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1.  Anti-Inflammatory Effects of TRAF-Interacting Protein in Rheumatoid Arthritis Fibroblast-Like Synoviocytes 
Mediators of Inflammation  2016;2016:3906108.
Rheumatoid arthritis (RA) is a chronic systemic inflammatory disease characterized by inflammatory cell infiltration, synovial inflammation, and cartilage destruction. Proliferative fibroblast-like synoviocytes (FLS) play crucial roles in both propagation of inflammation and joint damage because of their production of great amount of proinflammatory cytokines and proteolytic enzymes. In this study, we investigate the role of TRAF-interacting protein (TRIP) in regulating inflammatory process in RA-FLS. TRIP expression was attenuated in RA-FLS compared with osteoarthritis- (OA-) FLS. Overexpression of TRIP significantly inhibited the activation of NF-κB signaling and decreased the production of proinflammatory cytokines and matrix metalloproteinases (MMPs) in TNFα-stimulated RA-FLS. Furthermore, TRIP was found to interact with transforming growth factor β-activated kinase 1 (TAK1) and promoting K48-linked polyubiquitination of TAK1 in RA-FLS. Our results demonstrate that TRIP has anti-inflammatory effects on RA-FLS and suggest TRIP as a potential therapeutic target for human RA.
doi:10.1155/2016/3906108
PMCID: PMC5101391  PMID: 27847407
2.  Taurine promotes cognitive function in prenatally stressed juvenile rats via activating the Akt-CREB-PGC1α pathway 
Redox Biology  2016;10:179-190.
Substantial evidence has shown that the oxidative damage to hippocampal neurons is associated with the cognitive impairment induced by adverse stimuli during gestation named prenatal stress (PS). Taurine, a conditionally essential amino acid, possesses multiple roles in the brain as a neuromodulator or antioxidant. In this study, to explore the roles of taurine in PS-induced learning and memory impairment, prenatal restraint stress was set up and Morris water maze (MWM) was employed for testing the cognitive function in the one-month-old rat offspring. The mitochondrial reactive oxygen species (ROS) level,mitochondrial membrane potential (MMP), ATP and cytochrome c oxidase (CcO) activity and apoptosis-related proteins in the hippocampus were detected. The activity of the Akt-cyclic AMP response element-binding protein (CREB)-peroxisome proliferator-activated receptor–γ coactivator-1α (PGC1α) pathway in the hippocampus was measured. The results showed that high dosage of taurine administration in the early postnatal period attenuated impairment of spatial learning and memory induced by PS. Meanwhile, taurine administration diminished the increase in mitochondrial ROS, and recovered the reduction of MMP, ATP level and the activities of CcO, superoxide dismutase 2 (SOD2) and catalase induced by PS in the hippocampus. In addition, taurine administration recovered PS-suppressed SOD2 expression level. Taurine administration blocked PS-induced decrease in the ratio of Bcl-2/Bax and increase in the ratio of cleaved caspase-3/full-length caspase-3. Notably, taurine inhibited PS-decreased phosphorylation of Akt (pAkt) and phosphorylation of CREB (pCREB), which consequently enhanced the mRNA and protein levels of PGC1α. Taken together, these results suggest that high dosage of taurine administration during the early postnatal period can significantly improve the cognitive function in prenatally stressed juvenile rats via activating the Akt-CREB-PGC1α pathway. Therefore, taurine has therapeutic potential for prenatal stressed offspring rats in future.
Graphical abstract
fx1
Highlights
•Taurine attenuates prenatal stress (PS)-induced cognitive impairment.•Taurine reduces PS-induced neuronal apoptosis and mitochondrial dysfunction.•Taurine maintains the activities of SOD2 and catalase to repress ROS.•Taurine activates PS-suppressed Akt-CREB-PGC1α pathway.
doi:10.1016/j.redox.2016.10.004
PMCID: PMC5072153  PMID: 27768969
Prenatal stress; Hippocampus; Mitochondria; Taurine; Akt-CREB-PGC1α pathway
3.  LC-MS Based Sphingolipidomic Study on A2780 Human Ovarian Cancer Cell Line and its Taxol-resistant Strain 
Scientific Reports  2016;6:34684.
Drug resistance elicited by cancer cells continue to cause huge problems world-wide, for example, tens of thousands of patients are suffering from taxol-resistant human ovarian cancer. However, its biochemical mechanisms remain unclear. Sphingolipid metabolic dysregulation has been increasingly regarded as one of the drug-resistant mechanisms for various cancers, which in turn provides potential targets for overcoming the resistance. In the current study, a well-established LC-MS based sphingolipidomic approach was applied to investigate the sphingolipid metabolism of A2780 and taxol-resistant A2780 (A2780T) human ovarian cancer cell lines. 102 sphingolipids (SPLs) were identified based on accurate mass and characteristic fragment ions, among which 12 species have not been reported previously. 89 were further quantitatively analyzed by using multiple reaction monitoring technique. Multivariate analysis revealed that the levels of 52 sphingolipids significantly altered in A2780T cells comparing to those of A2780 cells. These alterations revealed an overall increase of sphingomyelin levels and significant decrease of ceramides, hexosylceramides and lactosylceramides, which concomitantly indicated a deviated SPL metabolism in A2780T. This is the most comprehensive sphingolipidomic analysis of A2780 and A2780T, which investigated significantly changed sphingolipid profile in taxol-resistant cancer cells. The aberrant sphingolipid metabolism in A2780T could be one of the mechanisms of taxol-resistance.
