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1.  Transformable masks for colloidal nanosynthesis 
Nature Communications  2018;9:563.
Synthetic skills are the prerequisite and foundation for the modern chemical and pharmaceutical industry. The same is true for nanotechnology, whose development has been hindered by the sluggish advance of its synthetic toolbox, i.e., the emerging field of nanosynthesis. Unlike organic chemistry, where the variety of functional groups provides numerous handles for designing chemical selectivity, colloidal particles have only facets and ligands. Such handles are similar in reactivity to each other, limited in type, symmetrically positioned, and difficult to control. In this work, we demonstrate the use of polymer shells as adjustable masks for nanosynthesis, where the different modes of shell transformation allow unconventional designs beyond facet control. In contrast to ligands, which bind dynamically and individually, the polymer masks are firmly attached as sizeable patches but at the same time are easy to manipulate, allowing versatile and multi-step functionalization of colloidal particles at selective locations.
The synthesis of patchy colloids is limited by poor control over the location and shape of ligand domains. Here, the authors use adaptable polymer masks to protect select areas of the particle during functionalization, allowing them to create patchy colloids with unconventional surface morphologies.
PMCID: PMC5805779  PMID: 29422677
2.  In Vitro Characterization and In Vivo Ultrasound Molecular Imaging of Nucleolin-Targeted Microbubbles 
Biomaterials  2016;118:63-73.
Nucleolin (NCL) plays an important role in tumor vascular development. An increased endothelial expression level of NCL has been related to cancer aggressiveness and prognosis and has been detected clinically in advanced tumors. Here, with a peptide targeted to NCL (F3 peptide), we created an NCL-targeted microbubble (MB) and compared the performance of F3-conjugated MBs with non-targeted (NT) MBs both in vitro and in vivo. In an in vitro study, F3-conjugated MBs bound 433 times more than NT MBs to an NCL-expressing cell line, while pretreating cells with 0.5 mM free F3 peptide reduced the binding of F3-conjugated MBs by 84%, n=4, p<0.001. We then set out to create a method to extract both the tumor wash-in and wash-out kinetics and tumor accumulation following a single injection of targeted MBs. In order to accomplish this, a series of ultrasound frames (a clip) was recorded at the time of injection and subsequent time points. Each pixel within this clip was analyzed for the minimum intensity projection (MinIP) and average intensity projection (AvgIP). We found that the MinIP robustly demonstrates enhanced accumulation of F3-conjugated MBs over the range of tumor diameters evaluated here (2 to 8 mm), and the difference between the AvgIP and the MinIP quantifies inflow and kinetics. The inflow and clearance were similar for unbound F3-conjugated MBs, control (non-targeted) and scrambled control agents. Targeted agent accumulation was confirmed by a high amplitude pulse and by a two-dimensional Fourier Transform technique. In summary, F3-conjugated MBs provide a new imaging agent for ultrasound molecular imaging of cancer vasculature, and we have validated metrics to assess performance using low mechanical index strategies that have potential for use in human molecular imaging studies.
Graphical abstract
PMCID: PMC5279957  PMID: 27940383
Angiogenesis; Molecular imaging; Peptide; Ultrasound contrast agents; Nucleolin; in vivo
3.  Suppression of OsMADS7 in rice endosperm stabilizes amylose content under high temperature stress 
Plant Biotechnology Journal  2017;16(1):18-26.
High temperature significantly alters the amylose content of rice, resulting in mature grains with poor eating quality. However, only few genes and/or quantitative trait loci involved in this process have been isolated and the molecular mechanisms of this effect remain unclear. Here, we describe a floral organ identity gene, OsMADS7, involved in stabilizing rice amylose content at high temperature. OsMADS7 is greatly induced by high temperature at the early filling stage. Constitutive suppression of OsMADS7 stabilizes amylose content under high temperature stress but results in low spikelet fertility. However, rice plants with both stable amylose content at high temperature and normal spikelet fertility can be obtained by specifically suppressing OsMADS7 in endosperm. GBSSI is the major enzyme responsible for amylose biosynthesis. A low filling rate and high expression of GBSSI were detected in OsMADS7 RNAi plants at high temperature, which may be correlated with stabilized amylose content in these transgenic seeds under high temperature. Thus, specific suppression of OsMADS7 in endosperm could improve the stability of rice amylose content at high temperature, and such transgenic materials may be a valuable genetic resource for breeding rice with elite thermal resilience.
