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1.  Mutations of Novel Influenza A(H10N8) Virus in Chicken Eggs and MDCK Cells 
Emerging Infectious Diseases  2014;20(9):1541-1543.
The recent emergence of human infection with influenza A(H10N8) virus is an urgent public health concern. Genomic analysis showed that the virus was conserved in chicken eggs but presented substantial adaptive mutations in MDCK cells. Our results provide additional evidence for the avian origin of this influenza virus.
doi:10.3201/eid2009.140257
PMCID: PMC4178415  PMID: 25148105
influenza A virus; mutation; genome; avian-origin; antiviral drug resistance; viruses; A(H10N8)
2.  Non-detection of Epstein-Barr virus and Human Papillomavirus in a region of high gastric cancer risk indicates a lack of a role for these viruses in gastric carcinomas 
Genetics and Molecular Biology  2013;36(2):183-184.
Gastric mucosa tissue was collected from patients with gastroduodenal diseases in a region of norrteastern China showing a high risk of gastric cancer incidence. The presence of EBV and HPV were assayed to investigate the relationship between gastric carcinomas and virus infection. Neither EBV nor HPV DNA was detected in tissue from the patients. The role of EBV and HPV in gastric cancer is not well understood and still needs to be clarified.
doi:10.1590/S1415-47572013005000018
PMCID: PMC3715283  PMID: 23885199
Human papillomavirus; Epstein-Barr virus; polymerase chain reaction; gastric carcinoma
3.  MicroRNA-26 governs profibrillatory inward-rectifier potassium current changes in atrial fibrillation 
The Journal of Clinical Investigation  2013;123(5):1939-1951.
Atrial fibrillation (AF) is a highly prevalent arrhythmia with pronounced morbidity and mortality. Inward-rectifier K+ current (IK1) is believed to be an important regulator of reentrant-spiral dynamics and a major component of AF-related electrical remodeling. MicroRNA-26 (miR-26) is predicted to target the gene encoding KIR2.1, KCNJ2. We found that miR-26 was downregulated in atrial samples from AF animals and patients and this downregulation was accompanied by upregulation of IK1/KIR2.1 protein. miR-26 overexpression suppressed expression of KCNJ2/KIR2.1. In contrast, miR-26 knockdown, inhibition, or binding-site mutation enhanced KCNJ2/KIR2.1 expression, establishing KCNJ2 as a miR-26 target. Knockdown of endogenous miR-26 promoted AF in mice, whereas adenovirus-mediated expression of miR-26 reduced AF vulnerability. Kcnj2-specific miR-masks eliminated miR-26–mediated reductions in Kcnj2, abolishing miR-26’s protective effects, while coinjection of a Kcnj2-specific miR-mimic prevented miR-26 knockdown-associated AF in mice. Nuclear factor of activated T cells (NFAT), a known actor in AF-associated remodeling, was found to negatively regulate miR-26 transcription. Our results demonstrate that miR-26 controls the expression of KCNJ2 and suggest that this downregulation may promote AF.
doi:10.1172/JCI62185
PMCID: PMC3635715  PMID: 23543060
4.  A continued saga of Boc5, the first non-peptidic glucagon-like peptide-1 receptor agonist with in vivo activities 
Acta Pharmacologica Sinica  2012;33(2):148-154.
Glucagon-like peptide-1 (GLP-1)-based therapy presents a promising option for treating type 2 diabetes. However, there are several limitations relative to the peptidic GLP-1 mimetics currently on the market or under development. This concern has led to a continued interest in the search for non-peptidic agonists for GLP-1 receptor (GLP-1R). Here, we briefly review the discovery, characterization and current status of a novel class of cyclobutane-derivative-based non-peptidic agonists for GLP-1R, including Boc5 and its newly discovered analogue WB4–24. Although the oral bioavailability of such compounds still poses great challenges, the progress made so far encourages us to identify a truly 'druggable' small molecule agonist for GLP-1R.
doi:10.1038/aps.2011.169
PMCID: PMC4010345  PMID: 22301855
type 2 diabetes; glucagon-like peptide-1; non-peptidic agonist; Boc5; G-protein coupled receptor
5.  MicroRNA expression profiling of mature ovarian teratomas 
Oncology Letters  2011;3(1):35-38.