doi:10.1038/srep34684
PMCID: PMC5050431  PMID: 27703266
4.  PI3K-GLUT4 Signal Pathway Associated with Effects of EX-B3 Electroacupuncture on Hyperglycemia and Insulin Resistance of T2DM Rats 
Objectives. To explore electroacupuncture's (EA's) effects on fasting blood glucose (FBG) and insulin resistance of type 2 diabetic mellitus (T2DM) model rats and give a possible explanation for the effects. Method. It takes high fat diet and intraperitoneal injection of streptozotocin (STZ, 30 mg/kg) for model preparation. Model rats were randomly divided into T2DM Model group, EA weiwanxiashu (EX-B3) group, and sham EA group (n = 12/group). EA (2 Hz continuous wave, 2 mA, 20 min/day, 6 days/week, 4 weeks) was applied as intervention. FBG, area under curve (AUC) of oral glucose tolerance test (OGTT), insulin resistance index (HOMA-IR), pancreatic B cell function index (HOMA-B), skeletal muscle phosphorylated phosphatidylinositol-3-kinase (PI3K), glucose transporter 4 (GLUT4), and membrane GLUT4 protein expression were measured. Results. EA weiwanxiashu (EX-B3) can greatly upregulate model rat's significantly reduced skeletal muscle PI3K (Y607) and membrane GLUT4 protein expression (P < 0.01), effectively reducing model rats' FBG and AUC of OGTT (P < 0.01). The effects are far superior to sham EA group. Conclusion. EA weiwanxiashu (EX-B3) can upregulate skeletal muscle phosphorylated PI3K protein expression, to stimulate membrane translocation of GLUT4 and thereby increase skeletal muscle glucose intake to treat T2DM.
doi:10.1155/2016/7914387
PMCID: PMC5021857  PMID: 27656242
5.  Efficacy and safety of olanzapine for treatment of patients with bipolar depression: Chinese subpopulation analysis of a double-blind, randomized, placebo-controlled study 
Background
Depression in bipolar I disorder responds to the atypical antipsychotic olanzapine. This subpopulation analysis assessed whether olanzapine is superior to placebo specifically in the treatment of Chinese patients with bipolar I depression.
Methods
This was a subpopulation analysis of a 6-week, multicenter, double-blind, parallel, randomized, placebo-controlled trial among 12 Chinese study centers. Eligible inpatients and outpatients were randomized to olanzapine (5 to 20 mg/day) or placebo. Patients were primarily assessed by the Montgomery-Åsberg Depression Rating Scale total score. Secondary assessments used a range of other efficacy and safety measures. This subpopulation analysis was underpowered to show statistically significant differences between treatment groups.
Results
In total, 210 patients (mean age 32.9 years at baseline, 54.3% females) were random-ized. Similar proportions of patients treated with olanzapine (75.0%) and placebo (72.9%) completed the double-blind phase. Baseline-to-endpoint least-squares mean ± standard error decrease in the Montgomery-Åsberg Depression Rating Scale total score in the olanzapine group (−13.55±0.80) was similar to that noted in the parent trial (−13.82±0.65). However, the difference between olanzapine and placebo groups was not statistically significant (P=0.44); this finding was also true for the secondary efficacy measures. A post hoc analysis showed a greater emergence of mania in the placebo group, which likely reduced the treatment difference between olanzapine and placebo in the primary efficacy measure. Safety data were consistent with the known safety profile of olanzapine, including a higher incidence of weight gain (≥7%) in the olanzapine group (24.1% vs 1.4%, P<0.001).
Conclusion
Olanzapine provides similar improvement in depression among Chinese and non-Chinese bipolar I patients. The lack of a statistically significant difference between the olanzapine and placebo groups in this Chinese subpopulation analysis may relate to an a priori lack of study power, and underestimation of the effect of olanzapine because of a greater emergence of mania in placebo-treated patients and missing data associated with a high early discontinuation rate.
Video abstract
doi:10.2147/NDT.S98927
PMCID: PMC5003102  PMID: 27601902
bipolar disorder; Chinese; depression; olanzapine
6.  Prevalence and its risk factors for low back pain among operation and maintenance personnel in wind farms 
Background
With the increasingly severe energy shortage and climate change problems, developing wind power has become a key energy development strategy and an inevitable choice to protect the ecological environment worldwide. The purpose of this study was to investigate the prevalence of low back pain (LBP) and analyze its risk factors among operation and maintenance personnel in wind farms (OMPWF).
