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1.  LDL in patients with subclinical hypothyroidism shows increased lipid peroxidation 
Population-based studies have demonstrated that subclinical hypothyroidism (SCH) is an independent risk factor for atherosclerosis (OR = 1.9). However, this connection cannot be entirely explained by dyslipidemia accompanied by SCH. Lipid peroxidation also plays an important role in the development of atherosclerosis. In this study, we aimed to evaluate oxidative stress in SCH patients, as measured according to concentrations of hydroxy-octadecadienoic acids (HODEs) and hydroxy-eicosatetraenoic acids (HETEs) in both plasma and low density lipoproteins (LDL).
Subjects and methods
The concentrations of HODEs and HETEs in both LDL and plasma were examined in euthyroid (n = 10), mild SCH (4.5 ≤ TSH <10 mU/L, n = 10), and significant SCH (TSH ≥ 10 mU/L, n = 10) subjects, using a liquid chromatograph-electrospray ionization- mass spectrometer. Then, we explored the relationship among LDL oxidation, TSH levels, and carotid intima-media thickness (IMT), a biomarker of subclinical atherosclerosis.
Serum LDL-C levels and mean-IMT in the significant SCH group were higher than in the euthyroid group (p < 0.05). The HODE and HETE concentrations clearly increased in the significant SCH patients compared with the euthyroid subjects, but there was no difference between the mild SCH and euthyroid groups. Among all subjects, linear and significant positive correlations were identified between TSH and mean-IMT after adjustment for confounding factors (r = 0.480, p = 0.018). Both 9-HODE (r = 0.376, p = 0.041) and 13-HODE (r = 0.447, p = 0.013) in LDL were linearly and positively correlated with TSH. The concentrations of HODEs (both 9-HODE and 13-HODE) in LDL were much higher in the thickened IMT group than in the normal IMT group (p = 0.017 and 0.015, respectively). HODEs in LDL were also positively associated with mean-IMT.
Our findings showed that lipid peroxidation was higher in the significant SCH patients than in the euthyroid subjects, which suggested that qualitative as well as quantitative changes in serum lipids resulting from SCH may add to atherosclerosis risk.
Electronic supplementary material
The online version of this article (doi:10.1186/s12944-015-0092-4) contains supplementary material, which is available to authorized users.
PMCID: PMC4548906  PMID: 26302822
Subclinical hypothyroidism; Oxidative stress; Low density lipoproteins
2.  Monoterpenoid Indole Alkaloids from Inadequately Dried Leaves of Alstonia scholaris 
Six new indole alkaloids, named alstoniascholarines L–Q (1–6), together with nineteen known analogues were isolated from the inadequately dried leaves of Alstonia scholaris. Their structures were elucidated on the basis of extensive analysis of spectroscopic data and by comparison of their physical and spectroscopic data with the literature values. In addition, the new alkaloids were tested for their cytotoxic and neurite outgrowth-promoting activities.
Electronic supplementary material
The online version of this article (doi:10.1007/s13659-015-0066-2) contains supplementary material, which is available to authorized users.
PMCID: PMC4567994  PMID: 26280886
Alstonia scholaris; Inadequately dried leaves; Indole alkaloids; Alstoniascholarine; Bioactivities
3.  Monoterpenoid Indole Alkaloids from Inadequately Dried Leaves of Alstonia scholaris 
Six new indole alkaloids, named alstoniascholarines L–Q (1–6), together with nineteen known analogues were isolated from the inadequately dried leaves of Alstonia scholaris. Their structures were elucidated on the basis of extensive analysis of spectroscopic data and by comparison of their physical and spectroscopic data with the literature values. In addition, the new alkaloids were tested for their cytotoxic and neurite outgrowth-promoting activities.
Electronic supplementary material
The online version of this article (doi:10.1007/s13659-015-0066-2) contains supplementary material, which is available to authorized users.
PMCID: PMC4567994  PMID: 26280886
Alstonia scholaris; Inadequately dried leaves; Indole alkaloids; Alstoniascholarine; Bioactivities
4.  Molecular phylogeny supports S-chaetae as a key character better than jumping organs and body scales in classification of Entomobryoidea (Collembola) 
Scientific Reports  2015;5:12471.