PMCID: PMC5785353  PMID: 28429576
rice; grain quality; amylose content; high temperature; seed development; MADS‐box gene
4.  MicroRNA-10b regulates epithelial–mesenchymal transition by modulating KLF4/KLF11/Smads in hepatocellular carcinoma 
Our previous work showed that miR-10b was overexpressed in hepatocellular carcinoma (HCC) and promoted HCC cell migration and invasion. Epithelial–mesenchymal transition (EMT) is involved in HCC metastasis. So, we suspected that miR-10b might participate in the HCC EMT.
We performed morphological analysis and immunofluorescence to observe the roles of miR-10b in HCC EMT. The expression of KLF11 and EMT markers were detected by real-time RT-PCR and western blot. The regulation roles of miR-10b on KLF11 and KLF4 were determined by luciferase reporter assay. The chromatin immunoprecipitation revealed the binding relationship between KLF4 and KLF11.
We found that overexpression of miR-10b could promote HCC EMT. miR-10b could upregulated KLF11 expression. The upregulation of KLF11 reduced the downstream molecular Smad7 expression, which upregulated the Smad3 expression to promote EMT development. Furthermore, the induction role of miR-10b in HCC EMT could be blocked by KLF11 siRNA. But our results showed that there was no direct regulation of miR-10b in KLF11 expression. Specifically, miR-10b could bind to the 3′UTR of KLF4 and inhibit KLF4 expression. KLF4 could directly bind to KLF11 promoter and downregulate KLF11 transcription.
Our results reveal that miR-10b downregulates KLF4, the inhibitory transcriptional factor of KLF11, which induces Smads signaling activity to promote HCC EMT. Our study presents the regulation mechanism of miR-10b in EMT through the KLF4/KLF11/Smads pathway for the first time and implicates miR-10b as a potential target for HCC therapies.
PMCID: PMC5773153
miR-10b; Hepatocellular carcinoma; Epithelial–mesenchymal transition; KLF4; KLF11
5.  Carotid artery wall shear stress is independently correlated with renal function in the elderly 
Oncotarget  2018;9(4):5251-5262.
Hemodynamic has increasingly been regarded as an important factor of renal function. However, the relationship between carotid artery wall shear stress (WSS) and renal function is not clarified. To investigate the relationship between carotid WSS and renal function, we recruited 761 older subjects aged 60 years and over from community-dwelling in the Shandong area, China. Carotid WSS, endothelial function, and estimated glomerular filtration rate (eGFR) were assessed in all subjects. Subjects were grouped by the interquartile of the carotid artery mean WSS. We found that the eGFRs derived from serum creatinine and/or cystatin C using three CKD-EPI equations were significantly higher and albumin/creatinine ratio was lower in the higher interquartile groups than in the lower interquartile groups (P <0.05). The mean WSS was independently correlated with eGFRs even after adjustment for confounders. Similar findings were found between carotid artery peak WSS and eGFRs and albumin/creatinine ratio. In addition, we found that endothelial function was strongly related to carotid WSS and renal function after adjustment for confounders. In conclusion, there is an independent correlation of carotid WSS with renal function in the elderly. The local rheologic forces may play an important role in renal function changing. The correlation may be mediated by regulation of endothelial function.
PMCID: PMC5797047
hemodynamic; wall shear stress; endothelial function; renal function; chronic kidney disease
6.  A Tet-Off gene expression system for validation of antifungal drug targets in a murine invasive pulmonary aspergillosis model 
Scientific Reports  2018;8:443.
Aspergillus fumigatus is one of the major causes of invasive pulmonary aspergillosis in immunocompromised patients. Novel antifungal therapy is in urgent need due to emerging resistance and adverse toxicity of current antifungal drugs. Gene products that are essential for Aspergillus viability during infection are attractive drug targets. To characterize these genes in vivo we developed a Tet-Off gene expression system in A. fumigatus, whereby the administration of doxycycline resulted in down regulation of the gene whose expression is under the control of the Tet-Off promoter. We tested the system on two potential drug targets, inosine 5′-monophosphate dehydrogenase (IMPDH) and L-ornithine N5-oxygenase (sidA) in a murine invasive pulmonary aspergillosis model. We show that depletion of IMPDH attenuated but did not completely abolish virulence in vivo whereas turning off the expression of sidA, which is required for iron acquisition, resulted in avirulence. We also investigated whether sidA expression could be controlled in a time-dependent manner in mice. Our results demonstrated that timing of doxycycline administration dramatically affects survival rate, suggesting that this genetic system can be used for testing whether an antifungal drug target is critical for fungal growth post-infection.
PMCID: PMC5765126  PMID: 29323188
9.  Analysis of sequential hair segments reflects changes in the metabolome across the trimesters of pregnancy 
Scientific Reports  2018;8:36.