Methods
A cross-sectional survey of 151 OMPWF was performed, and a comprehensive questionnaire, which was modified and combined from Nordic Musculoskeletal Questionnaires (NMQ), Washington State Ergonomics Tool (WSET) and Syndrome Checklist-90(SCL-90) was used to assess the prevalence and risk factors of LBP among OMPWF.
Results
The prevalence of LBP was 88.74 % (134/151) among OMPWF. The multivariable model highlighted four related factors: backrest, somatization, squatting and lifting objects weighing more than 10 lb more than twice per minute.
Conclusions
The prevalence of LBP among OMPWF appears to be high and highlights a major occupational health concern.
doi:10.1186/s12891-016-1180-y
PMCID: PMC4962352  PMID: 27461535
Wind farms; Low back pain; Risk factors; Ergonomic
7.  Discovery of Biaryl Amides as Potent, Orally Bioavailable, and CNS Penetrant RORγt Inhibitors 
ACS Medicinal Chemistry Letters  2015;6(7):787-792.
A novel series of biaryl amides was identified as RORγt inhibitors through core replacement of a starting hit 1. Structure–activity relationship exploration on the biaryl moiety led to discovery of potent RORγt inhibitors with good oral bioavailability and CNS penetration. Compounds 9a and 9g demonstrated excellent in vivo efficacy in EAE mice dose dependently with once daily oral administration.
doi:10.1021/acsmedchemlett.5b00122
PMCID: PMC4499822  PMID: 26191367
RORγt inhibitor; Th17 cell differentiation; biaryl amides; EAE; multiple sclerosis
8.  Dedicator of Cytokinesis 2, A Novel Regulator for Smooth Muscle Phenotypic Modulation and Vascular Remodeling 
Circulation research  2015;116(10):e71-e80.
Rationale
Vascular smooth muscle cell (SMC) phenotypic modulation and vascular remodeling contributes to the development of a number of vascular disorders such as restenosis after angioplasty, transplant vasculopathy, and atherosclerosis. The mechanisms underlying these processes, however, remain largely unknown.
Objective
The objective of this study is to determine the role of dedicator of cytokinesis 2 (DOCK2) in SMC phenotypic modulation and vascular remodeling.
Methods and Results
Platelet-derived growth factor-BB (PDGF-BB) induced DOCK2 expression while modulating SMC phenotype. DOCK2 deficiency diminishes PDGF-BB or serum-induced down regulation of SMC markers. Conversely, DOCK2 overexpression inhibits SMC marker expression in primary cultured SMC. Mechanistically, DOCK2 inhibits myocardin expression, blocks SRF nuclear location, attenuates myocardin binding to SRF, and thus attenuates myocardin-induced smooth muscle marker promoter activity. Moreover, DOCK2 and Kruppel-like factor 4 cooperatively inhibit myocardin-SRF interaction. In a rat carotid artery balloon-injury model, DOCK2 is induced in media layer SMC initially and neointima SMC subsequently following vascular injury. Knockdown of DOCK2 dramatically inhibits the neointima formation by 60%. Most importantly, knockout of DOCK2 in mice markedly blocks ligation-induced intimal hyperplasia while restoring SMC contractile protein expression.
Conclusions
Our studies identified DOCK2 as a novel regulator for SMC phenotypic modulation and vascular lesion formation following vascular injury. Therefore, targeting DOCK2 may be a potential therapeutic strategy for the prevention of vascular remodeling in proliferative vascular diseases.
doi:10.1161/CIRCRESAHA.116.305863
PMCID: PMC4426039  PMID: 25788409
Dedicator of cytokinesis 2; vascular smooth muscle cells; migration; proliferation; vascular remodeling
9.  Dual effects of VEGF-B on activating cardiomyocytes and cardiac stem cells to protect the heart against short- and long-term ischemia–reperfusion injury 
Aims
To investigate whether vascular endothelial growth factor B (VEGF-B) improves myocardial survival and cardiac stem cell (CSC) function in the ischemia–reperfusion (I/R) heart and promotes CSC mobilization and angiogenesis.
Methods and results
One hour after myocardial ischemia and infarction, rats were treated with recombinant human VEGF-B protein following 24 h or 7 days of myocardial reperfusion. Twenty-four hours after myocardial I/R, VEGF-B increased pAkt and Bcl-2 levels, reduced p-p38MAPK, LC3-II/I, beclin-1, CK, CK-MB and cTnt levels, triggered cardiomyocyte protection against I/R-induced autophagy and apoptosis, and contributed to the decrease of infarction size and the improvement of heart function during I/R. Simultaneously, an in vitro hypoxia-reoxygenation (H/R)-induced H9c2 cardiomyocyte injury model was used to mimic I/R injury model in vivo; in this model, VEGF-B decreased LDH release, blocked H/R-induced apoptosis by inhibiting cell autophagy, and these special effects could be abolished by the autophagy inducer, rapamycin. Mechanistically, VEGF-B markedly activated the Akt signaling pathway while slightly inhibiting p38MAPK, leading to the blockade of cell autophagy and thus protecting cardiomyocyte from H/R-induced activation of the intrinsic apoptotic pathway. Seven days after I/R, VEGF-B induced the expression of SDF-1α and HGF, resulting in the massive mobilization and homing of c-Kit positive cells, triggering further angiogenesis and vasculogenesis in the infracted heart and contributing to the improvement of I/R heart function.
