of ischemic stroke is a key goal of neuroprotection. Thrombolysis is currently the only approved treatment for ischemic stroke. However, its use is limited by the narrow therapeutic window and side effect of bleeding. Therefore, other interventions are desired that could potentially increase the perfusion of the penumbra. Here, we hypothesized that bilateral peripheral electrical stimulation will improve cerebral perfusion and restore cortical neurovascular response. We assess the outcomes of bilateral forepaw electrical stimulation at intensities of 2 and 4 mA, administered either unilaterally or bilaterally. We developed a combined electrocorticogram (ECoG)-functional photoacoustic microscopy (fPAM) system to evaluate the relative changes in cerebral hemodynamic function and electrophysiologic response to acute, focal stroke. The fPAM system is used for cerebral blood volume (CBV) and hemoglobin oxygen saturation (SO2) and the ECoG for neural activity, namely somatosensory-evoked potential (SSEP), interhemispheric coherence, and alpha-delta ratio (ADR) in response to forepaw stimulation. Our results confirmed the neuroprotective effect of bilateral forepaw stimulation at 2 mA as indicated by the 82% recovery of ADR and 95% improvement in perfusion into the region of penumbra. This experimental model can be used to study other potential interventions such as therapeutic hypertension and hypercarbia.
doi:10.1117/1.NPh.1.1.011007
PMCID: PMC4478786  PMID: 26157965
bilateral forepaw electrical stimulation; latent ipsilateral pathways; hyperacute ischemia; peri-infarct region; electrocorticography; functional photoacoustic microscopy; neuroprotection
19.  Grape seed proanthocyanidin protects liver against ischemia/reperfusion injury by attenuating endoplasmic reticulum stress 
AIM: To explore the effect of grape seed proanthocyanidin (GSP) in liver ischemia/reperfusion (IR) injury and alleviation of endoplasmic reticulum stress.
METHODS: Male Sprague-Dawley rats (220-250 g) were divided into three groups, namely, sham, IR, and GSP groups (n = 8 each). A liver IR (70%) model was established and reperfused for 6 h. Prior to reperfusion, the GSP group was administered with GSP (100 mg/kg) for 15 d, and liver histology was then investigated. Serum aminotransferase and inflammatory mediators coupled with superoxide dismutase and methane dicarboxylic aldehyde were detected. Western blot was conducted to analyze the expression of glucose-regulated protein 78, CCAAT/enhancer-binding protein homologous protein, activating transcription factor-4, inositol-requiring enzyme-1, procaspase-12, and nuclear factor-κb. Apoptotic cells were detected by TUNEL staining.
RESULTS: The serum aminotransferase, apoptotic cells, and Suzuki scores decreased in the GSP group compared with the IR group (Ps < 0.05). The methane dicarboxylic aldehyde level was decreased in the GSP group, but the superoxide dismutase level was reversed (Ps < 0.05). Similarly, GSP downregulated the proinflammatory factors and upregulated the levels of anti-inflammatory factors (Ps < 0.05). Western blot data showed that GSP increased glucose-regulated protein 78 expression and suppressed expression of CCAAT/enhancer-binding protein homologous protein, activating transcription factor-4, inositol-requiring enzyme-1, procaspase-12, and nuclear factor-κb compared with the IR group.
CONCLUSION: GSP possesses antioxidative, anti-inflammatory, and antiapoptotic effects by relieving endoplasmic reticulum stress through regulation of related signaling pathways to protect the liver against IR injury.
doi:10.3748/wjg.v21.i24.7468
PMCID: PMC4481441  PMID: 26139992
Anti-apoptosis; Endoplasmic reticulum stress; Grape seed proanthocyanidin; Inflammation; Ischemia/reperfusion injury
20.  Environmental enrichment and abstinence attenuate ketamine-induced cardiac and renal toxicity 
Scientific Reports  2015;5:11611.
