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1.  Exosomes in Mesenchymal Stem Cells, a New Therapeutic Strategy for Cardiovascular Diseases? 
Cardiovascular diseases (CVDs) are still a major cause of people deaths worldwide, and mesenchymal stem cells (MSCs) transplantation holds great promise due to its capacity to differentiate into cardiovascular cells and secrete protective cytokines, which presents an important mechanism of MSCs therapy for CVDs. Although the capability of MSCs to differentiate into cardiomyocytes (CMCs), endothelial cells (ECs) and vascular smooth muscle cells (VSMCs) has been well recognized in massive previous experiments both in vitro and in vivo, low survival rate of transplanted MSCs in recipient hearts suggests that therapeutic effects of MSCs transplantation might be also correlated with other underlying mechanisms. Notably, recent studies uncovered that MSCs were able to secret cholesterol-rich, phospholipid exosomes which were enriched with microRNAs (miRNAs). The released exosomes from MSCs acted on hearts and vessels, and then exerted anti-apoptosis, cardiac regeneration, anti-cardiac remodeling, anti-inflammatory effects, neovascularization and anti-vascular remodeling, which are considered as novel molecular mechanisms of therapeutic potential of MSCs transplantation. Here we summarized recent advances about the role of exosomes in MSCs therapy for CVDs, and discussed exosomes as a novel approach in the treatment of CVDs in the future.
PMCID: PMC4308409  PMID: 25632267
microRNA; exosomes; mesenchymal stem cell; myocardial infarction; reperfusion injury; pulmonary hypertension
2.  Deacetylase-Independent Function of HDAC3 in Transcription and Metabolism Requires Nuclear Receptor Corepressor 
Molecular cell  2013;52(6):10.1016/j.molcel.2013.10.022.
Histone deacetylases (HDACs) are believed to regulate gene transcription by catalyzing deacetylation reactions. HDAC3 depletion in mouse liver upregulates lipogenic genes and results in severe hepatosteatosis. Here we show that pharmacologic HDAC inhibition in primary hepatocytes causes histone hyperacetylation but does not upregulate expression of HDAC3 target genes. Meanwhile, deacetylase-dead HDAC3 mutants can rescue hepatosteatosis and repress lipogenic genes expression in HDAC3-depleted mouse liver, demonstrating that histone acetylation is insufficient to activate gene transcription. Mutations abolishing interactions with the nuclear receptor corepressor (NCOR or SMRT) render HDAC3 nonfunctional in vivo. Additionally, liver-specific knockout of NCOR, but not SMRT, causes metabolic and transcriptomal alterations resembling those of mice without hepatic HDAC3, demonstrating that interaction with NCOR is essential for deacetylase-independent function of HDAC3. These findings highlight non-enzymatic roles of a major HDAC in transcriptional regulation in vivo and warrant reconsideration of the mechanism of action of HDAC inhibitors.
PMCID: PMC3877208  PMID: 24268577
3.  Is concomitant radiotherapy necessary with gemcitabine-based chemotherapy in pancreatic cancer? 
World Journal of Gastroenterology : WJG  2014;20(46):17648-17655.
AIM: To evaluate the efficacy and safety of gemcitabine (GEM) plus radiotherapy compared with GEM alone for pancreatic cancer (PC).
METHODS: A systematic search for eligible studies comparing gemcitabine plus radiotherapy with gemcitabine alone for PC was performed using MEDLINE, EMBASE, and the Cochrane Library. A quality assessment was performed in each study. Meta-analyses were performed to study the pooled effects of relative risk with 95% confidence interval (CI).
RESULTS: A total of 336 participants from four original studies were included. Gemcitabine plus radiotherapy resulted in comparable overall survival (HR = 0.84, 95%CI: 0.53-1.34, P = 0.48) and progress free survival (HR = 0.99, 95%CI: 0.97-1.01, P = 0.36) to gemcitabine alone. Moreover, concomitant radiotherapy was associated with a significantly higher incidence of severe (grade 3 or greater) toxicities, mainly anemia, leukocytopenia, thrombocytopenia, anorexia, nausea/vomiting, and asthenia/fatigue.
CONCLUSION: Radiotherapy is not beneficial with gemcitabine-based chemotherapy for PC. Further exploration for better radiotherapy approaches and therapeutic regimens for the treatment of PC is warranted.
PMCID: PMC4265627  PMID: 25516680
Pancreatic cancer; Radiotherapy; Chemotherapy; Gemcitabine; Meta-analysis
4.  The Role of Sodium-Dependent Glucose Transporter 1 and Glucose Transporter 2 in the Absorption of Cyanidin-3-O-β-Glucoside in Caco-2 Cells 
Nutrients  2014;6(10):4165-4177.