The jumping organ (furcula) is the most characteristic structure among collembolans, and it is of great taxonomical values at higher levels. The largest superfamily Entomobryoidea is traditionally classified into four families only by the morphology of the furcula. Actually, many taxa among these families are strikingly similar in morphology without considering furcula. The phylogeny of Entomobryoidea was reconstructed here based on mitochondrial and ribosomal fragments. This indicated that both Paronellidae and Cyphoderidae were ingroups within Entomobryidae with the former polyphyletic. Topology tests, which used the likelihood and Bayesian approaches, also rejected the traditional hypotheses relying on furcula morphology. Further ancestral state reconstructions have revealed that traditional taxonomical characters, i.e., furcula and body scales, had multiple independent origins in Entomobryoidea whereas tergal specialized chaetae (S-chaetae) exhibited strong phylogenetic signals. By integrating both molecular and morphological evidence, the results of this study drastically undermine the present classification of Entomobryoidea. Tergal S-chaetotaxic pattern in combination with other characters are more reasonable in taxonomy at suprageneric levels than convergent furcula. This study provides new insights of the jumping organ, which could be adaptively modified during evolution of Collembola.
PMCID: PMC4515636  PMID: 26212216
5.  Comparison of Accelerated and Standard Hepatitis B Vaccination Schedules in High-Risk Healthy Adults: A Meta-Analysis of Randomized Controlled Trials 
PLoS ONE  2015;10(7):e0133464.
Selecting the most efficient vaccination schedule is an important issue.
To assess the beneficial and harmful effects of accelerated hepatitis B vaccination schedules in high-risk healthy adults.
We searched controlled trial registers of The Cochrane Library as well as MEDLINE, EMBASE, VIP Database for Chinese Technical Periodicals, and the Chinese National Knowledge Infrastructure databases for randomized controlled trials published up to December 2013 that compared accelerated hepatitis B vaccine schedules to the standard schedule in adults. The results were presented as relative risk with 95% confidence intervals. Fixed or random effect models were used for analysis.
We identified 10 randomized trials, all with one or more methodological weaknesses. Compared to the standard schedule, most accelerated schedules resulted in higher proportions of healthy vaccines more rapidly reaching anti-hepatitis B antibody levels >10 IU/L (P<0.05) initially and maintaining similar seroprotection rates after 6 months (P>0.05). Although accelerated schedules produced anti-hepatitis B levels higher than the standard schedule for the first month after the initial vaccine dose, they were significantly lower than the standard schedule after 6 months, except for an accelerated schedule that called for a fourth booster injection 12 months after the initial dose. Subjects administered accelerated vaccine schedules had similar compliance rate as those administered the standard schedule over the first 6 months of vaccination (relative risk = 1.00, 95% confidence interval: 0.84–1.21).
For rapid seroconversion and almost immediate short-term protection, accelerated vaccination schedules could be useful for at-risk groups. However, additional studies on the long-term protection and effectiveness of the primary doses of accelerated schedules are necessary.
PMCID: PMC4510064  PMID: 26196903
6.  First Report of a Clinical, Multidrug-Resistant Enterobacteriaceae Isolate Coharboring Fosfomycin Resistance Gene fosA3 and Carbapenemase Gene blaKPC-2 on the Same Transposon, Tn1721 
In order to understand the genetic background and dissemination mechanism of carbapenem resistance and fosfomycin resistance in Enterobacteriaceae isolates, we studied a clinical Escherichia coli strain HS102707 isolate and an Enterobacter aerogenes strain HS112625 isolate, both of which were resistant to carbapenem and fosfomycin and positive for the blaKPC-2 and fosA3 genes. In addition, a clinical Klebsiella pneumoniae strain HS092839 isolate which was resistant to carbapenem was also studied. A 70-kb plasmid was successfully transferred to recipient E. coli J53 by a conjugation test. PCR and Southern blot analysis showed that blaKPC-2 was located on this plasmid. The complete sequence of pHS102707 showed that this plasmid belongs to the P11 subfamily (IncP1) and has a replication gene, several plasmid-stable genes, an intact type IV secretion system gene cluster, and a composite transposon Tn1721-Tn3 that harbored blaKPC-2. Interestingly, a composite IS26 transposon carrying fosA3 was inserted in the Tn1721-tnpA gene in pHS102707 and pHS112625, leading to the disruption of Tn1721-tnpA and the deletion of Tn1721-tnpR. However, only IS26 with a truncated Tn21-tnpR was inserted in pHS092839 at the same position. To our knowledge, this is the first report of fosA3 and blaKPC-2 colocated in the same Tn1721-Tn3–like composite transposon on a novel IncP group plasmid.
PMCID: PMC4291370  PMID: 25367902
7.  Hepatolithiasis associated with intrahepatic heterotopic pancreas: a case report and literature review 
Diagnostic Pathology  2015;10:76.
Intrahepatic heterotopic pancreas is rarely reported in the literature. Here, we report a case of a 39-year-old male with intrahepatic heterotopic pancreas associated with primary cholesterol hepatolithiasis. Computed tomography (CT) scans revealed multiple cholesterol stones in intrahepatic bile ducts of the left lobe concomitant with intrahepatic cholangiectases. These observations were confirmed by magnetic resonance cholangiopaneretography (MRCP). The patient underwent transabdominal left hepatic lobectomy. Postoperative histological examination of the resected specimen showed pancreatic tissues distributed along the wall of the bile duct and composed of acinar cells and duct elements without islets of Langerhans, therefore strongly suggesting that the heterotopic pancreas occurred in response to chronic injury due to the primary cholesterol hepatolithiasis and was derived from the biliary epithelial cells.