The hair metabolome has been recognized as a valuable source of information in pregnancy research, as it provides stable metabolite information that could assist with studying biomarkers or metabolic mechanisms of pregnancy and its complications. We tested the hypothesis that hair segments could be used to reflect a metabolite profile containing information from both endogenous and exogenous compounds accumulated during the nine months of pregnancy. Segments of hair samples corresponding to the trimesters were collected from 175 pregnant women in New Zealand. The hair samples were analysed using gas chromatography-mass spectrometry and liquid chromatography-mass spectrometry. In healthy pregnancies, 56 hair metabolites were significantly different between the first and second trimesters, while 62 metabolites were different between the first and third trimesters (p < 0.05). Additionally, three metabolites in the second trimester hair samples were significantly different between healthy controls and women who delivered small-for-gestational-age infants (p < 0.05), and ten metabolites in third trimester hair were significantly different between healthy controls and women with gestational diabetes mellitus (p < 0.01). The findings from this pilot study provide improved insight into the changes of the hair metabolome during pregnancy, as well as highlight the potential of the maternal hair metabolome to differentiate pregnancy complications from healthy pregnancies.
PMCID: PMC5758601  PMID: 29311683
10.  Identification of a protective B-cell epitope of the Staphylococcus aureus GapC protein by screening a phage-displayed random peptide library 
PLoS ONE  2018;13(1):e0190452.
The impact of epidemic Staphylococcus aureus (S. aureus) on public health is increasing. Because of the abuse of antibiotics, the antibiotic resistance of S. aureus is increasing. Thus, there is an urgent need to develop new immunotherapies and immunoprophylaxes. Previous studies showed that the GapC protein of S. aureus, which is a surface protein with high glyceraldehyde 3-phosphate dehydrogenase activity, transferrin binding activity, and other biological activities, is highly conserved. GapC induces an effective humoral immune response in vivo. However, the B-cell epitopes of S. aureus GapC have not been well identified. Here we used the bioinformatics tools to analyze the sequence of GapC, and we generated protective anti-GapC monoclonal antibodies (mAbs). A protective mAb (1F4) showed strong specificity to GapC and the ability to induce macrophages to phagocytose S. aureus. We screened the motif 272GYTEDEIVSSD282, which was recognized by mAb 1F4, using a phage display system. Then, we used site-directed mutagenesis to identify key amino acids in the motif. Residues G272 D276 E277 I278 and V279 formed the core of the 272GYTEDEIVSSD282 motif. In addition, we showed that this epitope peptide induced a protective humoral immune response against S. aureus infection in immunized mice. Our results will be useful for the further study of epitope-based vaccines against S. aureus infection.
PMCID: PMC5755776  PMID: 29304128
11.  Retrospective analysis of relationships among the dose regimen, trough concentration, efficacy, and safety of teicoplanin in Chinese patients with moderate–severe Gram-positive infections 
Teicoplanin, an antibiotic, has poor clinical efficacy when using the current drug label’s recommended regimen, which is approved by the China Food and Drug Administration. This study explores the appropriate loading and maintenance doses of teicoplanin and evaluates the therapeutic target of teicoplanin trough concentration (minimum concentration [Cmin]).
Subjects and methods
All patients treated with teicoplanin from February 2015 to August 2016 at Zhengzhou Central Hospital were screened for enrollment. A total of 113 subjects were included and then divided into four groups: A (received three to six doses at a loading dose of 400 mg at 12-hour intervals, followed by maintenance dosing of 400 mg/day), B (received three doses at a loading dose of 400 mg at 12-hour intervals, followed by maintenance dosing of 400 mg/day), C (received two doses at a loading dose of 400 mg at 12-hour intervals, followed by maintenance dosing of 200 mg/day), and D (received one to three doses at a loading dose of 400 mg at 12-hour intervals, followed by maintenance dosing of 200 mg/day). Cmin values of teicoplanin were detected with high-performance liquid chromatography on day 4, 30 minutes before maintenance-dose administration. Teicoplanin Cmin, efficacy, and safety were compared among the four groups.
Mean Cmin differed significantly among the four groups (A, 18.11±6.37 mg/L; B, 15.91±4.94 mg/L; C, 17.06±5.66 mg/L; D, 11.97±3.76 mg/L) (P<0.001), with creatinine clearance of 89.62 (53.72–162.48), 49.66 (40.69–59.64), 27.17 (9.7–39.45), and 96.6 (17.63–394.73) mL/min, respectively. The ratio of loading dose for 3 days to creatinine clearance and serum Cmin were significantly correlated (R=0.59, P<0.001). The correlation between the estimated probability of success and teicoplanin Cmin was assessed using binary logistic regression (OR 2.049, P<0.001). Hepatotoxicity- and nephrotoxicity-incidence rates did not significantly differ among the four groups (P=0.859 and P=0.949, respectively).