Anthocyanins have multiple biological activities of benefit to human health. While a few studies have been conducted to evaluate the bioavailability of anthocyanins, the mechanisms of their absorption mechanism remain ill-defined. In the present study, we investigated the absorption mechanism of cyanidin-3-O-β-glucoside (Cy-3-G) in human intestinal epithelial (Caco-2) cells. Cy-3-G transport was assessed by measuring the absorptive and efflux direction. Inhibition studies were conducted using the pharmacological agents, phloridzin, an inhibitor of sodium-dependent glucose transporter 1 (SGLT1), or phloretin, an inhibitor of glucose transporter 2 (GLUT2). The results showed that phloridzin and phloretin significantly inhibited the absorption of Cy-3-G. In addition, Caco-2 cells transfected with small interfering RNA (siRNA) specific for SGLT1 or GLUT2 showed significantly decreased Cy-3-G absorption. These siRNA transfected cells also showed a significantly decreased rate of transport of Cy-3-G compared with the control group. These findings suggest that Cy-3-G absorption is dependent on the activities of SGLT1 and GLUT2 in the small intestine and that SGLT1 and GLUT2 could be a limiting step for the bioavailability of Cy-3-G.
PMCID: PMC4210911  PMID: 25314643
Cy-3-G; absorption; siRNA; SGLT1; GLUT2
5.  Mediation Role of C-Reactive Protein on the Association between Smoking Quantity and Type 2 Diabetes in Current Chinese Smokers 
Journal of Diabetes Research  2014;2014:171538.
Objective. Previous studies have indicated that cigarette smokers are more likely to develop type 2 diabetes and that both smoking and type 2 diabetes are associated with C-reactive protein (CRP). This study examined whether CRP mediates the association between smoking quantity and type 2 diabetes. Methods. Nine hundred and eighty-four current Chinese smokers were selected from a community-based chronic disease survey conducted in Guangzhou and Zhuhai. Type 2 diabetes was defined according to the WHO 1999 criteria. CRP was measured with flow cytometry. Binary logistic regression was performed to assess the mediation. Results. A positive association was observed between smoking quantity and type 2 diabetes (P < 0.05). After controlling for potential confounders, daily cigarette consumption was significantly associated with higher CRP levels. Current smokers with type 2 diabetes had higher CRP levels than smokers without type 2 diabetes. The association between the smoking quantity and type 2 diabetes was mediated by CRP, which accounted for 50.77% of the association. Conclusions. This study provides further evidence that smoking quantity is positively associated with type 2 diabetes and suggests that the association between smoking and type 2 diabetes might be mediated by CRP.
PMCID: PMC4106084  PMID: 25105149
6.  The Nuclear Receptor Rev-erbα Controls Circadian Thermogenic Plasticity 
Nature  2013;503(7476):10.1038/nature12642.
Circadian oscillation of body temperature is a basic, evolutionary-conserved feature of mammalian biology1. Additionally, homeostatic pathways allow organisms to protect their core temperatures in response to cold exposure2. However, the mechanism responsible for coordinating daily body temperature rhythm and adaptability to environmental challenges is unknown. Here we show that the nuclear receptor Rev-erbα, a powerful transcriptional repressor, links circadian and thermogenic networks through the regulation of brown adipose tissue (BAT) function. Mice exposed to cold fare dramatically better at 5 AM (Zeitgeber time 22) when Rev-erbα is barely expressed than at 5 PM (ZT10) when Rev-erbα is abundant. Deletion of Rev-erbα markedly improves cold tolerance at 5 PM, indicating that overcoming Rev-erbα-dependent repression is a fundamental feature of the thermogenic response to cold. Physiological induction of uncoupling protein 1 (UCP1) by cold temperatures is preceded by rapid down-regulation of Rev-erbα in BAT. Rev-erbα represses UCP1 in a brown adipose cell-autonomous manner and BAT UCP1 levels are high in Rev-erbα-null mice even at thermoneutrality. Genetic loss of Rev-erbα also abolishes normal rhythms of body temperature and BAT activity. Thus, Rev-erbα acts as a thermogenic focal point required for establishing and maintaining body temperature rhythm in a manner that is adaptable to environmental demands.
PMCID: PMC3839416  PMID: 24162845
7.  Comparative Analysis of P2X1, P2X2, P2X3, and P2X4 Receptor Subunits in Rat Nodose Ganglion Neurons 
PLoS ONE  2014;9(5):e96699.
Nodose ganglion (NG) neurons are visceral primary sensory neurons. The transmission and regulation of visceral sensation is mediated mainly by the P2X purinoceptor (P2X receptor). Although the characteristics of different P2X receptor subunits in the NG have been studied previously, comprehensive analyses have not been performed. In this study, we used immunohistochemistry, immunocytochemistry, and whole cell patch clamp techniques to compare the expression and function of P2X1, P2X2, P2X3, and P2X4 receptor subunits in adult rat NG neurons. Polyclonal antibodies against the four P2X subunits labeled different subpopulations of NG neurons. P2X1 and P2X3 were expressed mainly in small-to-medium sized NG neurons, whereas P2X2 and P2X4 were located mostly in medium- and larger-sized NG neurons. Over 36% of NG neurons were P2X3 positive, which was higher than the other three P2X subunits. In addition, different types of currents were recorded from neurons expressing different P2X subunits. The fast type of ATP current was recorded from neurons containing P2X1–4 subunits, the intermediate type of current was recorded from neurons containing the P2X1, P2X3, and P2X4 subunits, the slow type was recorded from neurons expressing P2X1–3, and/or P2X4 subunits, whereas the very slow type was recorded from neurons containing the P2X2 and P2X3 subunits. These comparative results provide an anatomical verification of the different subunits in NG neurons, and offer direct support for the idea that various functional NG populations have distinct responses to ATP, which might be in part due to the different expression profiles of diverse P2X subunits.