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PMCID: PMC4477297  PMID: 26099217
Heterotopic pancreas; Liver; Biliary tract; Hepatolithiasis; Metaplasia; Biliary epithelia cells
8.  Maleic Acid – but Not Structurally Related Methylmalonic Acid – Interrupts Energy Metabolism by Impaired Calcium Homeostasis 
PLoS ONE  2015;10(6):e0128770.
Maleic acid (MA) has been shown to induce Fanconi syndrome via disturbance of renal energy homeostasis, though the underlying pathomechanism is still under debate. Our study aimed to examine the pathomechanism underlying maleic acid-induced nephrotoxicity. Methylmalonic acid (MMA) is structurally similar to MA and accumulates in patients affected with methymalonic aciduria, a defect in the degradation of branched-chain amino acids, odd-chain fatty acids and cholesterol, which is associated with the development of tubulointerstitial nephritis resulting in chronic renal failure. We therefore used MMA application as a control experiment in our study and stressed hPTECs with MA and MMA to further validate the specificity of our findings. MMA did not show any toxic effects on proximal tubule cells, whereas maleic acid induced concentration-dependent and time-dependent cell death shown by increased lactate dehydrogenase release as well as ethidium homodimer and calcein acetoxymethyl ester staining. The toxic effect of MA was blocked by administration of single amino acids, in particular L-alanine and L-glutamate. MA application further resulted in severe impairment of cellular energy homeostasis on the level of glycolysis, respiratory chain, and citric acid cycle resulting in ATP depletion. As underlying mechanism we could identify disturbance of calcium homeostasis. MA toxicity was critically dependent on calcium levels in culture medium and blocked by the extra- and intracellular calcium chelators EGTA and BAPTA-AM respectively. Moreover, MA-induced cell death was associated with activation of calcium-dependent calpain proteases. In summary, our study shows a comprehensive pathomechanistic concept for MA-induced dysfunction and damage of human proximal tubule cells.
PMCID: PMC4473014  PMID: 26086473
9.  Platelet Glycoprotein IIIa Gene Polymorphism (Leu33Pro) and Aspirin Resistance in a Very Elderly Chinese Population 
Objectives: To study the relationship between platelet glycoprotein IIIa gene (GP IIIa) polymorphism (Leu33Pro) and aspirin resistance in a very elderly Chinese population. Methods: Four hundred fifty very elderly Chinese people receiving aspirin therapy were enrolled in the study. Patients who underwent arachnoid acid–induced platelet aggregation were then divided into two groups based on their resistance to aspirin: aspirin-resistant (AR) group (n=236) and aspirin-sensitive (AS) group (n=214). The Leu33Pro polymorphism of the GP IIIa gene was scanned by polymerase chain reaction–restriction fragment-length polymorphism. Results: In the AR group, 224 participants had the A1/A1 genotype and 12 had the A1/A2 genotype. All patients in the AS group had the A1/A1 genotype. Thus, there was significant difference between these two groups in the genotype distribution (p<0.05). Conclusion: The genetic polymorphism of the GP IIIa gene was associated with AR in a very elderly Chinese population.
PMCID: PMC4043438  PMID: 24720773
10.  An Automatic Occlusion Device for Remote Control of Tumor Tissue Ischemia 
We developed an automatic occlusion device for remote control of tumor tissue ischemia. The device consists of a flexible cannula encasing a shape memory alloy wire with its distal end connected to surgical suture. Regional tissue occlusion was tested on both the benchtop and the animal models. In the benchtop test, the occlusion device introduced quantitative and reproducible changes of blood flow in a tissue simulating phantom embedding a vessel simulator. In the animal test, the device generated a cyclic pattern of reversible ischemia in the right hinder leg tissue of a black male C57BL/6 mouse. We also developed a multimodal detector that integrates near infrared spectroscopy and electron paramagnetic resonance spectroscopy for continuous monitoring of tumor tissue oxygenation, blood content, and oxygen tension changes. The multimodal detector was tested on a cancer xenograft nude mouse undergoing reversible tumor ischemia. The automatic occlusion device and the multi-modal detector can be potentially integrated for closed-loop feedback control of tumor tissue ischemia. Such an integrated occlusion device may be used in multiple clinical applications such as regional hypoperfusion control in tumor resection surgeries and thermal ablation processes. In addition, the proposed occlusion device can also be used as a research tool to understand tumor oxygen transport and hemodynamic characteristics.