A loading dose of 400 mg at 12-hour intervals three to six times is needed to achieve the early target range (15–20 mg/L) and improve the clinical efficacy rate for normal-renal-function patients. It is urgently necessary to amend the drug label for the recommended regimen.
PMCID: PMC5759846
teicoplanin; loading dose; serum trough concentration; efficacy; safety; Chinese drug label
12.  Genetic dissection of QTLs and differentiation analysis of alleles for heading date genes in rice 
PLoS ONE  2018;13(1):e0190491.
Heading date is an important agronomic trait in rice (Oryza sativa L.); it determines the geographical and seasonal adaptability of the crop. Single segment substitution lines (SSSLs) have become the preferred experimental materials in mapping functional genetic variations as the particular chromosome segments from donor genotypes can be evaluated for their impact on the phenotype in a recurrent recipient background. The phenotypic differences can be attributed to the control of quantitative trait loci (QTLs). Here, we evaluated a library consisting of 1,123 SSSLs in the same genetic background of an elite rice variety, Huajingxian74 (HJX74), and revealed four SSSLs, W05-1-11-2-7-6 (W05), W08-16-3-2 (W08), W12-28-58-03-19-1 (W12), and W22-9-5-2-4-9-3 (W22), which had a significantly different heading date compared to HJX74. To further genetically dissect the QTLs controlling heading date on chromosomes 3, 6, and 10, four SSSLs were used to develop 15 secondary SSSLs with the smaller substituted segments. The qHD-3 heading date QTL detected in W05 and W08 was delimited to an interval of 4.15 cM, whereas qHD-6-1 and qHD-6-2 heading date QTLs dissected from the substituted segments in W12 were mapped to the intervals of 2.25-cM and 2.55-cM, respectively. The qHD-10 QTL detected on the substituted segment in W22 was mapped to an interval of 6.85-cM. The nucleotide and amino acid sequence changes for those genes in the secondary SSSLs were also revealed. The allele variations of those genes might contribute to the heading date QTLs on chromosome 3 (DTH3, OsDof12, and EHD4), chromosome 6 (Hd3a, Hd17, and RFT1), and chromosome 10 (Ehd1 and Ehd2). These sequence variations in heading date genes would be useful resources for further studying the function of genes, and would be important for rice breeding. Overall, our results indicate that secondary SSSLs were powerful tools for genetic dissection of QTLs and identification of differentiation in the genes.
PMCID: PMC5752018  PMID: 29298333
13.  The Impact of the National Essential Medicines Policy on Rational Drug Use in Primary Care Institutions in Jiangsu Province of China 
Essential medicine policy is a successful global health policy to promote rational drug use. The aim of this study was to evaluate the impact of the National Essential Medicines Policy (NEMP) on the rational drug use in primary care institutions in Jiangsu Province of China.
In this exploratory study, a multistage, stratified, random sampling was used to select 3400 prescriptions from 17 primary care institutions who implemented the NEMP before (Jan 2010) and after the implementation of the NEMP (Jan 2014). The analyses were performed in SPSS 18.0 and SPSS Clementine client.
After the implementation of the NEMP, the percentage of prescribed EML (Essential Medicines List) drugs rose significantly, the average number of drugs per prescription and average cost per prescription were declined significantly, while the differences of the prescription proportion of antibiotics and injection were not statistically significant. BP (Back Propagation) neural network analysis showed that the average number of drugs per prescription, the number of using antibiotics and hormone, regional differences, size of institutions, sponsorship, financial income of institutions, doctor degree, outpatient and emergency visits person times were important factors affecting the prescription costs, among these the average number of drugs per prescription has the greatest effect.
The NEMP can promote the rational use of drugs in some degree, but its role is limited. We should not focus only on the EML but also make comprehensive NEMP.
PMCID: PMC5756597
Primary care institutions; Rational drug use; National essential medicines policy; China
14.  Effect of second child intent on delivery mode after Chinese two child policy implementation: a cross sectional and prospective observational study of nulliparous women in Chongqing 
BMJ Open  2017;7(12):e018823.
To assess the influence of second child intent on the delivery preferences and final delivery modes of nulliparous women, particularly caesarean delivery on maternal request (CDMR), after implementation of China’s two child policy.
Cross sectional and prospective observational study.
A tertiary teaching hospital in Chongqing, China.