PMCID: PMC4010501  PMID: 24798490
8.  The molecular basis of TCR germline bias for MHC is surprisingly simple 
Nature immunology  2009;10(2):143-147.
The elusive etiology of germline bias of the T cell receptor (TCR) for major histocompatibility complex (MHC) has been clarified by recent ‘proof-of-concept’ structural results demonstrating the conservation of specific TCR-MHC interfacial contacts in complexes bearing common variable segments and MHC allotypes. We suggest that each TCR variable-region gene product engages each type of MHC through a ‘menu’ of structurally coded recognition motifs that have arisen through coevolution. The requirement for MHC-restricted T cell recognition during thymic selection and peripheral surveillance has necessitated the existence of such a coded recognition system. Given these findings, a reconsideration of the TCR–peptide-MHC structural database shows that not only have the answers been there all along but also they were predictable by the first principles of physical chemistry.
PMCID: PMC3982143  PMID: 19148199
9.  Identification of four novel serum protein biomarkers in sepsis patients encoded by target genes of sepsis-related miRNAs 
Clinical Science (London, England : 1979)  2014;126(Pt 12):857-867.
The goal of the present study was to identify novel protein biomarkers from the target genes of six serum miRNAs that we identified previously in patients with sepsis. The target genes were predicted by bioinformatics analysis; the levels of the respective proteins in the sera of patients with sepsis were detected by ELISA. ACVR2A (activin A receptor, type IIA), FOXO1 (forkhead box O1), IHH (Indian hedgehog), STK4 (serine/threonine kinase 4) and DUSP3 (dual specificity phosphatase 3) were predicted to be the targets of the six miRNAs, and their encoded proteins were used for biomarker identification. Levels of ACVR2A (P<0.01) and FOXO1 (P<0.01) were significantly different among normal controls, patients with sepsis, patients with severe sepsis and patients with septic shock. Furthermore, levels of ACVR2A (P=0.025), FOXO1 (P<0.001), IHH (P=0.001) and STK4 (P=0.001) were differentially expressed in survivors and non-survivors. DUSP3 levels were not significantly different between any groups. Conjoin analysis of the four differentially expressed proteins showed that the area under the curve of the predictive probabilities was 0.875 [95% CI (confidence interval): 0.785–0.965], which was higher than the SOFA (Sequential Organ Failure Assessment) and APACHE II (Acute Physiology and Chronic Health Evaluation II) scores. When the value of predictive probabilities was 0.449, the four proteins yielded a sensitivity of 68% and a specificity of 91%. Dynamic changes in ACVR2A, FOXO1 and IHH levels showed differential expression between survivors and non-survivors at all time points. On the basis of a combined analysis of the four identified proteins, their predictive value of 28-day mortality of patients with sepsis was better than the SOFA or APACHE II scores.
Four novel protein biomarkers encoded by the miRNA target genes were identified for patients with sepsis. The combined analysis of the four proteins indicated that their predictive value for sepsis prognosis was better than the values for the SOFA score and APACHE II score.
PMCID: PMC4202716  PMID: 24303815
ACVR2A (activin A receptor; type IIA); FOXO1 (forkhead box O1); IHH (Indian hedgehog); miRNA; sepsis; STK4 (serine/threonine kinase 4); ACVR2A, activin A receptor, type IIA; AIC, Akaike information criterion; APACHE II, Acute Physiology and Chronic Health Evaluation II; AUC, area under the curve; CI, confidence interval; CRP, C-reactive protein; DUSP3, dual specificity phosphatase 3; FOXO1, forkhead box O1; FRS2, factor receptor substrate 2; GO, Gene Ontology; ICU, intensive care unit; IHH, Indian hedgehog; IL-6, interleukin 6; IL-18, interleukin 18; KEGG, Kyoto Encyclopedia of Genes and Genomes; PCT, procalcitonin; ROC, receiver operating characteristic; SLC4A4, solute carrier family 4, member 4; SOFA, Sequential Organ Failure Assessment; STK4, serine/threonine kinase 4; TGF-β, transforming growth factor-β
10.  Protein tyrosine kinase regulation by ubiquitination: Critical roles of Cbl-family ubiquitin ligases 
Biochimica et biophysica acta  2012;1833(1):122-139.