PMCID: PMC4332819  PMID: 20082532
Occlusion; Reperfusion; Ischemia; Tumor; Oxygenation; Blood flow; Oxygen tension; Near infrared spectroscopy; Electron paramagnetic resonance spectroscopy; Shape memory alloy wire
11.  Draft Genome Sequence of Nocardia seriolae ZJ0503, a Fish Pathogen Isolated from Trachinotus ovatus in China 
Genome Announcements  2015;3(1):e01223-14.
Nocardia seriolae is a pathogen that causes nocardiosis in marine and freshwater fish. Here, we report the draft genome sequence of N. seriolae strain ZJ0503, which was isolated from Trachinotus ovatus in Guangdong, China.
PMCID: PMC4293623  PMID: 25555736
12.  Immunization interventions to interrupt hepatitis B virus mother-to-child transmission: a meta-analysis of randomized controlled trials 
BMC Pediatrics  2014;14:307.
This study aimed to determine the clinical efficacy of various immune interventions on mother-to-child transmission (MTCT) of hepatitis B virus (HBV).
We retrieved different immune strategies on how to prevent MTCT reported in the literature from Chinese and English electronic databases from the viewpoint of intrauterine and extrauterine prevention. Relative risk (RR) and 95% confidence interval (CI) methods were used.
Twenty-five articles on intrauterine prevention and 16 on extrauterine prevention were included in the analysis. Intrauterine prevention could reduce infants’ HBV infection rate (RR = 0.36, 95% CI: 0.28-0.45) and increase their anti-hepatitis B surface–positive rate (RR = 2.42, 95% CI: 1.46-4.01) at birth. Compared with passive immunization, passive-active immunization could reduce infants’ HBV infection rate (RR = 0.66, 95% CI: 0.52-0.84) at birth, even at more than 12 months of age (RR = 0.54, 95% CI: 0.42-0.69). Subgroup analysis demonstrated similar results except for pregnant women who were hepatitis B surface antigen–positive. Funnel plots and Egger’s tests showed publication bias mainly in intrauterine prevention not in extrauterine one.
The long-term protective effect of pregnant women injected with hepatitis B immunoglobulin during pregnancy should be further validated by large-scale randomized trials. Newborns of pregnant women who carried HBV should undergo a passive-active immunization strategy.
Electronic supplementary material
The online version of this article (doi:10.1186/s12887-014-0307-2) contains supplementary material, which is available to authorized users.
PMCID: PMC4297423  PMID: 25526664
Hepatitis B immunoglobulin; Hepatitis B virus; Meta-analysis; Mother-to-child transmission
13.  Nonintubated anesthesia for thoracic surgery 
Journal of Thoracic Disease  2014;6(12):1868-1874.
Nonintubated thoracic surgery has been used in procedures including pleura, lungs and mediastinum. Appropriate anesthesia techniques with or without sedation allow thoracic surgery patients to avoid the potential risks of intubated general anesthesia, particularly for the high-risk patients. However, nonintubated anesthesia for thoracic surgery has some benefits as well as problems. In this review, the background, indication, perioperative anesthetic consideration and management, and advantages and disadvantages are discussed and summarized.
PMCID: PMC4283309  PMID: 25589994
Thoracic surgery; nonintubated anesthesia; epidural block; anesthesia technique
14.  Mechanisms of linezolid resistance in staphylococci and enterococci isolated from two teaching hospitals in Shanghai, China 
BMC Microbiology  2014;14:292.
Linezolid is one of the most effective treatments against Gram-positive pathogens. However, linezolid-resistant/intermediate strains have recently emerged in worldwide. The purpose of this study was to analyse the prevalence and resistance mechanisms of linezolid-resistant/intermediate staphylococci and enterococci in Shanghai, China.
Thirty-two linezolid-resistant/intermediate strains, including 14 Staphylococcus capitis, three Staphylococcus aureus, 14 Enterococcus faecalis and one Enterococcus faecium clinical isolates, were collected in this study which displayed linezolid MICs of 8 to 512 μg/ml, 8–32 μg/ml, 4–8 μg/ml and 4 μg/ml, respectively. All linezolid-resistant S. capitis isolates had a novel C2131T mutation and a G2603T mutation in the 23S rRNA region, and some had a C316T (Arg106Cys) substitution in protein L4 and/or harboured cfr. Linezolid-resistant S. aureus isolates carried a C389G (Ala130Gly) substitution in protein L3, and/or harboured cfr. The cfr gene was flanked by two copies of the IS256-like element, with a downstream orf1 gene. Linezolid-resistant/intermediate enterococci lacked major resistance mechanisms. The semi-quantitative biofilm assay showed that 14 linezolid-resistant E. faecalis isolates produced a larger biofilm than linezolid-susceptible E. faecalis strains. Transmission electron microscopy showed the cell walls of linezolid-resistant/intermediate strains were thicker than linezolid-susceptible strains.