Conclusion
VEGF-B could contribute to a favorable short- and long-term prognosis for I/R via the dual manipulation of cardiomyocytes and CSCs.
Electronic supplementary material
The online version of this article (doi:10.1186/s12967-016-0847-3) contains supplementary material, which is available to authorized users.
doi:10.1186/s12967-016-0847-3
PMCID: PMC4855341  PMID: 27146579
Cardiac stem cells; VEGF-B; Mobilization; Apoptosis; Angiogenesis
10.  Quantitative profiling of sphingolipids in wild Cordyceps and its mycelia by using UHPLC-MS 
Scientific Reports  2016;6:20870.
In the present study, 101 sphingolipids in wild Cordyceps and its five mycelia were quantitatively profiled by using a fully validated UHPLC-MS method. The results revealed that a general rank order for the abundance of different classes of sphingolipids in wild Cordyceps and its mycelia is sphingoid bases/ceramides > phosphosphingolipids > glycosphingolipids. However, remarkable sphingolipid differences between wild Cordyceps and its mycelia were observed. One is that sphingoid base is the dominant sphingolipid in wild Cordyceps, whereas ceramide is the major sphingolipid in mycelia. Another difference is that the abundance of sphingomyelins in wild Cordyceps is almost 10-folds higher than those in most mycelia. The third one is that mycelia contain more inositol phosphorylceramides and glycosphingolipids than wild Cordyceps. Multivariate analysis was further employed to visualize the difference among wild Cordyceps and different mycelia, leading to the identification of respective sphingolipids as potential chemical markers for the differentiation of wild Cordyceps and its related mycelia. This study represents the first report on the quantitative profiling of sphingolipids in wild Cordyceps and its related mycelia, which provided comprehensive chemical evidence for the quality control and rational utilization of wild Cordyceps and its mycelia.
doi:10.1038/srep20870
PMCID: PMC4751452  PMID: 26868933
11.  Association of Single Nucleotide Polymorphisms in Toll-like Receptors with Acinetobacter baumanii Infectionin a Chinese Population 
Background:
During recent years, infection of Acinetobacter baumanii showed a rapid growth in hospitals and community. Toll-like receptors (TLRs) are the most important pattern recognition receptors, which play a critical role during recognizing invading pathogens by the natural immune system. Our objective was to determine the associations of TLRs polymorphisms with the susceptibility to A. baumanii infection in a Chinese population.
Methods:
We carried out a case-control study, genotyping 13 polymorphisms of TLR-2, TLR-4, TLR-5 and TLR-9 genes on 423 A. baumanii-infected patients and 385 exposed controls. Thirteen SNPs at the TLR-2 (rs3804099, rs7656411 and rs76112010), TLR-4 (rs1927914, rs10759932 and rs11536889), TLR-5 (rs1341987, rs1640827, rs1861172, rs2241097, rs5744174 and rs17163737) and TLR9 (rs187084) genes were analyzed. SNP genotyping was performed using an improved multiplex ligation detection reaction (iMLDR) technique.
Results:
The SNP of TLR-9, rs187084, was related to A. baumanii-infection significantly under recessive model (G/G, to A/A + G/A, P = 0.0064, OR = 0.59, 95% CI = 0.40–0.86) after adjustment with age. Besides, the haplotype GCG of TLR-4 was significantly associated with A. baumanii infection (P = 0.027).
Conclusion:
TLR-4 and TLR-9 may be related to the susceptibility to A. baumanii infection in a Chinese population.
PMCID: PMC4822389  PMID: 27057517
Acinetobacter baumanii; Gene polymorphisms; Toll-like receptors
12.  Genome-Wide Identification and Expression Analysis of the Tubby-Like Protein Family in the Malus domestica Genome 
Tubby-like proteins (TLPs), which have a highly conserved β barrel tubby domain, have been found to be associated with some animal-specific characteristics. In the plant kingdom, more than 10 TLP family members were identified in Arabidopsis, rice and maize, and they were found to be involved in responses to stress. The publication of the apple genome makes it feasible to systematically study the TLP family in apple. In this investigation, nine TLP encoding genes (TLPs for short) were identified. When combined with the TLPs from other plant species, the TLPs were divided into three groups (group A, B, and C). Most plant TLP members in group A contained an additional F-box domain at the N-terminus. However, no common domain was identified other than tubby domain either in group B or in group C. An analysis of the tubby domains of MdTLPs identified three types of conserved motifs. Motif 1 and 2, the signature motifs in the confirmed TLPs, were always present in MdTLPs, while motif 3 was absent from group B. Homology modeling indicated that the tubby domain of most MdTLPs had a closed β barrel, as in animal tubby domains. Expression profiling revealed that the MdTLP genes were expressed in multiple organs and were abundant in roots, stems, and leaves but low in flowers. An analysis of cis-acting elements showed that elements related to the stress response were prevalent in the promoter sequences of MdTLPs. Expression profiling by qRT-PCR indicated that almost all MdTLPs were up-regulated at some extent under abiotic stress, exogenous ABA and H2O2 treatments in leaves and roots, though different MdTLP members exhibited differently in leaves and roots. The results and information above may provide a basis for further investigation of TLP function in plants.