1000 low risk nulliparous women were initially involved, and were divided into two groups based on their intent on having a second child. 814 women who completed all interviews were analysed.
Main outcome measures
Preferred mode of delivery in second trimester and at admission; final delivery mode, CDMR.
814 women who completed all interviews were analysed, in whom 51.2% intended to have a second child. The preference for caesarean delivery (CD) at the second trimester between the intent and no intent group was 6.2% versus 17.9% (adjusted RR 0.35, 95% CI 0.20 to 0.63) and increased to 24.2% versus 37.3% (adjusted RR 0.65, 95% CI 0.45 to 0.94) at admission, respectively. The overall CD rates between the two groups were 41.0% versus 50.4% (adjusted RR 0.84, 95% CI 0.60 to 1.18), and the CDMR rates were 16.7% versus 29.0% (adjusted RR 0.56, 95% CI 0.37 to 0.86), respectively.
Women who intend to have a second child are less likely to request a CD, and high rates of CD and CDMR in nulliparous women may have decreased after implementation of China’s two child policy.
PMCID: PMC5770909  PMID: 29282269
China; two-child policy; nulliparous women; second-child Intent; caesarean delivery on maternal request
15.  Prognostic role of platelet to lymphocyte ratio in esophageal cancer: A meta-analysis 
Oncotarget  2017;8(67):112085-112093.
The prognostic role of inflammation index like platelet to lymphocyte ratio (PLR) in esophageal cancer remains controversial. We evaluated the prognostic significance of PLR in esophageal cancer patients.
We searched databases to identify relevant literatures. Pooled hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated. A meta-analysis was performed to evaluate the prognostic value of PLR in patients with esophageal cancer.
A total of 6,699 patients from 16 studies (17 cohorts) were finally enrolled in the meta-analysis. The results demonstrate that the elevated PLR predicted poorer overall survival (OS) (HR: 1.389, 95% CI: 1.161-1.663) and disease-free survival (DFS) (HR: 1.404, 95% CI: 1.169-1.687) and cancer-specific survival (CSS) (HR: 1.686, 95% CI: 1.146-2.480) in patients with esophageal cancer. Subgroup analysis revealed that the elevated PLR was also associated with poor OS in esophageal cancer treated by surgery (HR: 1.492, 95%CI: 1.149-1.938, P<0.05) and mixed treatment (HR: 1.222, 95%CI: 1.009-1.479, P<0.05). In addition, PLR Cut-off value≤160 (HR: 1.484, 95%CI: 1.088-2.024, P<0.05) and PLR Cut-off value>160 (HR: 1.391, 95%CI: 1.161-1.666, P<0.05).
This meta-analysis result suggested that PLR might be a significant predicative biomarker of poor prognosis for esophageal cancer patients.
PMCID: PMC5762381
platelet to lymphocyte ratio; esophageal cancer; prognosis; meta-analysis
16.  Stim2-Eb3 Association and Morphology of Dendritic Spines in Hippocampal Neurons 
Scientific Reports  2017;7:17625.
Mushroom spines form strong synaptic contacts and are essential for memory storage. We have previously demonstrated that neuronal store-operated calcium entry (nSOC) in hippocampal neurons is regulated by STIM2 protein. This pathway plays a key role in stability of mushroom spines and is compromised in different mice models of Alzheimer’s disease (AD). Actin was thought to be the sole cytoskeleton compartment presented in dendritic spines, however, recent studies demonstrated that dynamic microtubules with EB3 capped plus-ends transiently enter spines. We showed that STIM2 forms an endoplasmic reticulum (ER) Ca2+ -dependent complex with EB3 via Ser-x-Ile-Pro aminoacid motif and that disruption of STIM2-EB3 interaction resulted in loss of mushroom spines in hippocampal neurons. Overexpression of EB3 causes increase of mushroom spines fraction and is able to restore their deficiency in hippocampal neurons obtained from PS1-M146V-KI AD mouse model. STIM2 overexpression failed to restore mushroom dendritic spines after EB3 knockdown, while in contrast EB3 overexpression rescued loss of mushroom spines resulting from STIM2 depletion. We propose that EB3 is involved in regulation of dendritic spines morphology, in part due to its association with STIM2, and that modulation of EB3 expression is a potential way to overcome synaptic loss during AD.
PMCID: PMC5732248  PMID: 29247211
17.  Salvianolic acid B suppresses cell proliferation and induces apoptosis in osteosarcoma through p38-mediated reactive oxygen species generation 
Oncology Letters  2017;15(2):2679-2685.
