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1.  A novel role of kukoamine B: Inhibition of the inflammatory response in the livers of lipopolysaccharide-induced septic mice via its unique property of combining with lipopolysaccharide 
Kukoamine B (KB), derived from the traditional Chinese herb cortex Lycii, exerts anti-inflammatory effects due to its potent affinity with lipopolysaccharide (LPS) and CpG DNA; however, little is known regarding whether the in vivo administration of KB can effectively inhibit inflammation in septic mice. The present study thus aimed to investigate the inhibitory effects of KB on the inflammatory response in the livers of LPS-induced septic mice. KB treatment in the LPS-induced septic mice significantly decreased the plasma level of LPS. In addition, KB protected against liver injury, as confirmed by improved histology and decreased aminotransferase levels in the serum. Further experiments revealed that KB attenuated liver myeloperoxidase activity and reduced the expression of vascular cell adhesion molecule-1 and intercellular adhesion molecule-1. These effects were accompanied by decreases in the levels of tumor necrosis factor α and interleukin-1β in the liver tissue. In parallel, the activity of nuclear factor-κ-gene binding (NF-κB) in the livers of LPS-induced septic mice was markedly inhibited with KB treatment. In combination, these results demonstrate that KB inhibits inflammation in septic mice by reducing the concentrations of plasma LPS, decreasing leukocyte sequestration and interfering with NF-κB activation, and, therefore, suppressing the pro-adhesive phenotype of endothelial cells.
PMCID: PMC4316986  PMID: 25667619
kukoamine B; lipopolysaccharide; liver; inflammatory response; nuclear factor κ-light-chain-enhancer of activated B cells
2.  Oral Delivery of IL27 Recombinant Bacteria Attenuates Immune Colitis in Mice 
Gastroenterology  2013;146(1):210-221.e13.
Background & Aims
Treatment of inflammatory bowel disease (IBD) would benefit from specific targeting of therapeutics to the intestine. We developed a strategy for localized delivery of the immunosuppressive cytokine IL27, which is actively synthesized in situ by the food-grade bacterium Lactococcuslactis (LL-IL-27), and tested its ability to reduce colitis in mice.
The 2 genes encoding mouse IL27 were synthesized with optimal codon usage for L lactis and joined with a linker; a signal sequence was added to allow for secretion of the product. The construct was introduced into L lactis. Colitis was induced via transfer of CD4+CD45RBhi T cells into Rag−/− mice to induce colitis; 7.5 weeks later, LL-IL-27 was administered to mice via gavage. Intestinal tissues were collected and analyzed.
LL-IL-27 administration protected mice from T-cell transfer-induced enterocolitis and death. LL-IL-27 reduced disease activity scores, pathology features of large and small bowel, and levels of inflammatory cytokines in colonic tissue. LL-IL-27 also reduced numbers of CD4+ and IL17+ T cells in gut-associated lymphoid tissue. The effects of LL-IL-27 required production of IL10 by the transferred T cells. LL-IL-27 was more effective than either LL-IL-10 or systemic administration of recombinant IL27 in reducing colitis in mice. LL-IL-27 also reduced colitis in mice following administration of dextran sodium sulfate.
L lactis engineered to express IL27 (LL-IL-27) reduces colitis in mice, by increasing production of IL10. Mucosal delivery of LL-IL-27 could be a more effective and safer therapy for IBD.
PMCID: PMC3920828  PMID: 24120477
mouse model; Crohn’s Disease; ulcerative colitis; immune regulation
4.  Antibacterial properties of Acinetobacter baumannii phage Abp1 endolysin (PlyAB1) 
BMC Infectious Diseases  2014;14(1):681.
Acinetobacter baumannii has emerged as one of the most important hospital-acquired pathogens in the world, because of its resistance to almost all available antibiotic drugs. Endolysins from phages are attracting increasing interest as potential antimicrobial agents, especially for drug-resistant bacteria. We previously isolated and characterized Abp1, a virulent phage targeting the multidrug-resistant A. baumannii strain, AB1.
To evaluate the antimicrobial potential of endolysin from the Abp1 phage, the endolysin gene plyAB1 was cloned and over-expressed in Escherichia coli, and the lytic activity of the recombinant protein (PlyAB1) was tested by turbidity assessment and bacteria counting assays.
PlyAB1 exhibits a marked lytic activity against A. baumannii AB1, as shown by a decrease in the number of live bacteria following treatment with the enzyme. Moreover, PlyAB1 displayed a highly specific lytic effect against all of the 48 hospital-derived pandrug-resistant A. baumannii isolates that were tested. These isolates were shown to belong to different ST clones by multilocus sequence typing.