doi:10.3389/fpls.2016.01693
PMCID: PMC5107566  PMID: 27895653
tubby-like protein; bioinformatics; signature motifs; abiotic stress; apple
13.  Synergistic combination of microtubule targeting anticancer fludelone with cytoprotective panaxytriol derived from panax ginseng against MX-1 cells in vitro: experimental design and data analysis using the combination index method 
This brief article focuses on two aims: i) To investigate the in vitro pharmaco-dynamic interactions of combining synthetic potent microtubule targeting anticancer agent, Fludelone (FD) with cyto-protective agent, Panaxytriol (PXT) derived from Panax ginseng, and ii) To illustrate step-by-step operation for conducting two-drug combination in vitro using the combination index method, in terms of experimental design, data acquisition, computerized simulation and data interpretation. The Chou-Talalay method for drug combination is based on the median-effect equation, which provides the theoretical basis for the combination index (CI)-isobologram equation that allows quantitative determination of drug interactions, where CI<1, =1, and >1 indicates synergism, additive effect and antagonism, respectively. Based on these algorithms, computer software, CompySyn, is used for determining synergism and antagonism at all doses or effect levels simulated automatically. The use of Chou-Talalay’s CI method in quantifying synergism or antagonism is increasing steadily during the past two decades, however, confusing questions and pitfalls were still frequently raised by insufficient understanding of the theory, especially reflected when researchers trying to use the computerized software to design and conduct experiments. In order to specifically address the confusions and to illustrate the practical features of this method, in this paper, a selected example is given based on our unpublished data regarding the combinational pharmacologic interactions of FD and PXT against the growth of breast cancer cell line MX-1. The step-by-step operation from experimental design to the real data analysis is illustrated. The results indicated that FD and PXT combination in vitro exerted synergistic effect when cell growth inhibition was greater than 45%, with CI ranged 0.836-0.609 for the fractional inhibition of Fa=0.50~0.90, as shown by the Fa-CI plot and by the isobologram. Thus, quantitative conclusion of synergism is obtained using the Chou-Talalay CI method, under the well-defined simple conditions for the FD and PXT combinations in vitro.
PMCID: PMC4759401  PMID: 27073727
Fludelone; panaxytriol; synergism quantification; combination index; compusyn
14.  Early-Life Exposure to Clostridium leptum Causes Pulmonary Immunosuppression 
PLoS ONE  2015;10(11):e0141717.
Introduction
Low Clostridium leptum levels are a risk factor for the development of asthma. C. leptum deficiency exacerbates asthma; however, the impact of early-life C. leptum exposure on cesarean-delivered mice remains unclear. This study is to determine the effects of early-life C. leptum exposure on asthma development in infant mice.
Methods
We exposed infant mice to C. leptum (fed-CL) and then induced asthma using the allergen ovalbumin (OVA).
Results
Fed-CL increased regulatory T (Treg) cells in cesarean-delivered mice compared with vaginally delivered mice. Compared with OVA-exposed mice, mice exposed to C. leptum + OVA did not develop the typical asthma phenotype, which includes airway hyper-responsiveness, cell infiltration, and T helper cell subset (Th1, Th2, Th9, Th17) inflammation. Early-life C. leptum exposure induced an immunosuppressive environment in the lung concurrent with increased Treg cells, resulting in the inhibition of Th1, Th2, Th9, and Th17 cell responses.
Conclusion
These findings demonstrate a mechanism whereby C. leptum exposure modulates adaptive immunity and leads to failure to develop asthma upon OVA sensitization later in life.
doi:10.1371/journal.pone.0141717
PMCID: PMC4643994  PMID: 26565810
15.  CCL18 from tumor-associated macrophages promotes angiogenesis in breast cancer 
Oncotarget  2015;6(33):34758-34773.