Our data indicated that major resistance mechanisms, such as mutations in 23S rRNA and ribosomal proteins L3 and L4, along with cfr acquisition, played an important role in linezolid resistance. Secondary resistance mechanisms, such as biofilm formation and cell wall thickness, should also be taken into account.
PMCID: PMC4245736  PMID: 25420718
Linezolid resistance; Mutations of 23S rRNA and ribosomal proteins; cfr; Biofilm production; Cell wall thickness
15.  Optimal single-dose epidural neostigmine for postoperative analgesia after partial hepatectomy 
Indian Journal of Pharmacology  2014;46(6):613-616.
Neostigmine can produce analgesia by acting on the spinal cord. This study was to determine the optimal single-dose of epidural neostigmine for postoperative analgesia after partial hepatectomy.
Patients and Methods:
Twenty-six patients undergoing elective partial hepatectomy under general anesthesia combined with epidural block were studied. The dose of epidural neostigmine was determined using Dixon's up-and-down method, starting from neostigmine 100 μg with an interval of 25 μg. Thirty minutes after skin incision, a predetermined dose of neostigmine was injected via the epidural catheter. Each patient received 0.125% bupivacaine and fentanyl 2 μg/ml for patient controlled epidural analgesia (PCEA) after the operation. Assessment of analgesia quality was performed at 8 h and 24 h after the operation.
The ED50 of epidural neostigmine in combination with PCEA for satisfactory analgesia was 226.78 ± 33.20 μg. Probit analysis showed that the ED50 and ED95 of epidural neostigmine were 228.63 μg (95% CI = 197.95–299.77 μg) and 300.12 μg (95% CI = 259.44–741.65 μg), respectively.
The ED50 and ED95 of epidural neostigmine in combination with PCEA for satisfactory analgesia after partial hepatectomy were 228.63 μg (95% CI = 197.95–299.77 μg) and 300.12 μg (95% CI = 259.44–741.65 μg).
PMCID: PMC4264076  PMID: 25538332
Dixon's up-and-down method; neostigmine; optimal dose; postoperative analgesia; patient controlled epidural analgesia
16.  The role of integrin-β/FAK in cyclic mechanical stimulation in MG-63 cells 
Objective: This study aims to explore the function of Integrin-β/FAK in the mechanical signal transduction and the connection with downstream ERK signal pathways. Methods: Human osteosarcoma MG63 cell lines were used in this study. The effects of mechanical strain on the Integrin-β1 expression, FAK and ERK signal pathway in Human osteosarcoma MG63 cells were detected using RT-PCR and Western-blotting methods. The localization of FAK in Human osteosarcoma MG63 cells were determined using immunofluorescent method. The interaction between Integrin-β1 and FAK were detected by using co-immunoprecipitation method. Results: The expression of Integrin-β1 shows a notable bimodel distribution, mechanical strain stimulation can promote Integrin-β1 expression and the phosphorylation of FAK and ERK, mechanical strain activated FAK and ERK mediated by Integrin-β1. Conclusion: Integrin-β1 may play an important role in osteoblast proliferation differentiation process, it might feel external strain stimulation through ECM composition and makes FAK phosphated through the interaction with FAK, thus causing a series of activation of signal molecules. Finally it reduces MAPK (ERK) activation and cellular responses to finish mechanical signal transduction.
PMCID: PMC4270589  PMID: 25550780
Integrin-β; human osteosarcoma MG63 cells; mechanical stimulation; focal adhesion kinase (FAK); ERK signal pathway
17.  Testing Stem Cell Therapy in a Rat Model of Inflammatory Bowel Disease: Role of Bone Marrow Stem Cells and Stem Cell Factor in Mucosal Regeneration 
PLoS ONE  2014;9(10):e107891.
The gastrointestinal (GI) mucosal cells turnover regularly under physiological conditions, which may be stimulated in various pathological situations including inflammation. Local epithelial stem cells appear to play a major role in such mucosal renewal or pathological regeneration. Less is clear about the involvement of multipotent stem cells from blood in GI repair. We attempted to explore a role of bone marrow mesenchymal stromal cells (BMMSCs) and soluble stem cell factor (SCF) in GI mucosa regeneration in a rat model of inflammatory bowel diseases (IBD).
BMMSCs labelled with the fluorescent dye PKH26 from donor rats were transfused into rats suffering indomethacin-induced GI injury. Experimental effects by BMMSCs transplant and SCF were determined by morphometry of intestinal mucosa, double labeling of PKH26 positive BMMSCs with endogenous proliferative and intestinal cell markers, and western blot and PCR analyses of the above molecular markers in the recipient rats relative to controls.