The current study was designed to investigate the effect of abstinence in combination with environmental enrichment (EE) on cardiac and renal toxicity induced by 2 weeks of ketamine self-administration (SA) in rodents. In Experiment 1, one group of rats underwent ketamine SA for 14 days. In Experiment 2, the animals completed 2 weeks of ketamine SA followed by 2 and 4 weeks of abstinence. In Experiment 3, animals underwent 14 days of ketamine SA and 4 weeks of abstinence in which isolated environment (IE) and EE was introduced. The corresponding control groups were included for each experiment. Two weeks of ketamine SA caused significant increases in organ weight, Apoptosis Stimulating Fragment/Kidney Injury Molecule-1, and apoptotic level of heart and kidney. The extended length of withdrawal from ketamine SA partially reduced toxicity on the heart and kidney. Finally, introduction of EE during the period of abstinence greatly promoted the effect of abstinence on ketamine-induced cardiac and renal toxicity. The interactive effect of EE and abstinence was promising to promote the recovery of cardiac and renal toxicity of ketamine.
doi:10.1038/srep11611
PMCID: PMC4481381  PMID: 26112338
21.  Anti-atherosclerotic effects of the glucagon-like peptide-1 (GLP-1) based therapies in patients with type 2 Diabetes Mellitus: A meta-analysis 
Scientific Reports  2015;5:10202.
This study assessed the effect of GLP-1 based therapies on atherosclerotic markers in type 2 diabetes patients. 31 studies were selected to obtain data after multiple database searches and following inclusion and exclusion criteria. Age and BMI of the participants of longitudinal studies were 59.8 ± 8.3 years and 29.2 ± 5.7 kg/m2 (Mean±SD). Average duration of GLP-1 based therapies was 20.5 weeks. Percent flow-mediated diameter (%FMD) did not change from baseline significantly but when compared to controls, %FMD increased non-significantly following GLP-1-based therapies (1.65 [−0.89, 4.18]; P = 0.2; REM) in longitudinal studies and increased significantly in cross sectional studies (2.58 [1.68, 3.53]; P < 0.00001). Intima media thickness decreased statistically non-significantly by the GLP-1 based therapies. GLP-1 based therapies led to statistically significant reductions in the serum levels of brain natriuretic peptide (−40.16 [−51.50, −28.81]; P < 0.0001; REM), high sensitivity c-reactive protein (−0.27 [−0.48, −0.07]; P = 0.009), plasminogen activator inhibitor-1 (−12.90 [−25.98, 0.18]; P=0.05), total cholesterol (−5.47 [−9.55, −1.39]; P = 0.009), LDL-cholesterol (−3.70 [−7.39, −0.00]; P = 0.05) and triglycerides (−16.44 [−25.64, −7.23]; P = 0.0005) when mean differences with 95% CI in the changes from baselines were meta-analyzed. In conclusion, GLP-1-based therapies appear to provide beneficial effects against atherosclerosis. More randomized data will be required to arrive at conclusive evidence.
doi:10.1038/srep10202
PMCID: PMC4481643  PMID: 26111974
22.  Dynamic creation of a topologically-ordered Hamiltonian using spin-pulse control in the Heisenberg model 
Scientific Reports  2015;5:10076.
Hamiltonian engineering is an important approach for quantum information processing, when appropriate materials do not exist in nature or are unstable. So far there is no stable material for the Kitaev spin Hamiltonian with anisotropic interactions on a honeycomb lattice, which plays a crucial role in the realization of both Abelian and non-Abelian anyons. Here, we show two methods to dynamically realize the Kitaev spin Hamiltonian from the conventional Heisenberg spin Hamiltonian using pulse-control techniques based on the Baker-Campbell-Hausdorff (BCH) formula. In the first method, the Heisenberg interaction is changed into Ising interactions in the first process of the pulse sequence. In the next process of the first method, we transform them to a desirable anisotropic Kitaev spin Hamiltonian. In the second more efficient method, we show that if we carefully design two-dimensional pulses that vary depending on the qubit location, we can obtain the desired Hamiltonian in only one step of applying the BCH formula. As an example, we apply our methods to spin qubits based on quantum dots, in which the effects of both the spin-orbit interaction and the hyperfine interaction are estimated.
doi:10.1038/srep10076
PMCID: PMC4469982  PMID: 26081899
23.  Downregulation of microRNA-382 is associated with poor outcome of esophageal squamous cell carcinoma 
AIM: To study the potential prognostic role of microRNA-382 (miR-382) in esophageal squamous cell carcinoma (ESCC).
METHODS: Forty six patients were divided into 2 groups according to postoperative survival time: the poor outcome group (28 patients), who showed early metastasis but no recurrence, and died within 1 year after surgery, 12 patients of the group received postoperative chemotherapy treatment that was given after early metastasis happening; the good outcome group (18 patients), who had no clinical metastasis and recurrence, and survived 5 years or more after surgery, all patients did not receive any postoperative treatment. Total RNA was extracted from the patients’ formalin-fixed and paraffin-embedded esophageal cancer tissues. miR-382 level was evaluated using high-throughput real-time quantitative polymerase chain reaction analysis. The correlation between miR-382 level and clinicopathologic features was analyzed through COX regression model, and Kaplan-Meier analysis was used to analyze the relationship between miR-382 level and patient survival time.