The infiltration of tumor-associated macrophages (TAMs) is associated with extensive angiogenesis, which contributes to a poor prognosis in breast cancer. However, anti-angiogenic therapy with VEGF-specific monotherapy has been unsuccessful in treating breast cancer, and the molecular mechanisms associated with chemoresistance remain unclear. Here, we investigated whether CCL18, a chemokine produced by TAMs, can stimulate angiogenesis in breast cancer, as well as the underlying mechanisms. Double immunohistochemical staining for CCL18 and CD34/CD31/vWF was performed in 80 breast cancer samples to study the correlation between CCL18+ TAMs and microvascular density (MVD). Cocultures of TAMs with human umbilical vein endothelial cells (HUVECs) were used to model the inflammatory microenvironment, and CCL18-induced angiogenesis was evaluated both in vitro and in vivo. We demonstrated that CCL18+ TAM infiltration positively associated with MVD in breast cancer samples, which was correlated with tumor metastasis and poor prognosis. We confirmed, both in vitro and in vivo, that CCL18 and VEGF synergistically promoted endothelial cell migration and angiogenesis. Conversely, blocking CCL18 or VEGF with neutralizing antibodies synergistically inhibited the promigratory effects of TAMs. Silencing PITPNM3, a putative CCL18 receptor, on the surface of HUVECs abrogated CCL18-mediated promigration and the enhancement of HUVEC tube formation, independently of VEGFR signaling. Moreover, CCL18 exposure induced the endothelial-mesenchymal transformation and activated ERK and Akt/GSK-3β/Snail signaling in HUVECs, thereby contributing to its pro-angiogenic effects. In conclusion, our findings suggest that CCL18 released from TAMs promotes angiogenesis and tumor progression in breast cancer; thus, CCL18 may serve as a novel target for anti-angiogenic therapies.
PMCID: PMC4741488  PMID: 26416449
breast cancer; tumor-associated macrophage; angiogenesis; CCL18; PITPNM3
16.  PEP-1-SOD1 fusion proteins block cardiac myofibroblast activation and angiotensin II-induced collagen production 
Background
Oxidative stress is closely associated with cardiac fibrosis. However, the effect of copper, zinc-superoxide dismutase (SOD1) as a therapeutic agent is limited due to the insufficient transduction. This study was aimed to investigate the effect of PEP-1-SOD1 fusion protein on angiotensin II (ANG II)-induced collagen metabolism in rat cardiac myofibroblasts (MCFs).
Methods
MCFs were pretreated with SOD1 or PEP-1-SOD1 fusion protein for 2 h followed by incubation with ANG II for 24 h. Cell proliferation was measured by Cell Counting Kit-8. Superoxide anion productions were detected by both fluorescent microscopy and Flow Cytometry. MMP-1 and TIMP-1 were determined by ELISA. Intracellular MDA content and SOD activity were examined by commercial assay kits. Protein expression was analyzed by western blotting.
Results
PEP-1-SOD1 fusion protein efficiently transduced into MCF, scavenged intracellular O2−, decreased intracellular MDA content, increased SOD activity, suppressed ANG II-induced proliferation, reduced expression of TGF-β1, α-SMA, collagen type I and III, restored MMP-1 secretion, and attenuated TIMP-1 secretion.
Conclusion
PEP-1-SOD1 suppressed MCF proliferation and differentiation and reduced production of collagen type I and III. Therefore, PEP-1-SOD1 fusion protein may be a potential novel therapeutic agent for cardiac fibrosis.
Electronic supplementary material
The online version of this article (doi:10.1186/s12872-015-0103-4) contains supplementary material, which is available to authorized users.
doi:10.1186/s12872-015-0103-4
PMCID: PMC4597385  PMID: 26446519
Cell-penetrating peptide; Copper; Zinc-superoxide dismutase; Cardiac myofibroblasts; Collagen
17.  PDGF upregulates CLEC-2 to induce T regulatory cells 
Oncotarget  2015;6(30):28621-28632.
The effect of platelet derived growth factor (PDGF) on immune cells is not elucidated. Here, we demonstrate PDGF inhibited the maturation of human DCs and induced IL-10 secretion. Culture of PDGF-DCs with T cells induced the polarization of T cells towards FoxP3 expressing T regulatory cells that secreted IL-10. Gene expression studies revealed that PDGF induced the expression of C-type lectin like receptor member 2, (CLEC-2) receptor on DCs. Furthermore, DCs transfected with CLEC-2 induced T regulatory cells in DC-T cell co-culture. CLEC-2 is naturally expressed on platelets. Therefore, to confirm whether CLEC-2 is responsible for inducing the T regulatory cells, T cells were cultured with either CLEC-2 expressing platelets or soluble CLEC-2. Both conditions resulted in the induction of regulatory T cells. The generation of T regulatory cells was probably due to the binding of CLEC-2 with its ligand podoplanin on T cells, since crosslinking of podoplanin on the T cells also resulted in the induction of T regulatory cells. These data demonstrate that PDGF upregulates the expression of CLEC-2 on cells to induce T regulatory cells.
PMCID: PMC4745681  PMID: 26416420
Clec-2; dendritic cell; platelets; T regulatory cells; PDGF; podoplanin; Immunology and Microbiology Section; Immune response; Immunity
18.  A Novel Multilayered RFID Tagged Cargo Integrity Assurance Scheme 
Sensors (Basel, Switzerland)  2015;15(10):27087-27115.