MicroRNAs (miRNAs) are a class of endogenous, small, non-coding RNAs that regulate gene expression by targeting mRNAs and inhibiting expression via translation repression or RNA degradation. Emerging evidence indicates that miRNAs play a crucial role in the pathogenesis of human diseases, including tumor development. We profiled the miRNA expression between mature ovarian teratoma samples and matched normal tissues using miRNA microarrays, followed by validation with quantitative RT-PCR (qRT-PCR). The most highly expressed miRNAs in mature ovarian teratoma tissues were miRNA-520a-5p, miRNA-26b*, miRNA-421, miRNA-492 and miRNA-555, with a 1.3- to 2.6-fold change, whereas the least expressed miRNAs were miRNA-142-3p, let-7a, miRNA-19a, miRNA-34a, miRNA-620, miRNA-934, miRNA-657, miRNA-720, miRNA-22, miRNA-629 and miRNA-214, with a decreased level of 55–87% compared with normal tissues. The findings of the present study are the first to provide an altered miRNA profile for mature ovarian teratomas and differentially expressed miRNAs, which, if validated in future studies, may be essential in the pathogenesis of mature ovarian teratomas.
doi:10.3892/ol.2011.438
PMCID: PMC3362642  PMID: 22740852
microRNAs; mature ovarian teratomas; microarrays
6.  Deubiquitinase MYSM1 Is Essential for Normal Bone Formation and Mesenchymal Stem Cell Differentiation 
Scientific Reports  2016;6:22211.
Deubiquitinase MYSM1 has been shown to play a critical role in hematopoietic cell differentiation and hematopoietic stem cell (HSC) maintenance. Mesenchymal stem cells (MSCs) are multipotent stromal cells within the bone marrow. MSCs are progenitors to osteoblasts, chondrocytes, adipocytes, and myocytes. Although, MSCs have been extensively studied, the roles of MYSM1 in these cells remain unclear. Here we describe the function of MYSM1 on MSC maintenance and differentiation. In this report, we found that Mysm1−/− mice had a lower bone mass both in long bone and calvaria compared with their control counterpart. Preosteoblasts from Mysm1−/− mice did not show changes in proliferation or osteogenesis when compared to WT mice. Conversely, Mysm1−/− MSCs showed enhanced autonomous differentiation and accelerated adipogenesis. Our results demonstrate that MYSM1 plays a critical role in MSC maintenance and differentiation. This study also underscores the biological significance of deubiquitinase activity in MSC function. Mysm1 may represent a potential therapeutic target for controlling MSC lineage differentiation, and possibly for the treatment of metabolic bone diseases such as osteoporosis.
doi:10.1038/srep22211
PMCID: PMC4768166  PMID: 26915790
7.  Cross-reactivity between avian influenza A (H7N9) virus and divergent H7 subtypic- and heterosubtypic influenza A viruses 
Scientific Reports  2016;6:22045.
The number of human avian H7N9 influenza infections has been increasing in China. Understanding their antigenic and serologic relationships is crucial for developing diagnostic tools and vaccines. Here, we evaluated the cross-reactivities and neutralizing activities among H7 subtype influenza viruses and between H7N9 and heterosubtype influenza A viruses. We found strong cross-reactivities between H7N9 and divergent H7 subtypic viruses, including H7N2, H7N3, and H7N7. Antisera against H7N2, H7N3, and H7N7 could also effectively neutralize two distinct H7N9 strains. Two-way cross-reactivities exist within group 2, including H3 and H4, whereas one-way cross-reactivities were found across other groups, including H1, H10, H9, and H13. Our data indicate that the hemaglutinins from divergent H7 subtypes may facilitate the development of vaccines for distinct H7N9 infections. Moreover, serologic diagnoses for H7N9 infections need to consider possible interference from the cross-reactivity of H7N9 with other subtype influenza viruses.
doi:10.1038/srep22045
PMCID: PMC4764949  PMID: 26907865
8.  H18 Carbon: A New Metallic Phase with sp2-sp3 Hybridized Bonding Network 
Scientific Reports  2016;6:21879.
Design and synthesis of three-dimensional metallic carbons are currently one of the hot issues in contemporary condensed matter physics because of their fascinating properties. Here, based on first-principles calculations, we discover a novel stable metallic carbon allotrope (termed H18 carbon) in () symmetry with a mixed sp2-sp3 hybridized bonding network. The dynamical stability of H18 carbon is verified by phonon mode analysis and molecular dynamics simulations, and its mechanical stability is analyzed by elastic constants, bulk modulus, and shear modulus. By simulating the x-ray diffraction patterns, we propose that H18 carbon would be one of the unidentified carbon phases observed in recent detonation experiments. The analysis of the band structure and density of states reveal that this new carbon phase has a metallic feature mainly due to the C atoms with sp2 hybridization. This novel 3D metallic carbon phase is anticipated to be useful for practical applications such as electronic and mechanical devices.
doi:10.1038/srep21879
PMCID: PMC4763233  PMID: 26903234
9.  hTERT mediates gastric cancer metastasis partially through the indirect targeting of ITGB1 by microRNA-29a 
Scientific Reports  2016;6:21955.