The present study aimed to investigate the potential anticancer effect and mechanisms of salvianolic acid B on osteosarcoma. Salvianolic acid B suppressed osteosarcoma cell proliferation and induced apoptosis in the osteosarcoma MG63 cell line, and activated the expressions of cleaved caspase-3, phosphorylated-tumor protein (p)38 mitogen-activated protein kinase (p-p38 MAPK) and phosphorylated-p53 (p-p53) proteins in the MG63 cells. Additionally, Salvianolic acid B also increased the level of reactive oxygen species (ROS) generation in the MG63 cells. The silencing of p38 expression inhibited the anticancer effect of salvianolic acid B on the levels of cell proliferation, p-p53 protein expression and ROS generation level in the MG63 cells. All these data supported the hypothesis that the anticancer effect of salvianolic acid B includes the suppression of cell proliferation and induces apoptosis in MG63 cells, and that p38 is important in the anticancer effect of salvianolic acid B on osteosarcoma cells due to the direct regulation of ROS generation. These data suggest that salvianolic acid B is important in the proliferation of osteosarcoma cells due to the direct regulation of p38-mediated ROS signaling.
PMCID: PMC5777315
salvianolic Acid B; osteosarcoma; tumor protein 38; reactive oxygen species
18.  Motion guided Spatiotemporal Sparsity for high quality 4D-CBCT reconstruction 
Scientific Reports  2017;7:17461.
Conventional cone-beam computed tomography is often deteriorated by respiratory motion blur, which negatively affects target delineation. On the other side, the four dimensional cone-beam computed tomography (4D-CBCT) can be considered to describe tumor and organ motion. But for current on-board CBCT imaging system, the slow rotation speed limits the projection number at each phase, and the associated reconstructions are contaminated by noise and streak artifacts using the conventional algorithm. To address the problem, we propose a novel framework to reconstruct 4D-CBCT from the under-sampled measurements—Motion guided Spatiotemporal Sparsity (MgSS). In this algorithm, we try to divide the CBCT images at each phase into cubes (3D blocks) and track the cubes with estimated motion field vectors through phase, then apply regional spatiotemporal sparsity on the tracked cubes. Specifically, we recast the tracked cubes into four-dimensional matrix, and use the higher order singular value decomposition (HOSVD) technique to analyze the regional spatiotemporal sparsity. Subsequently, the blocky spatiotemporal sparsity is incorporated into a cost function for the image reconstruction. The phantom simulation and real patient data are used to evaluate this algorithm. Results show that the MgSS algorithm achieved improved 4D-CBCT image quality with less noise and artifacts compared to the conventional algorithms.
PMCID: PMC5727071
19.  Tanshinone II is a potent candidate for treatment of lipopolysaccharide-induced acute lung injury in rat model 
Oncology Letters  2017;15(2):2550-2554.
The present study aimed to investigate the effect of tanshinone II, isolated from Salvia miltiorrhiza Bunge, on lipopolysaccharide (LPS)-induced acute lung injury (ALI) in rats. Male Sprague-Dawley rats were divided into three groups: Control, LPS and tanshinone II. Animals in the tanshinone II and LPS groups were administered 10 mg/kg LPS, whereas those in the control group received an equal volume of normal saline. Tanshinone II treatment group were injected with 30 nm/kg tanshinone II at 1 h after LPS administration. The results revealed that LPS administration increased the bronchoalveolar lavage fluid protein concentration significantly compared with the control group. However, tanshinone II treatment significantly inhibited the LPS-induced increase in protein level. Treatment of the LPS-administered rats with tanshinone II prevented the formation of pulmonary edema, which was evidenced by low values for wet to dry lung weight ratio. The activity of myeloperoxidase and expression of malondialdehyde were significantly lower in lung homogenates from the tanshinone II group compared with the LPS group. Furthermore, tanshinone II treatment inhibited the expression of tumor necrosis factor-α and interleukin-6 in the blood plasma. Tissue sections of the tanshinone II group exhibited normal morphology and absence of neutrophil accumulation. However, in the LPS group, neutrophils accumulated and penetrated into the pulmonary tissues. These results suggested that tanshinone II protects the rats from LPS-induced ALI. Therefore tanshinone II may have clinical applications in the treatment of ALI.
PMCID: PMC5777273
lung injury; edema; neutrophils; alveolar space; prevention
20.  Multi-disciplinary team for early gastric cancer diagnosis improves the detection rate of early gastric cancer 
BMC Gastroenterology  2017;17:147.
Gastric cancer is a frequent malignant tumor worldwide and its early detection is crucial for curing the disease and enhancing patients’ survival rate. This study aimed to assess whether the multi-disciplinary team (MDT) can improve the detection rate of early gastric cancer (EGC).