To minimize cargo theft during transport, mobile radio frequency identification (RFID) grouping proof methods are generally employed to ensure the integrity of entire cargo loads. However, conventional grouping proofs cannot simultaneously generate grouping proofs for a specific group of RFID tags. The most serious problem of these methods is that nonexistent tags are included in the grouping proofs because of the considerable amount of time it takes to scan a high number of tags. Thus, applying grouping proof methods in the current logistics industry is difficult. To solve this problem, this paper proposes a method for generating multilayered offline grouping proofs. The proposed method provides tag anonymity; moreover, resolving disputes between recipients and transporters over the integrity of cargo deliveries can be expedited by generating grouping proofs and automatically authenticating the consistency between the receipt proof and pick proof. The proposed method can also protect against replay attacks, multi-session attacks, and concurrency attacks. Finally, experimental results verify that, compared with other methods for generating grouping proofs, the proposed method can efficiently generate offline grouping proofs involving several parties in a supply chain using mobile RFID.
doi:10.3390/s151027087
PMCID: PMC4634462  PMID: 26512673
radio-frequency identification; multilayered grouping proof; supply chain management; anonymity; multi-session attacks; concurrency attacks
19.  Integrated information storage and transfer with a coherent magnetic device 
Scientific Reports  2015;5:13665.
Quantum systems are inherently dissipation-less, making them excellent candidates even for classical information processing. We propose to use an array of large-spin quantum magnets for realizing a device which has two modes of operation: memory and data-bus. While the weakly interacting low-energy levels are used as memory to store classical information (bits), the high-energy levels strongly interact with neighboring magnets and mediate the spatial movement of information through quantum dynamics. Despite the fact that memory and data-bus require different features, which are usually prerogative of different physical systems – well isolation for the memory cells, and strong interactions for the transmission – our proposal avoids the notorious complexity of hybrid structures. The proposed mechanism can be realized with different setups. We specifically show that molecular magnets, as the most promising technology, can implement hundreds of operations within their coherence time, while adatoms on surfaces probed by a scanning tunneling microscope is a future possibility.
doi:10.1038/srep13665
PMCID: PMC4561894  PMID: 26347152
20.  Andrographolide plays an important role in bleomycin-induced pulmonary fibrosis treatment 
Pulmonary fibrosis (PF) leads to chronic inflammation and accumulation of macrophages, neutrophils, and lymphocytes in the alveoli. The factors involved in the development of PF include reactive oxygen species and tissue remodelling regulators. The present study demonstrates the effect of andrographolide on bleomycin (BLM)-induced PF in Sprague-Dawley rats. We investigated the total bronchoalveolar lavage fluid protein (BALF) and hydroxyproline (HYP) content along with the level of oxidative stress markers like malondialdehyde (MDA) and GSH/GSSG ratio. In addition, the levels of MMP-1 and TIMP-1 were also analysed. The results revealed an increase in BALF protein, HYP, and MDA contents and decrease in GSH/GSSG ratio of the lungs in animals treated with BLM. However, andrographolide treatment caused a reversal of the BLM induced changes after 20 or 40 days. Treatment with andrographolide suppressed oxidative stress with the decrease of MDA and the increase of the GSH/GSSG ratio. Andrographolide also improved the BLM mediated changes in the MMP-1/TIMP-1 ratio. Therefore, andrographolide has a potential therapeutic effect in the prevention of PF.
PMCID: PMC4612832  PMID: 26550147
Hydroxyproline; bronchoalveolar; inflammation; macrophages; lymphocytes
21.  Collapsing focal segmental glomerulosclerosis following long-term treatment with oral ibandronate: case report and review of literature 
BMC Cancer  2015;15:535.
Background
Renal toxicity has been reported with bisphosphonates such as pamidronate and zolidronate but not with ibandronate, in the treatment of breast cancer patients with bone metastasis. One of the patterns of bisphosphonate-induced nephrotoxicity is focal segmental glomerulosclerosis (FSGS) or its morphological variant, collapsing focal segmental glomerulosclerosis (CFSGS).
Case presentation
We describe a breast cancer patient who developed heavy proteinuria (protein/creatinine ratio 9.1) and nephrotic syndrome following treatment with oral ibandronate for 29 months. CFSGS was proven by biopsy. There was no improvement 1 month after ibandronate was discontinued. Prednisone and tacrolimus were started and she experienced a decreased in proteinuria.
Conclusion
In patient who develops ibandronate-associated CFSGS, proteinuria appears to be at least partially reversible with the treatment of prednisone and/or tacrolimus if the syndrome is recognized early and ibandronate is stopped.