Protein tyrosine kinases (PTKs) coordinate a broad spectrum of cellular responses to extracellular stimuli and cell–cell interactions during development, tissue homeostasis, and responses to environmental challenges. Thus, an understanding of the regulatory mechanisms that ensure physiological PTK function and potential aberrations of these regulatory processes during diseases such as cancer are of broad interest in biology and medicine. Aside from the expected role of phospho-tyrosine phosphatases, recent studies have revealed a critical role of covalent modification of activated PTKs with ubiquitin as a critical mechanism of their negative regulation. Members of the Cbl protein family (Cbl, Cbl-b and Cbl-c in mammals) have emerged as dominant “activated PTK-selective” ubiquitin ligases. Structural, biochemical and cell biological studies have established that Cbl protein-dependent ubiquitination targets activated PTKs for degradation either by facilitating their endocytic sorting into lysosomes or by promoting their proteasomal degradation. This mechanism also targets PTK signaling intermediates that become associated with Cbl proteins in a PTK activation-dependent manner. Cellular and animal studies have established that the relatively broadly expressed mammalian Cbl family members Cbl and Cbl-b play key physiological roles, including their critical functions to prevent the transition of normal immune responses into autoimmune disease and as tumor suppressors; the latter function has received validation from human studies linking mutations in Cbl to human leukemia. These newer insights together with embryonic lethality seen in mice with a combined deletion of Cbl and Cbl-b genes suggest an unappreciated role of the Cbl family proteins, and by implication the ubiquitin-dependent control of activated PTKs, in stem/progenitor cell maintenance. Future studies of existing and emerging animal models and their various cell lineages should help test the broader implications of the evolutionarily-conserved Cbl family protein-mediated, ubiquitin-dependent, negative regulation of activated PTKs in physiology and disease.
PMCID: PMC3628764  PMID: 23085373
Cbl; E3 ubiquitin ligase; Tyrosine kinase binding domain; Ubiquitination; Signal transduction; Animal model
11.  An Effective Cache Algorithm for Heterogeneous Storage Systems 
The Scientific World Journal  2013;2013:693845.
Modern storage environment is commonly composed of heterogeneous storage devices. However, traditional cache algorithms exhibit performance degradation in heterogeneous storage systems because they were not designed to work with the diverse performance characteristics. In this paper, we present a new cache algorithm called HCM for heterogeneous storage systems. The HCM algorithm partitions the cache among the disks and adopts an effective scheme to balance the work across the disks. Furthermore, it applies benefit-cost analysis to choose the best allocation of cache block to improve the performance. Conducting simulations with a variety of traces and a wide range of cache size, our experiments show that HCM significantly outperforms the existing state-of-the-art storage-aware cache algorithms.
PMCID: PMC3876902  PMID: 24453890
12.  Cbl-b Enhances Sensitivity to 5-Fluorouracil via EGFR- and Mitochondria-Mediated Pathways in Gastric Cancer Cells 
5-Fluorouracil (5-FU) is an essential component of anticancer chemotherapy against gastric cancer. However, the response rate of single drug is still limited. The ubiquitin ligase Cbl-b is a negative regulator of growth factor receptor signaling and is involved in the suppression of cancer cell proliferation. However, whether Cbl-b could affect 5-FU sensitivity remains unclear. The present study showed that Cbl-b knockdown caused higher proliferation concomitant with the decrease of apoptosis induced by 5-FU treatment in gastric cancer cell. Further mechanism investigation demonstrated that Cbl-b knockdown caused significant increase of phosphorylation of EGFR, ERK and Akt, decrease of mitochondrial membrane potential, and increase of expression ratio of Bcl-2/Bax. These results suggest that Cbl-b enhances sensitivity to 5-FU via EGFR- and mitochondria-mediated pathways in gastric cancer cells.
PMCID: PMC3876118  PMID: 24351824
Cbl-b; 5-fluorouracil; EGFR; ERK; PI3k/Akt; gastric cancer
13.  Antiflammin-1 attenuates bleomycin-induced pulmonary fibrosis in mice 
Respiratory Research  2013;14(1):101.
Antiflammin-1 (AF-1), a derivative of uteroglobin (UG), is a synthetic nonapeptide with diverse biological functions. In the present study, we investigated whether AF-1 has a protective effect against bleomycin-induced pulmonary fibrosis.
C57BL/6 mice were injected with bleomycin intratracheally to create an animal model of bleomycin-induced pulmonary fibrosis. On Day 7 and Day 28, we examined the anti-inflammatory effect and antifibrotic effect, respectively, of AF-1 on the bleomycin-treated mice. The effects of AF-1 on the transforming growth factor-beta 1 (TGF-β1)-induced proliferation of murine lung fibroblasts (NIH3T3) were examined by a bromodeoxycytidine (BrdU) incorporation assay and cell cycle analysis.