Human telomerase reverse transcriptase (hTERT) plays a key role in tumor invasion and metastasis, but the mechanism of its involvement in these processes is not clear. The purpose of this study is to investigate the possible molecular mechanism of hTERT in the promotion of gastric cancer (GC) metastasis. We found that the up-regulation of hTERT in gastric cancer cells could inhibit the expression of miR-29a and enhance the expression of Integrin β1 (ITGB1). In addition, the invasive capacity of gastric cancer cells was also highly increased after hTERT overexpression. Our study also found that the restoration of miR-29a suppressed the expression of ITGB1 and inhibited GC cell metastasis both in vitro and in vivo. Taken together, our results suggested that hTERT may promote GC metastasis through the hTERT-miR-29a-ITGB1 regulatory pathway.
doi:10.1038/srep21955
PMCID: PMC4763288  PMID: 26903137
10.  Efficacy and Safety of rAAV2-ND4 Treatment for Leber’s Hereditary Optic Neuropathy 
Scientific Reports  2016;6:21587.
Leber’s hereditary optic neuropathy (LHON) is a mitochondrially inherited disease leading to blindness. A mitochondrial DNA point mutation at the 11778 nucleotide site of the NADH dehydrogenase subunit 4 (ND4) gene is the most common cause. The aim of this study was to evaluate the efficacy and safety of a recombinant adeno-associated virus 2 (AAV2) carrying ND4 (rAAV2-ND4) in LHON patients carrying the G11778A mutation. Nine patients were administered rAAV2-ND4 by intravitreal injection to one eye and then followed for 9 months. Ophthalmologic examinations of visual acuity, visual field, and optical coherence tomography were performed. Physical examinations included routine blood and urine. The visual acuity of the injected eyes of six patients improved by at least 0.3 log MAR after 9 months of follow-up. In these six patients, the visual field was enlarged but the retinal nerve fibre layer remained relatively stable. No other outcome measure was significantly changed. None of the nine patients had local or systemic adverse events related to the vector during the 9-month follow-up period. These findings support the feasible use of gene therapy for LHON.
doi:10.1038/srep21587
PMCID: PMC4759604  PMID: 26892229
11.  Effectiveness of the clinical pharmacist in reducing mortality in hospitalized cardiac patients: a propensity score-matched analysis 
Background
Pharmacist-led medication review services have been assessed in the meta-analyses in hospital. Of the 135 relevant articles located, 21 studies met the inclusion criteria; however, there was no statistically significant difference found between pharmacists’ interventions and usual care for mortality (odds ratio 1.50, 95% confidence interval 0.65, 3.46, P=0.34). These analyses may not have found a statistically significant effect because they did not adequately control the wide variation in the delivery of care and patient selection parameters. Additionally, the investigators did not conduct research on the cases of death specifically and did not identify all possible drug-related problems (DRPs) that could cause or contribute to mortality and then convince physicians to correct. So there will be a condition to use a more precise approach to evaluate the effect of clinical pharmacist interventions on the mortality rates of hospitalized cardiac patients.
Objective
To evaluate the impact of the clinical pharmacist as a direct patient-care team member on the mortality of all patients admitted to the cardiology unit.
Methods
A comparative study was conducted in a cardiology unit of a university-affiliated hospital. The clinical pharmacists did not perform any intervention associated with improper use of medications during Phase I (preintervention) and consulted with the physicians to address the DRPs during Phase II (postintervention). The two phases were compared to evaluate the outcome, and propensity score (PS) matching was applied to enhance the comparability. The primary endpoint of the study was the composite of all-cause mortality during Phase I and Phase II.
Results
Pharmacists were consulted by the physicians to correct any drug-related issues that they suspected may cause or contribute to a fatal outcome in the cardiology ward. A total of 1,541 interventions were suggested by the clinical pharmacist in the study group; 1,416 (92.0%) of them were accepted by the cardiology team, and violation of incompatibilities had the highest percentage of acceptance by the cardiology team. All-cause mortality was 1.5% during Phase I (preintervention) and was reduced to 0.9% during Phase II (postintervention), and the difference was statistically significant (P=0.0005). After PS matching, all-cause mortality changed from 1.7% during Phase I down to 1.0% during Phase II, and the difference was also statistically significant (P=0.0074).
Conclusion
DRPs that were suspected to cause or contribute to a possibly fatal outcome were determined by clinical pharmacist service in patients hospitalized in a cardiology ward. Correction of these DRPs by physicians after pharmacist’s advice caused a significant decrease in mortality as analyzed by PS matching. The significant reduction in the mortality rate in this patient population observed in this study is “hypothesis generating” for future randomized studies.