RESULTS: miR-382 was differentially expressed in the two groups. Overall the average miR-382 level in the ESCC patients with good outcome was 9.8 ± 3.8, while miR-382 level in the ESCC patients with poor outcome was 3.0 ± 0.8. The differences of miR-382 levels between two groups were significant (P < 0.05). Kaplan-Meier analysis results showed that miR-382 expression level generally had a significant reverse-correlation with ESCC patient survival time (P < 0.001), in which the patients with higher expressions of miR-382 had a longer survival time either among individuals with the same tumor stage or among the overall patients.
CONCLUSION: miR-382 levels are reverse-correlated with ESCC poor outcomes, suggesting that miR-382 could be a potential predictive biomarker for both prognosis and treatment of ESCC.
doi:10.3748/wjg.v21.i22.6884
PMCID: PMC4462728  PMID: 26078564
Esophageal squamous cell carcinoma; miR-382; Metastasis; Outcome; Prognosis
24.  SYSTEMS BIOLOGY ANALYSES OF GENE EXPRESSION AND GENOME WIDE ASSOCIATION STUDY DATA IN OBSTRUCTIVE SLEEP APNEA 
The precise molecular etiology of obstructive sleep apnea (OSA) is unknown; however recent research indicates that several interconnected aberrant pathways and molecular abnormalities are contributors to OSA. Identifying the genes and pathways associated with OSA can help to expand our understanding of the risk factors for the disease as well as provide new avenues for potential treatment. Towards these goals, we have integrated relevant high dimensional data from various sources, such as genome-wide expression data (microarray), protein-protein interaction (PPI) data and results from genome-wide association studies (GWAS) in order to define sub-network elements that connect some of the known pathways related to the disease as well as define novel regulatory modules related to OSA. Two distinct approaches are applied to identify sub-networks significantly associated with OSA. In the first case we used a biased approach based on sixty genes/proteins with known associations with sleep disorders and/or metabolic disease to seed a search using commercial software to discover networks associated with disease followed by information theoretic (mutual information) scoring of the sub-networks. In the second case we used an unbiased approach and generated an interactome constructed from publicly available gene expression profiles and PPI databases, followed by scoring of the network with p-values from GWAS data derived from OSA patients to uncover sub-networks significant for the disease phenotype. A comparison of the approaches reveals a number of proteins that have been previously known to be associated with OSA or sleep. In addition, our results indicate a novel association of Phosphoinositide 3-kinase, the STAT family of proteins and its related pathways with OSA.
PMCID: PMC4465214  PMID: 21121029
25.  Levo-tetrahydropalmatine attenuates mouse blood-brain barrier injury induced by focal cerebral ischemia and reperfusion: Involvement of Src kinase 
Scientific Reports  2015;5:11155.
The restoration of blood flow following thrombolytic therapy causes ischemia and reperfusion (I/R) injury leading to blood-brain barrier (BBB) disruption and subsequent brain edema in patients of ischemic stroke. Levo-tetrahydropalmatine (l-THP) occurs in Corydalis genus and some other plants. However, whether l-THP exerts protective role on BBB disrpution following cerebral I/R remains unclear. Male C57BL/6N mice (23 to 28 g) were subjected to 90 min middle cerebral artery occlusion, followed by reperfusion for 24 h. l-THP (10, 20, 40 mg/kg) was administrated by gavage 60 min before ischemia. We found I/R evoked Evans blue extravasation, albumin leakage, brain water content increase, cerebral blood flow decrease, cerebral infarction and neurological deficits, all of which were attenuated by l-THP treatment. Meanwhile, l-THP inhibited tight junction (TJ) proteins down-expression, Src kinase phosphorylation, matrix metalloproteinases-2/9 (MMP-2/9) and caveolin-1 activation. In addition, surface plasmon resonance revealed binding of l-THP to Src kinase with high affinity. Then we found Src kinase inhibitor PP2 could attenuate Evans blue dye extravasation and inhibit the caveolin-1, MMP-9 activation, occludin down-expression after I/R, respectively. In conclusion, l-THP attenuated BBB injury and brain edema, which were correlated with inhibiting the Src kinase phosphorylation.
doi:10.1038/srep11155
PMCID: PMC4461916  PMID: 26059793

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