The results presented here show that PlyAB1 has potential as an antibiotic against drug-resistant A. baumannii.
Electronic supplementary material
The online version of this article (doi:10.1186/s12879-014-0681-2) contains supplementary material, which is available to authorized users.
PMCID: PMC4274762  PMID: 25495514
Pandrug-resistant Acinetobacter baumannii; Endolysins; Multilocus sequence typing
5.  Development of the science of mass casualty incident management: reflection on the medical response to the Wenchuan earthquake and Hangzhou bus fire*  
Objective: In this paper, we review the previous classic research paradigms of a mass casualty incident (MCI) systematically and reflect the medical response to the Wenchuan earthquake and Hangzhou bus fire, in order to outline and develop an improved research paradigm for MCI management. Methods: We searched PubMed, EMBASE, China Wanfang, and China Biology Medicine (CBM) databases for relevant studies. The following key words and medical subject headings were used: ‘mass casualty incident’, ‘MCI’, ‘research method’, ‘Wenchuan’, ‘earthquake’, ‘research paradigm’, ‘science of surge’, ‘surge’, ‘surge capacity’, and ‘vulnerability’. Searches were performed without year or language restriction. After searching the four literature databases using the above listed key words and medical subject headings, related articles containing research paradigms of MCI, 2008 Wenchuan earthquake, July 5 bus fire, and science of surge and vulnerability were independently included by two authors. Results: The current progresses on MCI management include new golden hour, damage control philosophy, chain of survival, and three links theory. In addition, there are three evaluation methods (medical severity index (MSI), potential injury creating event (PICE) classification, and disaster severity scale (DSS)), which can dynamically assess the MCI situations and decisions for MCI responses and can be made based on the results of such evaluations. However, the three methods only offer a retrospective evaluation of MCI and thus fail to develop a real-time assessment of MCI responses. Therefore, they cannot be used as practical guidance for decision-making during MCI. Although the theory of surge science has made great improvements, we found that a very important factor has been ignored—vulnerability, based on reflecting on the MCI response to the 2008 Wenchuan earthquake and July 5 bus fire in Hangzhou. Conclusions: This new paradigm breaks through the limitation of traditional research paradigms and will contribute to the development of a methodology for disaster research.
PMCID: PMC4265562  PMID: 25471837
Mass casualty incident; Surge; Vulnerability; Earthquake; Fire incident
6.  TGF-β1 Protection against Aβ1–42-Induced Neuroinflammation and Neurodegeneration in Rats 
Transforming growth factor (TGF)-β1, a cytokine that can be expressed in the brain, is a key regulator of the brain’s responses to injury and inflammation. Alzheimer’s disease (AD), the most common neurodegenerative disorder, involves inflammatory processes in the brain in addition to the hallmarks, amyloid-β (Aβ) plaques and neurofibrillary tangles. Recently, we have shown that T-helper (Th) 17 cells, a subpopulation of CD4+ T-cells with high proinflammation, also participate in the brain inflammatory process of AD. However, it is poorly known whether TGF-β1 ameliorates the lymphocyte-mediated neuroinflammation and, thereby, alleviates neurodegeneration in AD. Herein, we administered TGF-β1 via the intracerebroventricle (ICV) in AD model rats, by Aβ1–42 injection in both sides of the hippocampus, to show the neuroprotection of TGF-β1. The TGF-β1 administration after the Aβ1–42 injection ameliorated cognitive deficit and neuronal loss and apoptosis, reduced amyloid precursor protein (APP) expression, elevated protein phosphatase (PP)2A expression, attenuated glial activation and alleviated the imbalance of the pro-inflammatory/anti-inflammatory responses of T-lymphocytes, compared to the Aβ1–42 injection alone. These findings demonstrate that TGF-β1 provides protection against AD neurodegeneration and suggest that the TGF-β1 neuroprotection is implemented by the alleviation of glial and T-cell-mediated neuroinflammation.
PMCID: PMC4284696  PMID: 25470026
TGF-β1; Alzheimer’s disease; Aβ1–42; T-lymphocytes; microglia
7.  Psychometric properties of the osteoporosis assessment questionnaire (OPAQ) 2.0: results from the multiple outcomes of raloxifene evaluation (MORE) study 
We explored psychometric properties of the Osteoporosis Assessment Questionnaire 2.0 in terms of reliability, validity, and responsiveness with generic, clinical, demographic, and preference-based data collected from a population of postmenopausal women with osteoporosis.