Severe lung inflammation and fibrosis were observed in the bleomycin-treated mice on Day 7 and Day 28, respectively. Administration of AF-1 significantly reduced the number of neutrophils in the bronchoalveolar lavage fluid (BALF) and the levels of tumor necrosis factor-alpha (TNF-α) and interleukin-1 beta (IL-1β) in the lung homogenates on Day 7. Histological examination revealed that AF-1 markedly reduced the number of infiltrating cells on Day 7 and attenuated the collagen deposition and destruction of lung architecture on Day 28. The hydroxyproline (HYP) content was significantly decreased in the AF-1-treated mice. In vitro, AF-1 inhibited the TGF-β1-induced proliferation of NIH3T3 cells, which was mediated by the UG receptor.
AF-1 has anti-inflammatory and antifibrotic actions in bleomycin-induced lung injury. We propose that the antifibrotic effect of AF-1 might be related to its suppression of fibroblast growth in bleomycin-treated lungs and that AF-1 has potential as a new therapeutic tool for pulmonary fibrosis.
PMCID: PMC3856527  PMID: 24098933
Bleomycin; Pulmonary fibrosis; Antiflammin-1; Uteroglobin receptor
14.  Oncogenic Signaling by Leukemia-Associated Mutant Cbl Proteins 
Members of the Cbl protein family (Cbl, Cbl-b, and Cbl-c) are E3 ubiquitin ligases that have emerged as critical negative regulators of protein tyrosine kinase (PTK) signaling. This function reflects their ability to directly interact with activated PTKs and to target them as well as their associated signaling components for ubiquitination. Given the critical roles of PTK signaling in driving oncogenesis, recent studies in animal models and genetic analyses in human cancer have firmly established that Cbl proteins function as tumor suppressors. Missense mutations or small in-frame deletions within the regions of Cbl protein that are essential for its E3 activity have been identified in nearly 5% of leukemia patients with myelodysplastic/myeloproliferative disorders. Based on evidence from cell culture studies, in vivo models and clinical data, we discuss the potential signaling mechanisms of mutant Cbl-driven oncogenesis. Mechanistic insights into oncogenic Cbl mutants and associated animal models are likely to enhance our understanding of normal hematopoietic stem cell homeostasis and provide avenues for targeted therapy of mutant Cbl-driven cancers.
PMCID: PMC3757940  PMID: 23997989
Cbl; E3 ubiquitin ligase; MDS/MPN; Leukemia; Tyrosine kinase; Cellular signaling; Hematopoietic
15.  Circadian Epigenomic Remodeling and Hepatic Lipogenesis: Lessons from HDAC3 
Circadian rhythms have evolved to anticipate metabolic needs across the 24-hour light/dark cycle. This is accomplished by circadian expression of metabolic genes orchestrated by transcription factors through chromatin remodeling and histone modifications. Our recent genome-wide study on histone deacetylase 3 (HDAC3) in mouse liver provides novel insights into the molecular link between circadian rhythm and hepatic de novo lipogenesis. We found that liver-specific knockout of HDAC3 in adult mouse display severe hepatic steatosis associated with enhanced de novo lipogenesis and increased expression of lipogenic genes. Genome-wide analysis (ChIP-seq) revealed a pronounced circadian pattern of HDAC3 occupancy on genes involved in lipid metabolism, which is inversely related to histone acetylation and RNA polymerase II recruitment at these sites. The cistromes of HDAC3 and its binding partner, nuclear receptor co-repressor (NCoR), significantly overlap with that of Rev-erbα, a nuclear receptor directly involved in the core circadian machinery. Knockout of Rev-erbα in mouse also leads to hepatic steatosis and enhanced de novo lipogenesis. Collectively, these data suggest that the circadian epigenomic remodeling controlled by HDAC3, and largely directed by Rev-erbα, is essential for homeostasis of the lipogenic process in liver.
PMCID: PMC3755609  PMID: 21900149
16.  Clocks, Metabolism, and the Epigenome 
Molecular cell  2012;47(2):158-167.
Many behaviors and physiological activities in living organisms display circadian rhythms, allowing them to anticipate and prepare for the diurnal changes in the living environment. In this way, metabolic processes are aligned with the periodic environmental changes and behavioral cycles, such as the sleep/wake and fasting/feeding cycles. Disturbances of this alignment significantly increase the risk of metabolic diseases. Meanwhile, the circadian clock receives signals from the environment and feedback from metabolic pathways, and adjusts its activity and function. Growing evidence connects the circadian clock with epigenomic regulators. Here we review the recent advances in understanding the crosstalk between the circadian clock and energy metabolism through epigenomic programming and transcriptional regulation.
PMCID: PMC3408602  PMID: 22841001
17.  Diagnostic Value of Dynamics Serum sCD163, sTREM-1, PCT, and CRP in Differentiating Sepsis, Severity Assessment, and Prognostic Prediction 
Mediators of Inflammation  2013;2013:969875.