PKH26 positive BMMSCs were found in the recipient mucosa, partially colocalizing with the proliferating cell nuclear antigen (PCNA), Lgr5, Musashi-1 and ephrin-B3. mRNA and protein levels of PCNA, Lgr5, Musashi-1 and ephrin-B3 were elevated in the intestine in BMMSCs-treated rats, most prominent in the BMMSCs-SCF co-treatment group. The mucosal layer and the crypt layer of the small intestine were thicker in BMMSCs-treated rats, more evident in the BMMSCs-SCF co-treatment group.
BMMSCs and SCF participate in but may play a synergistic role in mucosal cell regeneration following experimentally induced intestinal injury. Bone marrow stem cell therapy and SCF administration may be of therapeutic value in IBD.
PMCID: PMC4195572  PMID: 25309991
18.  Effects of Astragaloside IV combined with the active components of Panax notoginseng on oxidative stress injury and nuclear factor-erythroid 2-related factor 2/heme oxygenase-1 signaling pathway after cerebral ischemia-reperfusion in mice 
Pharmacognosy Magazine  2014;10(40):402-409.
Astragalus and Panax notoginseng are traditional Chinese Medicines used for the treatments of ischemic cerebrovascular disease, being often combined together in China and achieving a good effect.
The objective of this study is to investigate the effects of astragaloside-IV (AST-IV) (the effective component of Astragalus) combined with ginsenoside Rg1, ginsenoside Rb1, notoginsenoside R1 (the effective components of P. notoginseng) on oxidative stress injury after cerebral ischemia-reperfusion in mice, and to explore the mechanisms through nuclear factor-erythroid 2-related factor-2/heme oxygenase-1 (Nrf2/HO-1) signaling pathway.
Materials and Methods:
C57BL/6 mice were randomly grouped after treated for 3 days, the model of cerebral ischemia-reperfusion injury was established, and the brain tissues were detected.
AST-IV combined with ginsenoside Rg1, ginsenoside Rb1, notoginsenoside R1 could increase significantly the survival rate of nerve cell; decrease the contents of malondialdehyde, nitric oxide, increase the activity of superoxide dismutase and the level of glutathione; Nrf2 was down-regulated in the cytoplasm while up-regulated in nucleus, nuclear translocation rate raised as well as HO-1 messenger ribonucleic acid and protein expressions increased. The effects of four active components combination were better than those of the active components alone.
Active components of Astragalus and P. notoginseng had the effects against cerebral ischemia-reperfusion injury, which were related to the antioxidative stress after cerebral ischemia-reperfusion. AST-IV combined with ginsenoside Rg1, ginsenoside Rb1, notoginsenoside R1 could strengthen the antagonism effects on ischemia-reperfusion and oxidative stress injury, the mechanism underlying might be associated with jointly activating Nrf2/HO-1 signaling pathway after cerebral ischemia-reperfusion.
PMCID: PMC4239715  PMID: 25422538
Astragaloside IV; combination; ginsenoside Rb1; ginsenoside Rg1; notoginsenoside R1; nuclear factor-erythroid 2-related factor-2/heme oxygenase
19.  Contribution of β-Lactamases and Porin Proteins OmpK35 and OmpK36 to Carbapenem Resistance in Clinical Isolates of KPC-2-Producing Klebsiella pneumoniae 
Fifty-seven carbapenem-resistant Klebsiella pneumoniae isolates belonging to ST11 (50 isolates), ST423 (5 isolates), and two other sequence types were studied. All were positive for blaKPC-2, blaTEM-1, and blaCTX-M-14. SDS-PAGE analysis of six representative isolates demonstrated varied porin expression. Nevertheless, when blaKPC-2 was deleted, carbapenem resistance was markedly reduced. Additionally, SHV-12, DHA-1, and/or VIM-1 appeared to contribute to accessory carbapenemase activity. In contrast, OmpK35 and/or OmpK36 deficiency seemed to serve only as a minor cooperative factor.