The Multiple Outcomes of Raloxifene Evaluation study was a randomized, placebo-controlled, multinational clinical trial evaluating efficacy and safety of raloxifene. The Osteoporosis Assessment Questionnaire 2.0, a generic quality of life measure (Nottingham Health Profile), and a preference-based measure (Health Utilities Index) were administered at baseline and annually. Psychometric properties of the 14 Osteoporosis Assessment Questionnaire 2.0 domains were evaluated by standard statistical techniques.
This study included a subset of 1477 women from the Multiple Outcomes of Raloxifene Evaluation study population completing the questionnaires. Mean (standard deviation) age was 68.4 (6.8) years. Prevalent vertebral fractures were found in 70% (n =1038) of women. Internal consistency was >0.7 in 9 Osteoporosis Assessment Questionnaire 2.0 domains. Correlations were moderate and significant for similar Osteoporosis Assessment Questionnaire 2.0 domain scores, Nottingham Health Profile domains, and Health Utilities Index scores. All but 2 Osteoporosis Assessment Questionnaire 2.0 domains distinguished between patients with or without prevalent vertebral fractures and detected worsening with increased number of vertebral fractures. Women with ≥1 incident vertebral fracture generally had a greater worsening in Osteoporosis Assessment Questionnaire 2.0 scores (excluding social activity and support of family and friends) from baseline to study endpoint compared with women without incident vertebral fractures.
Most domains in the Osteoporosis Assessment Questionnaire 2.0 demonstrated robust psychometric properties; however, several domains not showing these criteria may need to be reassessed and removed for a potentially shorter and validated version of the Osteoporosis Assessment Questionnaire.
Electronic supplementary material
The online version of this article (doi:10.1186/1471-2474-15-374) contains supplementary material, which is available to authorized users.
PMCID: PMC4246554  PMID: 25403238
Health-related quality of life; Osteoporosis; Vertebral fracture; Psychometric properties
8.  Crystal structure of hydro­cortisone 17-butyrate 
In the title compound, C25H36O6, the two central cyclo­hexane rings exhibit a chair conformation. The terminal cyclo­hexene and cyclo­pentane rings are in half-chair and envelope conformations (with the C atom bearing the methyl substit­uent as the flap), respectively. The methyl group of the butyrate chain is disordered over two orientations, with a refined occupancy ratio of 0.742 (6):0.258 (6). Intra­molecular O—H⋯O and C—H⋯O hydrogen bonds are observed. In the crystal, mol­ecules are linked by O—H⋯O hydrogen bonds into chains running parallel to the a axis.
PMCID: PMC4257404  PMID: 25553020
crystal structure; hydro­cortisone derivative; hydrogen bonds; pharmacological activity
9.  Wireless esophageal pH capsule for patients with gastroesophageal reflux disease: A multicenter clinical study 
World Journal of Gastroenterology : WJG  2014;20(40):14865-14874.
AIM: To investigate the feasibility and safety of pH capsule to monitor pH in patients with gastroesophageal reflux disease (GERD).
METHODS: Ninety-one patients with symptoms suggestive of GERD were enrolled in this study, 46 of whom were randomized to the pH capsule group; the remaining 45 patients used the conventional catheter and pH capsule simultaneously. The pH data and traces were recorded via automatic analysis, and capsule detachment was assessed using X-ray images. All of the patients were required to complete a questionnaire regarding tolerance with the capsule.
RESULTS: The capsules were successfully attached on the first attempt, and no early detachment of the capsules was observed. Compared to the 24-h pH data recorded with the conventional catheter, the data collected with the pH capsule showed no significant differences in 24-h esophageal acid exposure. The measurements of esophageal acid exposure over 24 h collected with the two devices showed a significant correlation (r2 = 0.996, P < 0.001). Capsule detachment occurred spontaneously in 89 patients, and 2 capsules required endoscopic removal due to chest pain. The capsule was associated with less interference with daily activity.
CONCLUSION: The wireless pH capsule provides a feasible and safe method for monitoring gastroesophageal reflux and therefore may serve as an important tool for diagnosing GERD.
PMCID: PMC4209549  PMID: 25356046
Wireless pH capsule; Feasibility; Safety; Conventional catheter; Gastroesophageal reflux disease
10.  Effect of gastrectomy with bursectomy on prognosis of gastric cancer: A meta-analysis 
World Journal of Gastroenterology : WJG  2014;20(40):14986-14991.
AIM: To evaluate the effect of bursectomy on overall survival, recurrence-free survival and safety of patients with gastric cancer by performing a meta-analysis.
METHODS: A literature search was performed in PubMed, EMBASE, and the Cochrane Library databases for clinical research that compared bursectomy with non-bursectomy published before October 2013. Inclusion and exclusion criteria were established and applied. Overall survival, recurrence-free survival, complications, hospital stay, operative time and blood loss were compared using hazard ratios (HRs), relative risks and weighted mean differences. Stata 12.0 software was used for statistical analysis.