Objective. To describe the dynamics changes of sCD163, soluble serum triggering receptor expressed on myeloid cells-1 (sTREM-1), procalcitonin (PCT), and C-reactive protein (CRP) during the course of sepsis, as well as their outcome prediction. Patients and Methods. An SIRS group (30 cases) and a sepsis group (100 cases) were involved in this study. Based on a 28-day survival, the sepsis was further divided into the survivors' and nonsurvivors' groups. Serum sTREM-1, sCD163, PCT, CRP, and WBC counts were tested on days 1, 3, 5, 7, 10, and 14. Results. On the ICU admission, the sepsis group displayed higher levels of sTREM-1, sCD163, PCT, and CRP than the SIRS group (P < 0.05). Although PCT and sTREM-1 are good markers to identify severity, sTREM-1 is more reliable, which proved to be a risk factor related to sepsis. During a 14-day observation, sCD163, sTREM-1, PCT, and SOFA scores continued to climb among nonsurvivors, while their WBC and CRP went down. Both sCD163 and SOFA scores are risk factors impacting the survival time. Conclusion. With regard to sepsis diagnosis and severity, sTREM-1 is more ideal and constitutes a risk factor. sCD163 is of a positive value in dynamic prognostic assessment and may be taken as a survival-impacting risk factor.
PMCID: PMC3713373  PMID: 23935252
18.  Mechanistic and structural insight into the functional dichotomy between interleukin-2 and interleukin-15 
Nature immunology  2012;13(12):1187-1195.
Interleukin-15 (IL-15) and IL-2 possess distinct immunological functions despite both signaling through IL-2Rβ and the common cytokine receptor γ-chain, γc, We find that in the IL-15—IL-15Rα—IL-2Rβ—γc quaternary complex structure, IL-15 heterodimerizes IL-2Rβ and γc identically to the IL-2—IL-2Rα—IL-2Rβ—γc complex, despite differing receptor-binding chemistries. IL-15Rα dramatically increases the affinity of IL-15 for IL-2Rβ, and this allostery is required for IL-15 trans-signaling versus IL-2 cis-signaling. Consistent with the identical IL-2Rβ—γc dimer geometry, IL-2 and IL-15 exhibited similar signaling properties in lymphocytes, with any differences resulting from disparate receptor affinities. Thus, IL-15 and IL-2 induce similar signals, and the cytokine-specificity of IL-2Rα versus IL-15Rα determines cellular responsiveness. These results provide important new insights for specific development of IL-15-versus IL-2-based immunotherapeutics.
PMCID: PMC3501574  PMID: 23104097
19.  Effects of Vitamin B6 Therapy for Sepsis Patients with Linezolid-Associated Cytopenias: A Retrospective Study☆ 
The common adverse effects of linezolid for treating septic patients with gram-positive cocci is anemia and thrombocytopenia, which limit its clinical application.
We determined the effects of vitamin B6 adjunctive therapy on linezolid-associated cytopenias, and retrospectively studied 75 septic patients who received at least 7 days of linezolid treatment.
Patients were divided into a linezolid treatment group (LTG; n = 41) that received linezolid only and a combination treatment group (CTG; n = 34) that received both linezolid and vitamin B6. Each group was further subdivided into those with sepsis and those with severe sepsis. Each patient had red blood cell (RBC), hemoglobin (Hb), hematocrit (Hct), and platelet (PLT) measurements at baseline (day 0) and every other day for 2 weeks during treatment; these parameters were compared between the groups and assessed for time-dependent trends.
For patients in the LTG, RBC, Hb, and Hct values showed statistically significant reductions over time, and these values were lower compared with the values in the CTG. The CTG also showed downward trends, except on the first day of treatment. The PLT count also decreased in both groups. Patients with severe sepsis had lower PLT counts in both treatment groups compared with the septic patients.
Septic patients who received a combination treatment of linezolid and vitamin B6 might show positive effects for linezolid-associated reductions in some hematologic parameters (RBC, Hb, and Hct). This combined treatment might also slow PLT reduction, which was more evident in patients with severe sepsis. identifier: NCT01295801.
PMCID: PMC3862191  PMID: 24385027
linezolid; linezolid-associated cytopenias; sepsis; vitamin B6
20.  Coumarins from the Herb Cnidium monnieri and Chemically Modified Derivatives as Antifoulants against Balanus albicostatus and Bugula neritina Larvae 
In the search for new environmental friendly antifouling (AF) agents, four coumarins were isolated from the herbal plant Cnidium monnieri, known as osthole (1), imperatorin (2), isopimpinellin (3) and auraptenol (4). Furthermore, five coumarin derivatives, namely 8-epoxypentylcoumarin (5), meranzin hydrate (6), 2′-deoxymetranzin hydrate (7), 8-methylbutenalcoumarin (8), and micromarin-F (9) were synthesized from osthole. Compounds 1, 2, 4, 7 showed high inhibitory activities against larval settlement of Balanus albicostatus with EC50 values of 4.64, 3.39, 3.38, 4.67 μg mL−1. Compound 8 could significantly inhibit larval settlement of Bugula neritina with an EC50 value of 3.87 μg mL−1. The impact of functional groups on anti-larval settlement activities suggested that the groups on C-5′ and C-2′/C-3′ of isoamylene chian could affect the AF activities.