PMCID: PMC3910872  PMID: 24277031
20.  A potential therapeutic effect of CYP2C8 overexpression on anti-TNF-α activity 
Epoxyeicosatrienoic acids (EETs) are generated from arachidonic acid catalysed by cytochrome P450 (CYP) epoxygenases. In addition to regulating vascular tone EETs may alleviate inflammation and ROS. The present study was conducted to determine whether CYP2C8 gene overexpression was able to increase the level of EETs, and subsequently prevent TNF-α induced inflammation and reactive oxygen species (ROS) in human umbilical vein endothelial cells (HUVECs) and macrophages. Peroxisome proliferator-activated receptor γ (PPARγ) activation, nuclear factor-κB (NF-κB) activation, endothelial nitric oxide synthase (eNOS) activation, gp-91 activation, and inflammatory cytokine expression were detected by western blot analysis or enzyme-linked immunosorbent assay. Intracellular reactive oxygen species (ROS) was measured by flow cytometry, while the migration of vascular smooth muscle cells (VSMCs) was detected by Transwell assay. pCMV-mediated CYP2C8 overexpression and its metabolites, EETs, markedly suppressed TNF-α induced inflammatory cytokines IL-6 and MCP-1 expression via the activation of NF-κB and degradation of IκBα. Moreover, pretreatment with 11,12-EET significantly blocked TNF-α-induced ROS production. CYP2C8-derived EETs also effectively alleviated the migration of VSMCs and improved the function of endothelial cells through the upregulation of eNOS, which was significantly decreased under the stimulation of TNF-α. Furthermore, these protective effects observed were mediated by PPARγ activation. To the best of our knowledge, the results of the present study demonstrated for the first time that CYP2C8-derived EETs exerted antivascular inflammatory and anti-oxidative effects, at least in part, through the activation of PPARγ. Thus, the CYP2C8 gene may be useful in the prevention and treatment of vascular inflammatory diseases.
PMCID: PMC4121355  PMID: 25017038
CYP2C8; epoxyeicosatrienoic acids; inflammation; reactive oxygen species; nuclear factor-κB; atherosclerosis
21.  Left Ventricular Myocardial Function in Hemodialysis and Nondialysis Uremia Patients: A Three-Dimensional Speckle-Tracking Echocardiography Study 
PLoS ONE  2014;9(6):e100265.
Several studies have demonstrated that uremic patients who have preserved left ventricular ejection fraction (LVEF) could still have the potential for systolic dysfunction. The aim of this study was to assess the differences between the left ventricular (LV) myocardial function in hemodialysis and nondialysis uremic patients based on three-dimensional speckle-tracking echocardiography.
The study population consisted of 35 maintenance hemodialysis patients (the hemodialysis group), 30 uremic patients who were hospitalized for the creation of a primary arteriovenous fistula (the nondialysis group), and 32 healthy volunteers. All of the patients had normal left ventricular ejection fractions (i.e., 55% or greater). Three-dimensional speckle tracking echocardiography was performed to assess the left ventricle's global three-dimensional strain, regional longitudinal strain, circumferential strain, and radial strain.
The left ventricular regional longitudinal strain, radial strain, circumferential strain, and global three-dimensional strain were significantly decreased in the nondialysis patients compared with the other two groups (all, P<0.001). However, the three-dimensional strain and the regional longitudinal strain were lower in the hemodialysis patients than in the controls (P<0.01). In the hemodialysis patients and the control group, the longitudinal strain, circumferential strain, and radial strain were higher at the apical level than they were at the basal level and midlevels. A multivariate linear regression analysis showed that the blood urea nitrogen and creatinine levels were independently associated with the values of the global three-dimensional strain (β = −0.217, P = 0.000; β = −0.243, P = 0.011, respectively) and the longitudinal strain (β = −0.154, P = 0.032; β = −0.188, P = 0.029, respectively).
Three-dimensional speckle-tracking echocardiography may detect myocardial dysfunction in patients with uremia who have preserved LVEF. The global three-dimensional strain and the regional longitudinal strain appear to be superior in hemodialysis patients compared with nondialysis patients.
PMCID: PMC4069011  PMID: 24959903
22.  Population pharmacokinetics of trastuzumab emtansine (T-DM1), a HER2-targeted antibody–drug conjugate, in patients with HER2-positive metastatic breast cancer: clinical implications of the effect of covariates 
Trastuzumab emtansine (T-DM1) is an antibody–drug conjugate comprising the humanized monoclonal antibody trastuzumab linked to DM1, a highly potent cytotoxic agent. A population pharmacokinetic (PK) analysis was performed to estimate typical values and interindividual variability of T-DM1 PK parameters and the effects of clinically relevant covariates.
Serum samples were collected from 671 patients with human epidermal growth factor receptor 2-positive locally advanced or metastatic breast cancer (MBC) who received single-agent T-DM1 in five phase I to phase III studies. Nonlinear mixed-effects modeling with the first-order conditional estimation method was used.
A linear two-compartment model with first-order elimination from the central compartment described T-DM1 PKs in the clinical dose range. T-DM1 elimination clearance was 0.676 L/day, volume of distribution in the central compartment (Vc) was 3.127 L, and terminal elimination half-life was 3.94 days. Age, race, region, and renal function did not influence T-DM1 PK. Given the low-to-moderate effect of all statistically significant covariates on T-DM1 exposure, none of these covariates is expected to result in a clinically meaningful change in T-DM1 exposure.
T-DM1 PK properties are consistent and predictable in patients. A further refinement of dose based on baseline covariates other than body weight for the current 3.6 mg/kg regimen would not yield clinically meaningful reductions in interindividual PK variability in patients with MBC.