RESULTS: Four studies including 1130 patients were available for the analysis (430 in the bursectomy group, 700 in the non-bursectomy group). No statistically significant difference was observed in the rate of complications between the bursectomy group and the non-bursectomy group. Bursectomy did not have a significant effect (combined HR = 1.14, 95%CI: 0.88-1.47) on overall survival, and it was not a significant factor for recurrence-free survival (combined HR = 1.06, 95%CI: 0.82-1.37).
CONCLUSION: Gastrectomy with bursectomy is not superior to non-bursectomy in terms of survival. Bursectomy is not recommended as a routine procedure for the surgical treatment of gastric cancer.
PMCID: PMC4209563  PMID: 25356060
Gastric cancer; Bursectomy; Prognosis; Gastrectomy; Meta-analysis
11.  Fusion Protein Linkers: Property, Design and Functionality 
Advanced drug delivery reviews  2012;65(10):1357-1369.
As an indispensable component of recombinant fusion proteins, linkers have shown increasing importance in the construction of stable, bioactive fusion proteins. This review covers the current knowledge of fusion protein linkers and summarizes examples for their design and application. The general properties of linkers derived from naturally-occurring multi-domain proteins can be considered as the foundation in linker design. Empirical linkers designed by researchers are generally classified into 3 categories according to their structures: flexible linkers, rigid linkers, and in vivo cleavable linkers. Besides the basic role in linking the functional domains together (as in flexible and rigid linkers) or releasing free functional domain in vivo (as in in vivo cleavable linkers), linkers may offer many other advantages for the production of fusion proteins, such as improving biological activity, increasing expression yield, and achieving desirable pharmacokinetic profiles.
PMCID: PMC3726540  PMID: 23026637
bifunctional recombinant proteins; spacer; pharmacokinetics; pharmacodynamics
12.  Fatty Acids as Therapeutic Auxiliaries for Oral and Parenteral Formulations 
Advanced drug delivery reviews  2012;65(10):1331-1339.
Many drugs have decreased therapeutic activity due to issues with absorption, distribution, metabolism and excretion. The co-formulation or covalent attachment of drugs with fatty acids has demonstrated some capacity to overcome these issues by improving intestinal permeability, slowing clearance and binding serum proteins for selective tissue uptake and metabolism. For orally administered drugs, albeit at low level of availability, the presence of fatty acids and triglycerides in the intestinal lumen may promote intestinal uptake of small hydrophilic molecules. Small lipophilic drugs or acylated hydrophilic drugs also show increased lymphatic uptake and enhanced passive diffusional uptake. Fatty acid conjugation of small and large proteins or peptides have exhibited protracted plasma half-lives, site-specific delivery and sustained release upon parenteral administration. These improvements are most likely due to associations with lipid-binding serum proteins, namely albumin, LDL and HDL. These molecular interactions, although not fully characterized, could provide the ability of using the endogenous carrier systems for improving therapeutic outcomes.
PMCID: PMC3537895  PMID: 22921839
Drug delivery; protein binding; endogenous drug carriers; albumin; drug absorption; drug formulation; fatty acids; triglycerides; lipid prodrugs; reversible lipidization
13.  Lack of Impact of Mild Obstructive Sleep Apnea on Sleepiness, Mood and Quality of Life 
Background and Objectives
Obstructive sleep apnea (OSA) is associated with sleepiness, depression and reduced quality of life. However, it is unclear whether mild OSA has these negative impacts. Using data from the Apnea Positive Pressure Long-term Efficacy Study (APPLES), this study determined whether participants with mild OSA had greater sleepiness, more depressive symptoms and poorer quality of life in comparison to those without OSA.
239 individuals evaluated for participation in APPLES with a baseline apnea hypopnea index (AHI) < 15 /hour were assigned to 1 of 2 groups: No OSA (N=40, AHI < 5 /hour) or Mild OSA (N=199, 5 to <15 /hour) based on their screening polysomnogram. Scores on their Epworth Sleepiness Scale (ESS), Stanford Sleepiness Scale (SSS), Hamilton Rating Scale for Depression (HAM-D), Profile of Mood States (POMS) and Sleep Apnea Quality of Life Index (SAQLI) were compared between groups.
There were no significant differences between the No OSA and Mild OSA groups on any of the 5 measures: ESS (No OSA, 9.8 ± 3.5 vs Mild OSA, 10.6 ± 4.3, p=0.26), SSS,(2.8 ± 0.9 vs. 2.9 ± 1.0, p=0.52), HAM-D (4.6 ± 3.0 vs. 4.9 ± 4.7, p=0.27), POMS (33.5 ± 22.3 vs. 28.7 ± 22.0, p=0.70), SAQLI (4.5 ± 0.8 vs. 4.7 ± 0.7, p=0.39).