Video abstract
doi:10.2147/TCRM.S98300
PMCID: PMC4762444  PMID: 26937196
drug-related problems; cardiology ward; clinical pharmacists; intervention; propensity score matching
12.  Allosteric coupling between proximal C-terminus and selectivity filter is facilitated by the movement of transmembrane segment 4 in TREK-2 channel 
Scientific Reports  2016;6:21248.
TREK-2, a member of two-pore-domain potassium channel family, regulates cellular excitability in response to diverse stimuli. However, how such stimuli control channel function remains unclear. Here, by characterizing the responses of cytosolic proximal C-terminus deletant (ΔpCt) and transmembrane segment 4 (M4)-glycine hinge mutant (G312A) to 2-Aminoethoxydiphenyl borate (2-APB), an activator of TREK-2, we show that the transduction initiated from pCt domain is allosterically coupled with the conformation of selectivity filter (SF) via the movements of M4, without depending on the original status of SF. Moreover, ΔpCt and G312A also exhibited blunted responses to extracellular alkalization, a model to induce SF conformational transition. These results suggest that the coupling between pCt domain and SF is bidirectional, and M4 movements are involved in both processes. Further mechanistic exploration reveals that the function of Phe316, a residue close to the C-terminus of M4, is associated with such communications. However, unlike TREK-2, M4-hinge of TREK-1 only controls the transmission from pCt to SF, rather than SF conformational changes triggered by pHo changes. Together, our findings uncover the unique gating properties of TREK-2, and elucidate the mechanisms for how the extracellular and intracellular stimuli harness the pore gating allosterically.
doi:10.1038/srep21248
PMCID: PMC4754649  PMID: 26879043
13.  Pathogenicity of a currently circulating Chinese variant pseudorabies virus in pigs 
World Journal of Virology  2016;5(1):23-30.
AIM: To test the pathogenicity of pseudorabies virus (PRV) variant HN1201 and compare its pathogenicity with a classical PRV Fa strain.
METHODS: The pathogenicity of the newly-emerging PRV variant HN1201 was evaluated by different inoculating routes, virus loads, and ages of pigs. The classical PRV Fa strain was then used to compare with HN1201 to determine pathogenicity. Clinical symptoms after virus infection were recorded daily and average daily body weight was used to measure the growth performance of pigs. At necropsy, gross pathology and histopathology were used to evaluate the severity of tissue damage caused by virus infection.
RESULTS: The results showed that the efficient infection method of RPV HN1201 was via intranasal inoculation at 107 TCID50, and that the virus has high pathogenicity to 35- to 127-d old pigs. Compared with Fa strain, pigs infected with HN1201 showed more severe clinical symptoms and pathological lesions. Immunochemistry results revealed HN1201 had more abundant antigen distribution in extensive organs.
CONCLUSION: All of the above results suggest that PRV variant HN1201 was more pathogenic to pigs than the classical Fa strain.
doi:10.5501/wjv.v5.i1.23
PMCID: PMC4735551  PMID: 26870671
Pseudorabies virus; Pathogenicity; Virus variant; Gross pathology; Histopathology
14.  RGD-Targeted Ultrasound Contrast Agent for Longitudinal Assessment of Hep-2 Tumor Angiogenesis In Vivo 
PLoS ONE  2016;11(2):e0149075.
Objective
To prepare arginine-glycine-aspartate (RGD)-targeted ultrasound contrast microbubbles (MBs) and explore the feasibility of their use in assessing dynamic changes in αvβ3 integrin expression in a murine model of tumor angiogenesis.
Methods
RGD peptides were conjugated to the surfaces of microbubbles via biotin-avidin linkage. Microbubbles bearing RADfK peptides were prepared as controls. The RGD-MBs were characterized using an Accusizer 780 and optical microscopy. The binding specificity of the RGD-MBs for ανβ3-expressing endothelial cells (bEnd.3) was demonstrated in vitro by a competitive inhibition experiment. In an in vivo study, mice bearing tumors of three different stages were intravenously injected with RGD-MBs and subjected to targeted, contrast-enhanced, high-frequency ultrasound. Subsequently, tumors were harvested and sectioned for immunofluorescence analysis of ανβ3 expression.
Results
The mean size of the RGD-MBs was 2.36 ± 1.7 μm. The RGD-MBs showed significantly higher adhesion levels to bEnd.3 cells compared to control MBs (P < 0.01). There was rarely binding of RGD-MBs to αvβ3-negative MCF-7 cells. Adhesion of the RGD-MBs to the bEnd.3 cells was significantly inhibited following treatment with anti-alpha(v) antibodies. The quantitative acoustic video intensity for high-frequency, contrast-enhanced ultrasound imaging of subcutaneous human laryngeal carcinoma (Hep-2) tumor xenografts was significantly higher in small tumors (19.89 ± 2.49) than in medium tumors (11.25 ± 2.23) and large tumors (3.38 ± 0.67) (P < 0.01).