Electronic supplementary material
The online version of this article (doi:10.1007/s00280-014-2500-2) contains supplementary material, which is available to authorized users.
PMCID: PMC4112050  PMID: 24939213
Ado-trastuzumab emtansine; T-DM1; HER2; Pharmacokinetics; Metastatic breast cancer
23.  Dlx6 Regulates Molecular Properties of the Striatum and Central Nucleus of the Amygdala 
The Journal of comparative neurology  2011;519(12):2320-2334.
We describe here the prenatal telencephalic expression of Dlx6 RNA and β-galactosidase driven from a mutant Dlx6 locus. The mutant Dlx6 allele, which we believe is either a null or severe hypomorph, has an IRES-lacZ-neomycin resistance cassette inserted into the Dlx6 homeobox coding sequence (Dlx6LacZ). We compared expression from the Dlx6-lacZ (Dlx6LacZ) allele in heterozygotes (Dlx6LacZ/+), with the expression of Dlx1, Dlx2, Dlx5 and Dlx6 RNA. Like these wild-type alleles, Dlx6LacZ is expressed in the developing ganglionic eminences, and their derivatives. Unlike the other Dlx genes, Dlx6 and Dlx6LacZ expression is not readily observed in tangentially migrating interneurons. In addition to Dlx6’s expression at later stages of differentiation of many basal ganglia nuclei, it shows particularly robust expression in the central nucleus of the amygdala. Histological analysis of Dlx6 mutants (Dlx6LacZ/LacZ) shows that this homeobox transcription factor is required for molecular properties of the striatum, nucleus accumbens, olfactory tubercle, and central nucleus of the amygdala. For instance, we observed reduced of Golf, RXRγ, and Tiam2 expression in the striatum, and reduced Dlx5 expression in the central nucleus of the amygdala. RNA expression array analysis of the E18.5 striatum was useful in identifying the transcription factors that are expressed in this tissue, but did not identify major changes in gene expression in the Dlx6LacZ/LacZ mutant.
PMCID: PMC4019376  PMID: 21452241
Dlx; striatum; amygdala; mouse; development
24.  Extracts from Curcuma zedoaria Inhibit Proliferation of Human Breast Cancer Cell MDA-MB-231 In Vitro 
Objective. To evaluate the effect of petroleum ether extracts of Curcuma zedoaria on the proliferation of human triple negative breast cancer cell line MDA-MB-231. Methods. The reagents were isolated from Curcuma zedoaria by petroleum ether fraction. It was assayed by CCK8 for MDA-MB-231 cellular viability with various concentrations and days, cell cycle analyses, Western Blot analysis, and Realtime Reverse Transcriptase PCR analyses for chemokines molecules including E-cadherin, and E-selectin, and adhesion molecules including CCR7, SLC, SDF-1, and CXCR4. Epirubicin was used as control in the study. Results. MDA-MB-231 cells were inhibited by petroleum ether extracts of Curcuma zedoaria (P < 0.05), and the inhibition rate was dependent on concentrations and time. Petroleum ether extracts of Curcuma zedoaria as well as Epirubicin produce a significant G0/G1 cell cycle arrest. The level of expression of proteins E-cadherin and E-cadherin mRNA was significantly increased, while proteins SDF-1, CCR7, and CXCR4 mRNA were decreased after being incubated with petroleum ether extracts of Curcuma zedoaria at the concentrations of 300 μg/mL than control (P < 0.05). The differences were that the protein CXCR4 mRNA expression level was higher than vehicle. Conclusions. MDA-MB-231 cells were inhibited by petroleum ether extracts of Curcuma zedoaria.
PMCID: PMC4026840  PMID: 24883070
25.  Surface-Enhanced Raman Scattering Study on Graphene-Coated Metallic Nanostructure Substrates 
Graphene, which has a linear electronic band structure, is widely considered as a semimetal. In the present study, we combine graphene with conventional metallic surface-enhanced Raman scattering (SERS) substrates to achieve higher sensitivity of SERS detection. We synthesize high-quality, single-layer graphene sheets by chemical vapor deposition (CVD) and transfer them from copper foils to gold nanostructures, i.e., nanoparticle or nanohole arrays. SERS measurements are carried out on methylene blue (MB) molecules. The combined graphene nanostructure substrates show about threefold or ninefold enhancement in the Raman signal of MB, compared with the bare nanohole or nanoparticle substrates, respectively. The difference in the enhancement factors is explained by the different morphologies of graphene on the two substrates with the aid of numerical simulations. Our study indicates that applying graphene to SERS substrates can be an effective way to improve the sensitivity of conventional metallic SERS substrates.
PMCID: PMC3998773  PMID: 24772200
Graphene; SERS; Plasmonics; Nanostructure

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