Individuals with mild OSA in this cohort do not have worse sleepiness, mood or quality of life in comparison to those without OSA.
PMCID: PMC4163952  PMID: 25232509
14.  Proteomics reveals potential non-neuronal cholinergic receptor-effectors in endothelial cells 
Acta Pharmacologica Sinica  2014;35(9):1137-1149.
The non-neuronal acetylcholine system (NNAS) in endothelial cells participates in modulating endothelial function, vascular tone, angiogenesis and inflammation, thus plays a critical role in cardiovascular diseases. In this study, we used a proteomic approach to study potential downstream receptor-effectors of NNAS that were involved in regulating cellular function in endothelial cells.
Human umbilical vein endothelial cells were incubated in the presence of acetylcholine, oxotremorine, pilocarpine or nicotine at the concentration of 10 μmol/L for 12 h, and the expressed proteins in the cells were separated and identified with two-dimensional electrophoresis (2-DE) and LC-MS. The protein spots with the largest changes were identified by LC-MS. Biowork software was used for database search of the peptide mass fingerprints.
Over 1200 polypeptides were reproducibly detected in 2-DE with a pH range of 3–10. Acetylcholine, oxotremorine, pilocarpine and nicotine treatment caused 16, 9, 8 and 9 protein spots, respectively, expressed differentially. Four protein spots were identified as destrin, FK506 binding protein 1A (FKBP1A), macrophage migration inhibitory factor (MIF) and profilin-1. Western blotting analyses showed that treatment of the cells with cholinergic agonists significantly decreased the expression of destrin, FKBP1A and MIF, and increased the expression of profilin-1.
A set of proteins differentially expressed in endothelial cells in response to cholinergic agonists may have important implications for the downstream biological effects of NNAS.
PMCID: PMC4155524  PMID: 25088000
non-neuronal acetylcholine system; endothelial cell; cholinergic agonist; destrin; FK506 binding protein 1A; macrophage migration inhibitory factor; profilin-1; proteomics; cardiovascular disease
15.  Molecules and mechanisms controlling the active DNA demethylation of the mammalian zygotic genome 
Protein & Cell  2014;5(11):827-836.
The active DNA demethylation in early embryos is essential for subsequent development. Although the zygotic genome is globally demethylated, the DNA methylation of imprinted regions, part of repeat sequences and some gamete-specific regions are maintained. Recent evidence has shown that multiple proteins and biological pathways participate in the regulation of active DNA demethylation, such as TET proteins, DNA repair pathways and DNA methyltransferases. Here we review the recent understanding regarding proteins associated with active DNA demethylation and the regulatory networks controlling the active DNA demethylation in early embryos.
PMCID: PMC4225482  PMID: 25152302
active DNA demethylation; zygote; 5-hmC; 5-mC; preimplantation embryo; TET proteins
16.  Molecules and mechanisms controlling the active DNA demethylation of the mammalian zygotic genome 
Protein & Cell  2014;5(11):827-836.
The active DNA demethylation in early embryos is essential for subsequent development. Although the zygotic genome is globally demethylated, the DNA methylation of imprinted regions, part of repeat sequences and some gamete-specific regions are maintained. Recent evidence has shown that multiple proteins and biological pathways participate in the regulation of active DNA demethylation, such as TET proteins, DNA repair pathways and DNA methyltransferases. Here we review the recent understanding regarding proteins associated with active DNA demethylation and the regulatory networks controlling the active DNA demethylation in early embryos.
PMCID: PMC4225482  PMID: 25152302
active DNA demethylation; zygote; 5-hmC; 5-mC; preimplantation embryo; TET proteins
17.  Risk factors for bone metastasis in patients with primary lung cancer: study protocol for a systematic review 
BMJ Open  2014;4(7):e005202.
Bone metastasis (BM) in patients with primary lung cancer poses a serious health problem. Numerous risk factors have been hypothesised to predict BM in these patients, but research studies are of mutable quality, and may not be of value in clinical evaluation.
Methods and analysis
We will search a number of electronic databases including PubMed, MEDLINE, Web of Science, EMBASE, the Cochrane Library (Cochrane Database of Systematic Reviews) and the Cochrane Central Register of Controlled Trials (CENTRAL). We will carry out a secondary search for articles from references of included articles (from January 1990 to June 2014). Primary and secondary outcomes will be BM and skeletal-related events information. We will summarise the effect estimates of risk factors and use random-effect models to pool the estimates, if the outcomes and characteristics in studies are comparable. The quality of the study will be assessed using the Newcastle–Ottawa Scale and the Cochrane Collaboration tool.