The detection rate of EGC at the Digestive Endoscopy Center, Affiliated Hospital, Zunyi Medical College, China between September 2013 and September 2015 was analyzed. MDT for the diagnosis of EGC in the hospital was established in September 2014. The study was divided into 2 time periods: September 1, 2013 to August 31, 2014 (period 1) and September 1, 2014 to September 1, 2015 (period 2).
A total of 60,800 patients’ gastroscopies were performed during the two years. 61 of these patients (0.1%) were diagnosed as EGC, accounting for 16.44% (61/371) of total patients with gastric cancer. The EGC detection rate before MDT (period 1) was 0.05% (16/29403), accounting for 9.09% (16/176) of total patients with gastric cancer during this period. In comparison, the EGC detection rate during MDT (period 2) was 0.15% (45/31397), accounting for 23% (45/195) of total patients with gastric cancer during this period (P < 0.05). Univariate and multivariate logistic analyses showed that intensive gastroscopy for high risk patients of gastric cancer enhanced the detection rate of EGC in cooperation with Department of Pathology (OR = 10.1, 95% CI 2.39–43.3, P < 0.05).
MDT could improve the endoscopic detection rate of EGC.
Electronic supplementary material
The online version of this article (10.1186/s12876-017-0711-9) contains supplementary material, which is available to authorized users.
PMCID: PMC5719518  PMID: 29212444
Early gastric cancer; Diagnosis; Intensive gastroscopy; Multi-disciplinary team
21.  Oridonin synergistically enhances JQ1-triggered apoptosis in hepatocellular cancer cells through mitochondrial pathway 
Oncotarget  2017;8(63):106833-106843.
Bromodomain and Extra-Terminal Domain (BET) inhibitors, such as JQ1 have emerged as novel drug candidates and are being enthusiastically pursued in clinical trials for the treatment of cancer. However, many solid cancers are resistance to BET inhibitors. To explore methods for improving the therapeutic potential of BET inhibitors, we investigated the combinational activity of JQ1 with Oridonin, a bioactive molecules derived from Traditional Chinese Medicine in hepatocellular carcinoma (HCC) cells. Our results showed that Oridonin synergistically enhanced the abilities of JQ1 to inhibit cell viability in HCC cells and, significantly augmented JQ1-triggered apoptosis in HCC cells and in HCC cancer stem-like cells. Moreover, Oridonin dose-dependently inhibited the expression of several anti-apoptotic proteins, such as Bcl-2, Mcl-1, and x-linked inhibitor of apoptosis (xIAP) in HCC cells. Cell fractionation and western blotting analysis showed that the enhancement of apoptosis by Oridonin was associated with cytochrome c release, activation of caspase-9, -3 and cleavage of PARP, indicating the activation of mitochondrial apoptosis pathway. Altogether, our findings demonstrate that Oridonin may be used to effectively enhance the sensitivity of BET inhibitors in HCC therapy via downregulation of the expression of multiple anti-apoptotic proteins.
PMCID: PMC5739777
JQ1; Oridonin; HCC; Apoptosis; Bcl-2
22.  Variants of Rab GTPase-effector binding protein-2 cause variation in the collateral circulation and severity of stroke 
Stroke  2016;47(12):3022-3031.
Background and Purpose
The extent (number and diameter) of collateral vessels varies widely and is a major determinant, along with arteriogenesis (collateral remodeling), of variation in severity of tissue injury following large artery occlusion. Differences in genetic background underlie the majority of the variation in collateral extent in mice, through alterations in collaterogenesis (embryonic collateral formation). In brain and other tissues, ~80% of the variation in collateral extent among different mouse strains has been linked to a region on chromosome 7. We recently used congenic (CNG) fine-mapping of C57BL/6 (B6, high extent) and BALB/cBy (BC, low extent) mice to narrow the region to a 737 Kb locus, Dce1. Herein, we report the causal gene.
We used additional CNG mapping and knockout mice to narrow the number of candidate genes. Subsequent inspection identified a non-synonymous SNP between B6 and BC within Rabep2 (rs33080487). We then created B6 mice with the BC SNP at this locus plus three other lines for predicted alteration or knockout of Rabep2 using gene editing.
The single amino acid change caused by rs33080487 accounted for the difference in collateral extent and infarct volume between B6 and BC mice attributable to Dce1. Mechanistically, variants of Rabep2 altered collaterogenesis during embryogenesis but had no effect on angiogenesis examined in vivo and in vitro. Rabep2 deficiency altered endosome trafficking known to be involved in VEGF-A→VEGFR2 signaling required for collaterogenesis.