PMCID: PMC3565316  PMID: 23303279
antifouling activity; Cnidium monnieri; coumarins; osthole; structure-activity relationship
21.  Predictive factors of endoscopic submucosal dissection procedure time for gastric superficial neoplasia 
AIM: To identify the determinants of endoscopic submucosal dissection (ESD) operation time.
METHODS: This investigation was conducted as a single-center, prospective study in which ESD was performed by the same endoscopist at the Chinese PLA General Hospital. A total of 173 patients underwent ESD operations performed by Dr. Lu from July 2007 to December 2011, and 183 lesions were enrolled. Patient gender, age, tumor location, gross type, tumor size, pathological type and adhesions were recorded prospectively. The order of treatment represented the experience of the operator. Univariate analysis and multivariate analysis were performed to evaluate the relationships between these factors and ESD procedure time.
RESULTS: Univariate analysis showed the ESD time was closely related to the gender (P = 0.0210), tumor size (P < 0.0001), location (P < 0.0001), gross type (P < 0.0001) and adhesion (P = 0.0010). The surgical proficiency level was associated with ESD time in unit area (P < 0.0001). Multivariate analysis revealed that the ESD time was positively correlated with tumor size (P < 0.0001), adhesion (P < 0.0001) and location (P < 0.0001), but negatively correlated with surgical proficiency level (P = 0.0046).
CONCLUSION: Large tumor size, adjacency to the cardia, and adhesion are predictors of a long ESD time, whereas high surgical proficiency level predicts a short ESD time.
PMCID: PMC3531687  PMID: 23323001
Endoscopic submucosal dissection; Procedure time; Gastric superficial neoplasia; Predictive factors
22.  Lack of association between four SNPs in the SLC22A3-LPAL2-LPA gene cluster and coronary artery disease in a Chinese Han population: a case control study 
Lipoprotein (a) (Lp [a]) is known being correlated with coronary artery disease (CAD). The SLC22A3-LPAL2-LPA gene cluster, relating with modulating the level of plasma Lp (a), has recently been reported to be associated with CAD in Caucasians. The purpose of this study was to verify whether this finding can be expanded to the Chinese Han population.
Methods and Results
Using a Chinese Han sample, which consisted of 1012 well-characterized CAD patients and 889 healthy controls, we tested the associations of four SNPs (rs2048327, rs3127599, rs7767084 and rs10755578) in the SLC22A3-LPAL2-LPA gene cluster, and their inferred haplotypes with the risk of CAD. Allelic, genotypic and haplotype association analyses all showed that the gene cluster was not associated with CAD in this Chinese Han sample.
We for the first time explored the association of the four SNPs in the SLC22A3-LPAL2-LPA gene cluster with CAD in a large Chinese Han sample. Nevertheless, this study did not reveal any significant evidence of this gene cluster to increase the risk of CAD in this population.
PMCID: PMC3478218  PMID: 23036009
Association study; CAD; Lp(a); SLC22A3-LPAL2-LPA; SNP
23.  Diagnostic value of urine sCD163 levels for sepsis and relevant acute kidney injury: a prospective study 
BMC Nephrology  2012;13:123.
Sepsis is a common syndrome in critically ill patients and easily leads to the occurrence of acute kidney injury (AKI), with high mortality rates. This study aimed to investigate the diagnostic value of urine soluble CD163 (sCD163) for identification of sepsis, severity of sepsis, and for secondary AKI, and to assess the patients’ prognosis.
We enrolled 20 cases with systemic inflammatory response syndrome (SIRS), 40 cases with sepsis (further divided into 17 sepsis cases and 23 severe sepsis cases) admitted to the intensive care unit (ICU), and 20 control cases. Results for urine sCD163 were recorded on the day of admission to the ICU, and AKI occurrence was noted.
On the day of ICU admission, the sepsis group exhibited higher levels of urine sCD163 (74.8 ng/ml; range: 47.9-148.3 ng/ml) compared with those in the SIRS group (31.9 ng/ml; 16.8-48.0, P < 0.001). The area under the curve (AUC) was 0.83 (95% confidence interval [CI]: 0.72-0.94, P < 0.001) the sensitivity was 0.83, and the specificity was 0.75 (based on a cut-off point of 43.0 ng/ml). Moreover, the severe sepsis group appeared to have a higher level of sCD163 compared with that in the sepsis group (76.2; 47.2-167.5 ng/ml vs. 74.2; 46.2-131.6 ng/ml), but this was not significant. For 15 patients with AKI, urine sCD163 levels at AKI diagnosis were significantly higher than those of the remaining 35 sepsis patients upon ICU admission (121.0; 74.6-299.1 ng/ml vs. 61.8; 42.8-128.3 ng/ml, P = 0.049). The AUC for urine sCD163 was 0.688 (95% CI: 0.51-0.87, P = 0.049). Sepsis patients with a poor prognosis showed a higher urine sCD163 level at ICU admission (98.6; 50.3-275.6 ng/ml vs. 68.0; 44.8-114.5 ng/ml), but this was not significant. Patients with AKI with a poor prognosis had higher sCD163 levels than those in patients with a better prognosis (205.9; 38.6-766.0 ng/ml vs. 80.9; 74.9-141.0 ng/ml), but this was not significant.