Trial registration number
PMCID: PMC4120433  PMID: 25059970
18.  Rosiglitazone accentuates the adipogenesis of hemangioma-derived mesenchymal stem cells induced by adipogenic media 
Hemangioma-derived mesenchymal stem cells (Hem-MSCs) expressed PPAR-γ, the key transcription factor in adipogenesis. We supposed that rosiglitazone, the agonist of PPAR-γ, may promote the adipogenesis of Hem-MSCs. In this study, MSCs were isolated from proliferating hemangioma. Four groups were set up, which were Group A (DMEM-LG/10% FBS), Group B (1 μM rosiglitazone + DMEM-LG/10% FBS), Group C (adipogenic media), and Group D (1 μM rosiglitazone + adipogenic media). Cells were cultured in the medium above. On the day 7 and 14, Oil Red “O” staining and Western blot were performed to detect the cytoplasmic lipid and perilipin A in the cells. The results showed that cytoplasmic lipid appeared in Group C and D, and no cytoplasmic lipid in Group A and B on the day 7 and 14. Analysis of Oil Red “O” staining showed the area of staining in Group D was significantly larger than that in Group C. Analysis of western blot showed no expression of perilipin A in Group A and B, and upregulated expression in Groups C and D, with the greater upregulation in Group D. In conclusion, our study demonstrated that rosiglitazone promoted the adipogenesis of Hem-MSCs initiated by adipogenic media via the activation of PPAR-γ pathway. The results may put forward the possibility of treating hemangioma via PPAR-γ pathway.
PMCID: PMC4132137  PMID: 25126173
Hemangioma; mesenchymal stem cells; adipogenesis; rosiglitazone; PPAR-γ
19.  Role of JNK Activation and Mitochondrial Bax Translocation in Allicin-Induced Apoptosis in Human Ovarian Cancer SKOV3 Cells 
Background. Allicin, the major component of freshly crushed garlic, is one of the most biologically active compounds of garlic; it has been reported to induce apoptosis in cancer cells; however, the mechanism by which allicin exerts its apoptotic effects is not fully understood. The aim of the present study was to further elucidate the apoptotic pathways induced by allicin in the human ovarian cancer cell line SKOV3. Methods. Cell proliferation and apoptosis were measured by cell-counting assay and flow cytometry analysis. Activation of the signaling pathway was screened by human phospho-kinase array analysis, and the activated pathway and its related proteins were further confirmed by western blot analysis. Results. Allicin induced SKOV3 cell apoptosis and JNK phosphorylation in a time- and dose-dependent manner, but these were significantly blocked by SP600125 (an inhibitor of JNK). The findings suggest that JNK phosphorylation is related to the action of allicin on SKOV3 cells. Furthermore, JNK activation induced Bcl-2 family activation, triggered mitochondria-mediated signaling pathways, and led to the translocation of a considerable amount of Bax and cytochrome c release. Conclusions. JNK activation and mitochondrial Bax translocation are involved in allicin-induced apoptosis in SKOV3 cells. Our data input new insights to the literature of allicin-induced apoptosis.
PMCID: PMC4109593  PMID: 25097657
20.  Fetal and adult fibroblasts display intrinsic differences in tendon tissue engineering and regeneration 
Scientific Reports  2014;4:5515.
Injured adult tendons do not exhibit optimal healing through a regenerative process, whereas fetal tendons can heal in a regenerative fashion without scar formation. Hence, we compared FFs (mouse fetal fibroblasts) and AFs (mouse adult fibroblasts) as seed cells for the fabrication of scaffold-free engineered tendons. Our results demonstrated that FFs had more potential for tendon tissue engineering, as shown by higher levels of tendon-related gene expression. In the in situ AT injury model, the FFs group also demonstrated much better structural and functional properties after healing, with higher levels of collagen deposition and better microstructure repair. Moreover, fetal fibroblasts could increase the recruitment of fibroblast-like cells and reduce the infiltration of inflammatory cells to the injury site during the regeneration process. Our results suggest that the underlying mechanisms of better regeneration with FFs should be elucidated and be used to enhance adult tendon healing. This may assist in the development of future strategies to treat tendon injuries.
PMCID: PMC4080701  PMID: 24992450
21.  Regulation of the SK3 channel by MicroRNA-499 - potential role in atrial fibrillation 
MicroRNAs are important regulators of gene expression, including those involving electrical remodeling in atrial fibrillation (AF). Recently, KCNN3, the gene that encodes the small conductance calcium-activated potassium channel 3 (SK3), was found to be strongly associated with AF.