Conclusions
RGD-MBs enable noninvasive in vivo visualization of changes in tumor angiogenesis during tumor growth in subcutaneous cancer xenografts.
doi:10.1371/journal.pone.0149075
PMCID: PMC4749330  PMID: 26862757
15.  miR-203 inhibits proliferation and self-renewal of leukemia stem cells by targeting survivin and Bmi-1 
Scientific Reports  2016;6:19995.
Drug resistance is one of the leading causes of failed cancer therapy in the treatment of acute myeloid leukemia. Although the mechanisms of resistance are poorly understood, they may be related to the presence of leukemia stem cells (LSCs). Down-regulation of the miR-203 reportedly contributes to oncogenesis and chemo-resistance in multiple cancers. We found that miR-203 expression was down-regulated in CD34 + AML cells as compared with CD34− cells isolated from patients as well as in LSC-enriched (CD34 + CD38−) cell lines KG-1a or MOLM13. Additionally, re-expression of miR-203 led to decreased cell proliferation, self-renewal, and sphere formation in LSCs. Moreover, miR-203 was found to directly target the 3′un-translated regions of survivin and Bmi-1 mRNAs affecting proliferation and self-renewal in LSCs. In this study, we identified a novel miR-203/survivin/Bmi-1 axis involved in the regulation of biological properties of LSCs. This axis may represent a new therapeutic target for acute myeloid leukemia and a potential prognosis/diagnostic marker for LSCs therapy.
doi:10.1038/srep19995
PMCID: PMC4742816  PMID: 26847520
16.  Integrated Translatomics with Proteomics to Identify Novel Iron–Transporting Proteins in Streptococcus pneumoniae 
Streptococcus pneumoniae (S.pneumoniae) is a major human pathogen causing morbidity and mortality worldwide. Efficiently acquiring iron from the environment is critical for S. pneumoniae to sustain growth and cause infection. There are only three known iron-uptake systems in Streptococcal species responsible for iron acquisition from the host, including ABC transporters PiaABC, PiuABC, and PitABC. Besides, no other iron-transporting system has been suggested. In this work, we employed our newly established translating mRNA analysis integrated with proteomics to evaluate the possible existence of novel iron transporters in the bacterium. We simultaneously deleted the iron-binding protein genes of the three iron-uptake systems to construct a piaA/piuA/pitA triple mutant (Tri-Mut) of S. pneumoniae D39, in which genes and proteins related to iron transport should be regulated in response to the deletion. With ribosome associated mRNA sequencing-based translatomics focusing on translating mRNA and iTRAQ quantitative proteomics based on the covalent labeling of peptides with tags of varying mass, we indeed observed a large number of genes and proteins representing various coordinated biological pathways with significantly altered expression levels in the Tri-Mut mutant. Highlighted in this observation is the identification of several new potential iron-uptake ABC transporters participating in iron metabolism of Streptococcus. In particular, putative protein SPD_1609 in operon 804 was verified to be a novel iron-binding protein with similar function to PitA in S. pneumoniae. These data derived from the integrative translatomics and proteomics analyses provided rich information and insightful clues for further investigations on iron-transporting mechanism in bacteria and the interplay between Streptococcal iron availability and the biological metabolic pathways.
doi:10.3389/fmicb.2016.00078
PMCID: PMC4738293  PMID: 26870030
translatomics; proteomics; S. pneumoniae; iron-acquisition system; iron-transporting protein
17.  Application of Multiplex PCR Coupled with Matrix-Assisted Laser Desorption Ionization–Time of Flight Analysis for Simultaneous Detection of 21 Common Respiratory Viruses 
Journal of Clinical Microbiology  2015;53(8):2549-2554.
Respiratory infections continue to pose a significant threat to human health. It is important to accurately and rapidly detect respiratory viruses. To compensate for the limits of current respiratory virus detection methods, we developed a 24-plex analysis (common respiratory virus-mass spectrometry [CRV-MS]) that can simultaneously detect and identify 21 common respiratory viruses based on a matrix-assisted laser desorption ionization–time of flight (MALDI-TOF) mass spectrometry system. To evaluate the efficacy of the CRV-MS method, we used 102 samples that were confirmed positive for these common respiratory viruses. All tests using the CRV-MS method were effective, with no cross-reactivity observed with other common respiratory viruses. To confirm the usefulness of the CRV-MS method, we screened 336 nasal and throat swabs that were collected from adults or children with suspected viral acute respiratory tract infections using the CRV-MS method and consensus PCR/reverse transcription-PCR (RT-PCR) methods. Excluding four RNase P-negative samples, the CRV-MS and consensus PCR/RT-PCR methods detected respiratory viruses in 92.5% (307/332) and 89.5% (297/332) of the samples, respectively. The two methods yielded identical results for 306 (92.2%) samples, including negative results for 25 samples (7.5%) and positive results for 281 samples (84.6%). Differences between the two methods may reflect their different sensitivities. The CRV-MS method proved to be sensitive and robust, and it can be used in large-scale epidemiological studies of common respiratory virus infections.
doi:10.1128/JCM.00943-15
PMCID: PMC4508422  PMID: 26019198
18.  Leucine supplementation via drinking water reduces atherosclerotic lesions in apoE null mice 
Acta Pharmacologica Sinica  2015;37(2):196-203.