doi:10.1186/s12885-015-1536-y
PMCID: PMC4510889  PMID: 26197890
Collapsing glomerulopathy; Focal segmental glomerulosclerosis; Bisphosphonates; Ibandronate
22.  Effect of Huaier on the proliferation and apoptosis of human gastric cancer cells through modulation of the PI3K/AKT signaling pathway 
The aim of the present study was to investigate the effect of Huaier on the proliferation and apoptosis of the MKN45 and SGC7901 gastric cancer cell lines. The MTT assay was used to measure the effects of Huaier on the growth of the cells, while cell cycle distribution and apoptosis levels were analyzed using flow cytometry. Western blotting was used to assess the levels of proteins associated with the apoptotic pathway. It was found that cell survival decreased with the increase in the concentration of Huaier, and the apoptosis rates were increased in a dose-dependent manner both in MKN45 and SGC7901 cells. The number of cells in the G2/M phase in the Huaier-treated groups was increased in a dose-dependent manner compared with that in the control group. Huaier inhibited phosphorylated- (p-)AKT1, phosphatidylinositol 3-kinase (PI3K), pyruvate dehydrogenase kinase isoform 1, p-phosphatidylinositol 3,4,5-trisphosphate 3-phosphatase and dual-specificity protein phosphatase and B-cell lymphoma 2 expression and upregulated cleaved-caspase-9 expression in a dose-dependent manner. In conclusion, Huaier can strongly inhibit gastric cancer cell proliferation by inhibiting cyclin B1 expression, promoting G2/M-phase arrest and modulating the PI3K/AKT signaling pathway, and can induce gastric cancer cell apoptosis by modulating the PI3K/AKT signaling pathway in dose-dependent manner.
doi:10.3892/etm.2015.2600
PMCID: PMC4533155  PMID: 26622467
Huaier; alanine aminotransferase assay; gastric cancer; MKN45; SGC7901; apoptosis
23.  Re-Examining of Moffitt’s Theory of Delinquency through Agent Based Modeling 
PLoS ONE  2015;10(6):e0126752.
Moffitt’s theory of delinquency suggests that at-risk youths can be divided into two groups, the adolescence- limited group and the life-course-persistent group, predetermined at a young age, and social interactions between these two groups become important during the adolescent years. We built an agent-based model based on the microscopic interactions Moffitt described: (i) a maturity gap that dictates (ii) the cost and reward of antisocial behavior, and (iii) agents imitating the antisocial behaviors of others more successful than themselves, to find indeed the two groups emerging in our simulations. Moreover, through an intervention simulation where we moved selected agents from one social network to another, we also found that the social network plays an important role in shaping the life course outcome.
doi:10.1371/journal.pone.0126752
PMCID: PMC4465023  PMID: 26062022
24.  Cordyceps sinensis attenuates renal fibrosis and suppresses BAG3 induction in obstructed rat kidney 
BAG3 regulates a number of cellular processes, including cell proliferation, apoptosis, adhesion and migration, and epithelial-mesenchymal transition (EMT). However, the role of BAG3 in renal tubular EMT and renal interstitial fibrosis remains elusive. This study aimed to examine the dynamic expression of BAG3 during renal fibrosis, and to investigate the efficacy of Cordyceps sinensis (C. sinensis) on renal fibrosis. A rat model of unilateral ureteral obstruction (UUO) was established, and the expression of BAG3 and α-SMA, and the efficacy of C. sinensis on renal fibrosis induced by UUO were examined. The results showed that UUO led to collagen accumulation, which was significantly suppressed by C. sinensis. UUO increased the expression of BAG3 and α-SMA, a mesenchymal marker, while UUO induced BAG3 and α-SMA expression was significantly inhibited by C. sinensis. In addition, immunohistochemical staining demonstrated that BAG3 immunoreactivity was restricted to tubular epithelium. In conclusion, BAG3 is a potential target for the prevention and/or treatment of renal fibrosis, and C. Sinensis is a promising agent for renal fibrosis.
PMCID: PMC4494144  PMID: 26175854
BAG3; Cordyceps sinensis; unilateral ureteral obstruction; renal fibrosis
25.  The mealybug Phenacoccus solenopsis suppresses plant defense responses by manipulating JA-SA crosstalk 
Scientific Reports  2015;5:9354.
Induced plant defenses against herbivores are modulated by jasmonic acid-, salicylic acid-, and ethylene-signaling pathways. Although there is evidence that some pathogens suppress plant defenses by interfering with the crosstalk between different signaling pathways, such evidence is scarce for herbivores. Here, we demonstrate that the mealybug Phenacoccus solenopsis suppresses the induced defenses in tomato. We found that exogenous JA, but not SA, significantly decreased mealybug feeding time and reduced nymphal performance. In addition, constitutive activation of JA signaling in 35s::prosys plants reduced mealybug survival. These data indicate that the JA signaling pathway plays a key role in mediating the defense responses against P. solenopsis. We also found that mealybug feeding decreased JA production and JA-dependent defense gene expression, but increased SA accumulation and SA-dependent gene expression. In SA-deficient plants, mealybug feeding did not suppress but activated JA accumulation, indicating that the suppression of JA-regulated defenses depends on the SA signaling pathway. Mealybugs benefit from suppression of JA-regulated defenses by exhibiting enhanced nymphal performance. These findings confirm that P. solenopsis manipulates plants for its own benefits by modulating the JA-SA crosstalk and thereby suppressing induced defenses.
doi:10.1038/srep09354
PMCID: PMC4366759  PMID: 25790868

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