This study sought to evaluate the changes in atrial myocardial microRNAs in patients with permanent AF and to determine the role of microRNA on the regulation of cardiac SK3 expression.
Atrial tissue obtained during cardiac surgery from patients (4 sinus rhythm and 4 permanent AF) was analyzed by microRNA arrays. Potential targets of microRNAs were predicted by software programs. The effects of specific microRNAs on target gene expression were evaluated in HL-1 cells from a continuously proliferating mouse hyperplastic atrial cardiomyocyte cell line. Interactions between microRNAs and targets were further evaluated by luciferase reporter assay and by Argonaute pull-down assay.
Twenty one microRNAs showed significant, greater than two-fold changes in AF. miR-499 was upregulated by 2.33 fold (P<0.01) in AF atria, whereas SK3 protein expression was down-regulated by 46% (P<0.05). Transfection of miR-499 mimic in HL-1 cells resulted in the downregulation of SK3 protein expression, while that of miR-499 inhibitor upregulated SK3 expression. Binding of miR-499 to the 3′UTR of KCNN3 was confirmed by luciferase reporter assay and by the enhanced presence of SK3 mRNA in Argonaute pulled-down microRNA-induced silencing complexes (mRISC) after transfection with miR-499.
Atrial miRNA-499 is significantly upregulated in AF, leading to SK3 downregulation and possibly contributing to the electrical remodeling in AF.
PMCID: PMC3710704  PMID: 23499625
atrial fibrillation; microRNA; SK3 channel; electrical remodeling; small-conductance calcium-activated potassium channel
22.  Is right ventricular mid-septal pacing superior to apical pacing in patients with high degree atrio-ventricular block and moderately depressed left ventricular function?*  
Objective: We are aimed to investigate whether right ventricular mid-septal pacing (RVMSP) is superior to conventional right ventricular apical pacing (RVAP) in improving clinical functional capacity and left ventricular ejection fraction (LVEF) for patients with high-degree atrio-ventricular block and moderately depressed left ventricle (LV) function. Methods: Ninety-two patients with high-degree atrio-ventricular block and moderately reduced LVEF (ranging from 35% to 50%) were randomly allocated to RVMSP (n=45) and RVAP (n=47). New York Heart Association (NYHA) functional class, echocardiographic LVEF, and distance during a 6-min walk test (6MWT) were determined at 18 months after pacemaker implantation. Serum levels of N-terminal pro-brain natriuretic peptide (NT-proBNP) were measured using an enzyme-linked immunosorbent assay (ELISA) kit. Results: Compared with baseline, NYHA functional class remained unchanged at 18 months, distance during 6MWT (485 m vs. 517 m) and LVEF (36.7% vs. 41.8%) were increased, but BNP levels were reduced (2352 pg/ml vs. 710 pg/ml) in the RVMSP group compared with those in the RVAP group, especially in patients with LVEF 35%–40% (for all comparisons, P<0.05). However, clinical function capacity and LV function measurements were not significantly changed in patients with RVAP, despite the pacing measurements being similar in both groups, such as R-wave amplitude and capture threshold. Conclusions: RVMSP provides a better clinical utility, compared with RVAP, in patients with high-degree atrioventricular block and moderately depressed LV function whose LVEF levels ranged from 35% to 40%.
PMCID: PMC4116854  PMID: 24903987
Mid-septal pacing; Apical pacing; Impaired heart function
23.  Genetically shaping morphology of the filamentous fungus Aspergillus glaucus for production of antitumor polyketide aspergiolide A 
For filamentous fungi, the basic growth unit of hyphae usually makes it sensitive to shear stress which is generated from mechanical force and dynamic fluid in bioreactor, and it severely decreases microbial productions. The conventional strategies against shear-sensitive conundrum in fungal fermentation usually focus on adapting agitation, impeller type and bioreactor configuration, which brings high cost and tough work in industry. This study aims to genetically shape shear resistant morphology of shear-sensitive filamentous fungus Aspergillus glaucus to make it adapt to bioreactor so as to establish an efficient fermentation process.