Aim:
Recent evidence suggests that the essential amino acid leucine may be involved in systemic cholesterol metabolism. In this study, we investigated the effects of leucine supplementation on the development of atherosclerosis in apoE null mice.
Methods:
ApoE null mice were fed with chow supplemented with leucine (1.5% w/v) in drinking water for 8 week. Aortic atherosclerotic lesions were examined using Oil Red O staining. Plasma lipoprotein-cholesterol levels were measured with fast protein liquid chromatography. Hepatic gene expression was detected using real-time PCR and Western blot analyses.
Results:
Leucine supplementation resulted in 57.6% reduction of aortic atherosclerotic lesion area in apoE null mice, accompanied by 41.2% decrease of serum LDL-C levels and 40.2% increase of serum HDL-C levels. The body weight, food intake and blood glucose level were not affected by leucine supplementation. Furthermore, leucine supplementation increased the expression of Abcg5 and Abcg8 (that were involved in hepatic cholesterol efflux) by 1.28- and 0.86-fold, respectively, and significantly increased their protein levels. Leucine supplementation also increased the expression of Srebf1, Scd1 and Pgc1b (that were involved in hepatic triglyceride metabolism) by 3.73-, 1.35- and 1.71-fold, respectively. Consequently, leucine supplementation resulted in 51.77% reduction of liver cholesterol content and 2.2-fold increase of liver triglyceride content. Additionally, leucine supplementation did not affect the serum levels of IL-6, IFN-γ, TNF-α, IL-10 and IL-12, but markedly decreased the serum level of MCP-1.
Conclusion:
Leucine supplementation effectively attenuates atherosclerosis in apoE null mice by improving the plasma lipid profile and reducing systemic inflammation.
doi:10.1038/aps.2015.88
PMCID: PMC4753376  PMID: 26687933
amino acid; leucine supplementation; atherosclerosis; lipid metabolism; ABCG5; ABCG8; apoE null mice; inflammation
19.  A Functional Polymorphism (rs2494752) in the AKT1 Promoter Region and Gastric Adenocarcinoma Risk in an Eastern Chinese Population 
Scientific Reports  2016;6:20008.
AKT is an important signal transduction protein that plays a crucial role in cancer development. Therefore, we evaluated associations between single nucleotide polymorphisms (SNPs) in the AKT promoter region and gastric cancer (GCa) risk in a case-control study of 1,110 GCa patients and 1,114 matched cancer-free controls. We genotyped five SNPs (AKT1 rs2494750G >C, AKT1 rs2494752A >G, AKT1 rs10138227C >T, AKT2 rs7254617G>A and AKT2 rs2304186G >T) located in the 5′ upstream regulatory, first intron or promoter regions. In the logistic regression analysis, a significantly elevated GCa risk was associated with the rs2494752 AG/GG variant genotypes (adjusted odds ratio [OR] = 1.20, 95% confidence interval [CI] = 1.02–1.42) under a dominant genetic model, and this risk was more evident in subgroups of ever drinkers. The luciferase reporter assay showed that the rs2494752 G allele significantly increased luciferase activity. Our results suggest that the potentially functional AKT1 rs2494752 SNP may affect GCa susceptibility, likely by modulating the AKT1 promoter transcriptional activity. Larger, independent studies are warranted to validate our findings.
doi:10.1038/srep20008
PMCID: PMC4730221  PMID: 26818920
20.  Preclinical Models for Investigation of Herbal Medicines in Liver Diseases: Update and Perspective 
Liver disease results from a dynamic pathological process associated with cellular and genetic alterations, which may progress stepwise to liver dysfunction. Commonly, liver disease begins with hepatocyte injury, followed by persistent episodes of cellular regeneration, inflammation, and hepatocyte death that may ultimately lead to nonreversible liver failure. For centuries, herbal remedies have been used for a variety of liver diseases and recent studies have identified the active compounds that may interact with liver disease-associated targets. Further study on the herbal remedies may lead to the formulation of next generation medicines with hepatoprotective, antifibrotic, and anticancer properties. Still, the pharmacological actions of vast majority of herbal remedies remain unknown; thus, extensive preclinical studies are important. In this review, we summarize progress made over the last five years of the most commonly used preclinical models of liver diseases that are used to screen for curative herbal medicines for nonalcoholic fatty liver disease, liver fibrosis/cirrhosis, and liver. We also summarize the proposed mechanisms associated with the observed liver-protective, antifibrotic, and anticancer actions of several promising herbal medicines and discuss the challenges faced in this research field.