This study shows, for the first time, the potential value of urine sCD163 levels for identifying sepsis and diagnosing AKI, as well as for assessment of patients’ prognosis.
Trial Registration
PMCID: PMC3506529  PMID: 23013330
Urine; Soluble CD163 (sCD163); Sepsis; Systemic inflammatory response syndrome (SIRS); Prognosis; Acute kidney injury (AKI)
24.  Clinical Significance of Soluble Hemoglobin Scavenger Receptor CD163 (sCD163) in Sepsis, a Prospective Study 
PLoS ONE  2012;7(7):e38400.
We investigated serum soluble CD163 (sCD163) levels for use in the diagnosis, severity assessment, and prognosis of sepsis in the critical ill patients and compared sCD163 with other infection-related variables.
During july 2010 and April 2011, serum was obtained from 102 sepsis patients (days 1, 3, 5, 7, and 10 after admission to an ICU) and 30 systemic inflammatory response syndrome (SIRS) patients with no sepsis diagnosed. Serum levels of sCD163, procalcitonon (PCT), and C reactive protein (CRP) were determined respectively. Sequential organ failure assessment (SOFA) scores for sepsis patients were also recorded. Then evaluated their roles in sepsis.
The sCD163 levels were 0.88(0.78–1.00)ug/mL for SIRS patients, 1.50(0.92–2.00)ug/mL for moderate sepsis patients, and 2.95(2.18–5.57)ug/mL for severe sepsis patients on day1. The areas under the ROC curves for sCD163, CRP, and PCT for the diagnosis of sepsis were, respectively, 0.856(95%CI: 0.791–0.921), 0.696(95%CI: 0.595–0.797), and 0.629(95%CI: 0.495–0.763), At the recommended cut-off 1.49 ug/mL for sCD163, the sensitivity is 74.0% with 93.3% specificity. Based on 28-day survivals, sCD163 levels in the surviving group stay constant, while they tended to gradually increase in the non-surviving group.The area under the ROC curve for sCD163 for sepsis prognosis was 0.706(95%CI 0.558–0.804). Levels of sCD163 with cut-off point >2.84 ug/mL have sensitivity of 55.8.0%, specificity 80.4%.Common risk factors for death and sCD163 were included in multivariate logistic regression analysis; the odds ratios (OR) for sCD163 and SOFA scores for sepsis prognosis were 1.173 and 1.396, respectively (P<0.05). Spearman rank correlation analysis showed that sCD163 was weakly, but positively correlated with CRP, PCT, and SOFA scores (0.2< r <0.4, P<0.0001), but not with leukocyte counts (r <0.2, P = 0.450).
Serum sCD163 is superior to PCT and CRP for the diagnosis of sepsis and differentiate the severity of sepsis. sCD163 levels were more sensitive for dynamic evaluations of sepsis prognosis. Serum sCD163 and SOFA scores are prognostic factors for sepsis.
Trial Registration ChiCTR-ONC-10000812
PMCID: PMC3401183  PMID: 22911680
25.  Novel HER2 Aptamer Selectively Delivers Cytotoxic Drug to HER2-positive Breast Cancer Cells in Vitro 
Aptamer-based tumor targeted drug delivery system is a promising approach that may increase the efficacy of chemotherapy and reduce the related toxicity. HER2 protein is an attractive target for tumor-specific drug delivery because of its overexpression in multiple malignancies, including breast, gastric, ovarian, and lung cancers.
In this paper, we developed a new HER2 aptamer (HB5) by using systematic evolution of ligands by exponential enrichment technology (SELEX) and exploited its role as a targeting ligand for delivering doxorubicin (Dox) to breast cancer cells in vitro.
The selected aptamer was an 86-nucleotide DNA molecule that bound to an epitope peptide of HER2 with a Kd of 18.9 nM. The aptamer also bound to the extracellular domain (ECD) of HER2 protein with a Kdof 316 nM, and had minimal cross reactivity to albumin or trypsin. In addition, the aptamer was found to preferentially bind to HER2-positive but not HER2-negative breast cancer cells. An aptamer-doxorubicin complex (Apt-Dox) was formulated by intercalating Dox into the DNA structure of HB5. The Apt-Dox complex could selectively deliver Dox to HER2-positive breast cancer cells while reducing the drug intake by HER2-negative cells in vitro. Moreover, Apt-Dox retained the cytotoxicity of Dox against HER2-positive breast cancer cells, but reduced the cytotoxicity to HER2-negative cells.
The results suggest that the selected HER2 aptamer may have application potentials in targeted therapy against HER2-positive breast cancer cells.
PMCID: PMC3583217  PMID: 22817844
Aptamer; HER2; Breast cancer; Tumor targeted therapy

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