Hyphal morphology shaping by modifying polarized growth genes of A. glaucus was applied to reduce its shear-sensitivity and enhance aspergiolide A production. Degenerate PCR and genome walking were used to obtain polarized growth genes AgkipA and AgteaR, followed by construction of gene-deficient mutants by homologous integration of double crossover. Deletion of both genes caused meandering hyphae, for which, ΔAgkipA led to small but intense curves comparing with ΔAgteaR by morphology analysis. The germination of a second germ tube from conidiospore of the mutants became random while colony growth and development almost maintained the same. Morphology of ΔAgkipA and ΔAgteaR mutants turned to be compact pellet and loose clump in liquid culture, respectively. The curved hyphae of both mutants showed no remarkably resistant to glass bead grinding comparing with the wild type strain. However, they generated greatly different broth rheology which further caused growth and metabolism variations in bioreactor fermentations. By forming pellets, the ΔAgkipA mutant created a tank environment with low-viscosity, low shear stress and high dissolved oxygen tension, leading to high production of aspergiolide A (121.7 ± 2.3 mg/L), which was 82.2% higher than the wild type.
A new strategy for shaping fungal morphology by modifying polarized growth genes was applied in submerged fermentation in bioreactor. This work provides useful information of shaping fungal morphology for submerged fermentation by genetically modification, which could be valuable for morphology improvement of industrial filamentous fungi.
PMCID: PMC4039328  PMID: 24886193
Filamentous fungi; Aspergillus glaucus; Genetically morphology shaping; Shear stress; Aspergiolide A
24.  PDGFR-β (+) perivascular cells from infantile hemangioma display the features of mesenchymal stem cells and show stronger adipogenic potential in vitro and in vivo  
Infantile hemangioma, a common benign tumor of infancy, grows quickly in the first year of life, and then regresses slowly to fibrofatty tissue in childhood. The accumulation of fibrofatty tissue in hemangioma involution indicates adipogenesis during this period. Perivascular cells (PCs) from multiple organs display multi-lineage differentiation, including adipogenesis. So we supposed that PCs in hemangioma may contribute to the adipogenesis in the involution. In this study, PDGFR-β (+) PCs was isolated from hemangioma tissue (hemangioma-derived perivascular cells, Hem-PCs) by fluorescence-activated cell sorter. In vitro, Hem-PCs showed fibroblast-like morphology. Immunofluorescence staining and flow cytometry showed Hem-PCs expressed MSCs markers CD105, CD90, CD29 and vimentin, pericyte markers α-SMA and PDGFR-β, stem cell marker CD133, and the adipogenic transcription factor PPAR-γ, but not hematopoietic/endothelial markers CD45, CD34, CD31, and flt-1. In vitro inductions confirmed multi-lineage differentiation of Hem-PCs, especially strong adipogenic potential. Then a murine model was established to observe in vivo differentiation of Hem-PCs by subcutaneous injection of cells/Matrigel compound into nude mice. The results showed Hem-PCs differentiated into adipocytes in vivo. To the best of our knowledge, this is the first study reporting the isolation of multipotential PDGFR-β (+) PCs from hemangioma, and observing their adipogenic differentiation in vivo. PCs may be the cellular basis of adipogenesis in hemangioma involution, and may be the target cells of adipogenic induction to promote hemangioma involution.
PMCID: PMC4097281  PMID: 25031705
Hemangioma; perivascular cells; mesenchymal stem cells; adipogenesis
25.  Glycation of Apoprotein A-I Is Associated With Coronary Artery Plaque Progression in Type 2 Diabetic Patients 
Diabetes Care  2013;36(5):1312-1320.
To investigate whether glycation level of apoprotein (apo)A-I is associated with coronary artery disease (CAD) and plaque progression in patients with type 2 diabetes.
Among 375 consecutive type 2 diabetic patients undergoing quantitative coronary angiography (QCA) and intravascular ultrasound (IVUS), 82 patients with nonsignificant stenosis (luminal diameter narrowing <30% [group I]) and 190 patients with significant CAD (luminal diameter stenosis ≥70% [group II]) were included for analysis of apoA-I glycation level and serum activity of lecithin: cholesterol acyltransferase (LCAT). The control group had 136 healthy subjects. At the 1-year follow-up, angiography and IVUS were repeated mainly in group II patients for plaque progression assessment.
Relative intensity of apoA-I glycation by densitometry was increased, and serum LCAT activity was decreased stepwise across groups control, I, and II. These two measurements were associated with the number of diseased coronary arteries and extent index in group II. During 1-year follow-up, QCA detected 45 patients with plaque progression in 159 subjects, and IVUS found 38 patients with plaque progression in 127 subjects. Baseline relative intensity of apoA-I glycation was significantly increased in patients with plaque progression compared with those without, with values associated with changes in QCA and IVUS measurements. Multivariable regression analysis revealed that baseline relative intensity of apoA-I glycation was an independent determinant of CAD and plaque progression in type 2 diabetic patients.
ApoA-I glycation level is associated with the severity of CAD and coronary artery plaque progression in type 2 diabetic patients.
PMCID: PMC3631856  PMID: 23230102

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