doi:10.1155/2016/4750163
PMCID: PMC4749812  PMID: 26941826
21.  Effects of probenecid and cimetidine on the pharmacokinetics of nemonoxacin in healthy Chinese volunteers 
Purpose
To investigate the effects of probenecid and cimetidine on the pharmacokinetics of nemonoxacin in humans.
Methods
Two independent, open-label, randomized, crossover studies were conducted in 24 (12 per study) healthy Chinese volunteers. In Study 1, each volunteer received a single oral dose of 500 mg of nemonoxacin alone or with 1.5 g of probenecid divided into three doses within 25 hours. In Study 2, each volunteer received a single oral dose of 500 mg of nemonoxacin alone or with multiple doses of cimetidine (400 mg thrice daily for 7 days). The plasma and urine nemonoxacin concentrations were determined using validated liquid chromatography–tandem mass spectrometry methods.
Results
Coadministration of nemonoxacin with probenecid reduced the renal clearance (CLr) of nemonoxacin by 22.6%, and increased the area under the plasma concentration–time curve from time 0 to infinity (AUC0−∞) by 26.2%. Coadministration of nemonoxacin with cimetidine reduced the CLr of nemonoxacin by 13.3% and increased AUC0−∞ by 9.4%. Coadministration of nemonoxacin with probenecid or cimetidine did not significantly affect the maximum concentration of nemonoxacin or the percentage of the administered dose recovered in the urine.
Conclusion
Although probenecid reduced the CLr and increased the plasma exposure of nemonoxacin, these effects are unlikely to be clinically meaningful at therapeutic doses. Cimetidine had weaker, clinically meaningless effects on the pharmacokinetics of nemonoxacin.
doi:10.2147/DDDT.S95934
PMCID: PMC4725632  PMID: 26855561
nemonoxacin; probenecid; cimetidine; clinical pharmacokinetics; drug–drug interaction
22.  Native low density lipoprotein promotes lipid raft formation in macrophages 
Molecular Medicine Reports  2016;13(3):2087-2093.
Oxidized low-density lipoprotein (LDL) has an important role in atherogenesis; however, the mechanisms underlying cell-mediated LDL oxidation remain to be elucidated. The present study investigated whether native-LDL induced lipid raft formation, in order to gain further insight into LDL oxidation. Confocal microscopic analysis revealed that lipid rafts were aggregated or clustered in the membrane, which were colocalized with myeloperoxidase (MPO) upon native LDL stimulation; however, in the presence of methyl-β-cyclodextrin (MβCD), LDL-stimulated aggregation, translocation, and colocalization of lipid rafts components was abolished.. In addition, lipid raft disruptors MβCD and filipin decreased malondialdehyde expression levels. Density gradient centrifugation coupled to label-free quantitative proteomic analysis identified 1,449 individual proteins, of which 203 were significantly upregulated following native-LDL stimulation. Functional classification of the proteins identified in the lipid rafts revealed that the expression levels of translocation proteins were upregulated. In conclusion, the results of the present study indicated that native-LDL induced lipid raft clustering in macrophages, and the expression levels of several proteins were altered in the stimulated macrophages, which provided novel insights into the mechanism underlying LDL oxidation.
doi:10.3892/mmr.2016.4781
PMCID: PMC4768993  PMID: 26781977
macrophages; lipid rafts; low density lipoprotein; atherosclerosis; proteomics
23.  Misdiagnosis and Mistherapy of Crohn's Disease as Intestinal Tuberculosis 
Medicine  2016;95(1):e2436.