Naturally occurring variants of Rabep2 are major determinants of variation in collateral extent and stroke severity in mice.
PMCID: PMC5134893  PMID: 27811335
collateral circulation; ischemic stroke; Rabep2; Rabaptin-5beta; Dce1
23.  MALE STERILE6021 (MS6021) is required for the development of anther cuticle and pollen exine in maize 
Scientific Reports  2017;7:16736.
The anther cuticle and pollen wall function as physical barriers that protect genetic material from various environmental stresses. The anther cuticle is composed of wax and cutin, the pollen wall includes exine and intine, and the components of the outer exine are collectively called sporopollenin. Other than cuticle wax, cutin and sporopollenin are biopolymers compounds. The precise constituents and developmental mechanism of these biopolymeric are poorly understood. Here, we reported a complete male sterile mutant, male sterile6021, in maize. The mutant displayed a smooth anther surface and irregular pollen wall formation before anthesis, and its tapetum was degraded immaturely. Gas chromatography-mass spectrometry analysis revealed a severe reduction of lipid derivatives in the mutant anther. We cloned the gene by map based cloning. It encoded a fatty acyl carrier protein reductase that was localized in plastids. Expression analysis indicated that MS6021 was mainly expressed in the tapetum and microspore after the microspore was released from the tetrad. Functional complementation of the orthologous Arabidopsis mutant demonstrated that MS6021 is conserved between monocots and dicots and potentially even in flowering plants. MS6021 plays a conserved, essential role in the successful development of anther cuticle and pollen exine in maize.
PMCID: PMC5711870  PMID: 29196635
24.  Disordered oropharyngeal microbial communities in H7N9 patients with or without secondary bacterial lung infection 
Emerging Microbes & Infections  2017;6(12):e112-.
Secondary bacterial lung infection (SBLI) is a serious complication in patients with H7N9 virus infection, and increases disease severity. The oropharyngeal (OP) microbiome helps prevent colonisation of respiratory pathogens. We aimed to investigate the OP microbiome of H7N9 patients with/without secondary bacterial pneumonia using 16S rRNA gene sequencing. OP swab samples were collected from 51 H7N9 patients (21 with SBLI and 30 without) and 30 matched healthy controls (HCs) and used for comparative composition, diversity and richness analyses of microbial communities. Principal coordinates analysis successfully distinguished between the OP microbiomes of H7N9 patients and healthy subjects, and the OP microbiome diversity of patients with SBLI was significantly increased. There was significant dysbiosis of the OP microbiome in H7N9 patients, with an abundance of Leptotrichia, Oribacterium, Streptococcus, Atopobium, Eubacterium, Solobacterium and Rothia species in patients with SBLI, and Filifactor, Megasphaera and Leptotrichia species in patients without SBLI, when compared with HCs. Importantly, Haemophilus and Bacteroides species were enriched in HCs. These findings revealed dysbiosis of the OP microbiota in H7N9 patients, and identified OP microbial risk indicators of SBLI, suggesting that the OP microbiome could provide novel and non-invasive diagnostic biomarkers for early microbiota-targeted prophylactic therapies for SBLI prevention.
PMCID: PMC5750457  PMID: 29259328
H7N9; microbiota-targeted prophylactic therapies; oropharyngeal microbiome; secondary bacterial lung infection
25.  Paleoclimatic information recorded in fluid inclusions in halites from Lop Nur, Western China 
Scientific Reports  2017;7:16411.
The homogenization temperature (Th) of primary fluid inclusions in halite can be used for paleoclimate interpretations. Lop Nur, in Central Asia, is an extremely arid zone where large amounts of glauberite were deposited from the late Middle to Late Pleistocene. This deposition was accompanied by formation of large-scale potash-bearing brines. However, quantitative paleotemperature data are still lacking, hindering reconstruction of Quaternary climate conditions and their control over potash formation. We measured the Th of inclusions in halite from the salt field and the top of Upper Pleistocene strata in Lop Nur. The maximum homogenization temperature (Th MAX) of inclusions in halite from the salt field was 41.1 °C, consistent with the maximum ambient temperature (43.4 °C) in the same period. The Th MAX of inclusions in halite from the Upper Pleistocene strata ranged from 35.6 °C to 43 °C, where maximum air temperatures may have reached 37.9 °C to 45.3 °C. The results show that a hot and arid climate prevailed in Lop Nur at the end of the Late Pleistocene. Furthermore, changes of the brine chemical composition due to supply variations instead of climate change, may have caused glauberite deposition to cease at the end of the Late Pleistocene.
PMCID: PMC5703717  PMID: 29180658

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