Abstract
The differential diagnosis of Crohn's disease (CD) and intestinal tuberculosis (ITB) remains difficult as the clinical symptoms of the 2 digestive diseases are so similar. Here we report a case where a patient was initially misdiagnosed with ITB prior to the correct CD diagnosis. The 46-year-old male patient was hospitalized elsewhere for pain in the right lower abdomen and underwent an appendectomy. The pathological diagnosis was ITB and the patient was administered antituberculosis therapy for 1 year. Afterward, the patient was readmitted to the hospital for a right lower abdominal mass. A computed tomography scan revealed intestinal gas, fistula, and abdominal mass. We performed a right hemicolectomy on the patient. Postoperatively, we diagnosed the patient with CD, based on patient history and pathological examination. According to the CD active index (CDAI), the patient was at high risk and began treatment with infliximab. The patient has remained in complete remission and made a good recovery after 8-months follow-up. We compared this case with the results of a literature review on the misdiagnosis between CD and ITB (26 previously reported cases) to determine the characteristics of misdiagnosed cases. We found that distinguishing between ITB and CD is difficult because of their varied clinical presentation, nonspecific investigative tools, and profound similarities even in pathological specimens. Although a CT scan to determine the morphology of the bowel wall is a key for correct diagnosis, each case still poses challenges for diagnosis and administrating the appropriate treatment.
doi:10.1097/MD.0000000000002436
PMCID: PMC4706269  PMID: 26735549
24.  Deciphering the streamlined genome of Streptomyces xiamenensis 318 as the producer of the anti-fibrotic drug candidate xiamenmycin 
Scientific Reports  2016;6:18977.
Streptomyces xiamenensis 318, a moderate halophile isolated from a mangrove sediment, produces the anti-fibrotic compound xiamenmycin. The whole genome sequence of strain 318 was obtained through long-read single-molecule real-time (SMRT) sequencing, high-throughput Illumina HiSeq and 454 pyrosequencing technologies. The assembled genome comprises a linear chromosome as a single contig of 5,961,401-bp, which is considerably smaller than other reported complete genomes of the genus Streptomyces. Based on the antiSMASH pipeline, a total of 21 gene clusters were predicted to be involved in secondary metabolism. The gene cluster responsible for the biosynthesis of xiamenmycin resides in a strain-specific 61,387-bp genomic island belonging to the left-arm region. A core metabolic network consisting of 104 reactions that supports xiamenmycin biosynthesis was constructed to illustrate the necessary precursors derived from the central metabolic pathway. In accordance with the finding of a putative ikarugamycin gene cluster in the genome, the targeted chemical profiling of polycyclic tetramate macrolactams (PTMs) resulted in the identification of ikarugamycin. A successful genome mining for bioactive molecules with different skeletons suggests that the naturally minimized genome of S. xiamenensis 318 could be used as a blueprint for constructing a chassis cell with versatile biosynthetic capabilities for the production of secondary metabolites.
doi:10.1038/srep18977
PMCID: PMC4705527  PMID: 26744183
25.  Heparanase regulates in vitro VEGF-C expression and its clinical significance to pancreatic ductal cell adenocarcinoma 
Oncology Letters  2016;11(2):1327-1334.
Heparanase (HPSE) and vascular endothelial growth factor C (VEGF-C) are important cytokines that promote metastasis and angiogenesis in numerous malignant neoplasms, however, their association remains unclear in pancreatic ductal cell adenocarcinoma (PDAC). The present study aimed to investigate whether HPSE has a positive correlation with VEGF-C expression and to uncover the role it plays in the in vitro invasion of BxPC-3 cells (a pancreatic carcinoma cell line), and to analyze the value of joint detection of HPSE and VEGF-C for PDAC patients. A recombinant plasmid, GV230/HPSE was constructed and BxPC-3 cells were transiently transfected with GV230/HPSE or siRNA against HPSE. The expression levels of HPSE and VEGF-C were compared using reverse transcription quantitative PCR (RT-qPCR) and immunoblotting. The metastatic potential of treated BxPC-3 cells was evaluated using a Transwell® invasion assay. The relative mRNA levels of HPSE and VEGF-C in 34 PDAC specimens were assessed by RT-qPCR. The results of the RT-qPCR demonstrated a 10.7- and 3.24-fold elevation (P<0.01) of HPSE mRNA and VEGF-C mRNA, respectively, in GV230/HPSE group, whereas the HPSE siRNA group were downregulated for these mRNAs (−2.45-fold, P<0.01; −1.84-fold, P<0.01). The same pattern for protein expression was detected using immunoblot assays. In Transwell® invasion assays 138±5 cells in GV230/HPSE group and 53±4 cells in siRNA group migrated through the Matrigel®. A negative correlation between the mRNA levels of HPSE and VEGF-C in PDAC specimens and the prognosis factors of the postoperative patients was identified. Spearman rank correlation analysis indicated a positive correlation between HPSE and VEGF-C in PDAC (r=0.812, P<0.01). HPSE regulates the expression of VEGF-C and facilitates invasion of BxPC-3 in vitro. Joint detection of HPSE and VEGF-C may therefore be clinically useful in determining the prognosis of pancreatic cancer patients.
doi:10.3892/ol.2016.4085
PMCID: PMC4734281  PMID: 26893739
pancreatic ductal cell adenocarcinoma; heparanase; VEGF-C; gene overexpression; RNA interference; metastasis

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