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1.  Efficient biodegradation of chlorophenols in aqueous phase by magnetically immobilized aniline-degrading Rhodococcus rhodochrous strain 
Background
Chlorophenols are environmental contaminants, which are highly toxic to living beings due to their carcinogenic, mutagenic and cytotoxic properties. Bacterial degradation has been considered a cost-effective and eco-friendly method of removing chlorophenols, compared to the traditional physical–chemical processes.
Results
In this study, we first developed an efficient process for the biodegradation of chlorophenols by magnetically immobilized Rhodococcus rhodochrous cells. R. rhodochrous DSM6263 degrades chlorophenols following the first step of hydroxylation at the ortho-positions of chlorophenolic rings. The cells immobilized by k-carrageenan with 9 g/L Fe3O4 nanoparticles could efficiently degrade 2-chlorophenol, 4-chlorophenol, 2,3-dichlorophenol and their mixture, which were even higher than those by free cells. The magnetically nanoparticle-immobilized cells could be used at least for six cycles.
Conclusion
Given the much easier separation by an external magnetic field and high degradation efficiency, this study provides a promising technique for improving biocatalysts used in the bioremediation process for chlorophenols in wastewater.
doi:10.1186/s12951-016-0158-0
PMCID: PMC4715327  PMID: 26772816
Chlorophenols; Rhodococcus rhodochrous; Magnetic immobilization; Bioremediation
2.  Efficient fermentative production of polymer-grade d-lactate by an engineered alkaliphilic Bacillus sp. strain under non-sterile conditions 
Background
Polylactic acid (PLA) is one important chemical building block that is well known as a biodegradable and a biocompatible plastic. The traditional lactate fermentation processes need CaCO3 as neutralizer to maintain the desired pH, which results in an amount of insoluble CaSO4 waste during the purification process. To overcome such environmental issue, alkaliphilic organisms have the great potential to be used as an organic acid producer under NaOH-neutralizing agent based fermentation. Additionally, high optical purity property in d-lactic acid is now attracting more attention from both scientific and industrial communities because it can improve mechanical properties of PLA by blending l- or d-polymer together. However, the use of low-price nitrogen source for d-lactate fermentation by alkaliphilic organisms combined with NaOH-neutralizing agent based process has not been studied. Therefore, our goal was the demonstrations of newly simplify high-optical-purity d-lactate production by using low-priced peanut meal combined with non-sterile NaOH-neutralizing agent based fermentation.
Results
In this study, we developed a process for high-optical-purity d-lactate production using an engineered alkaliphilic Bacillus strain. First, the native l-lactate dehydrogenase gene (ldh) was knocked out, and the d-lactate dehydrogenase gene from Lactobacillus delbrueckii was introduced to construct a d-lactate producer. The key gene responsible for exopolysaccharide biosynthesis (epsD) was subsequently disrupted to increase the yield and simplify the downstream process. Finally, a fed-batch fermentation under non-sterile conditions was conducted using low-priced peanut meal as a nitrogen source and NaOH as a green neutralizer. The d-lactate titer reached 143.99 g/l, with a yield of 96.09 %, an overall productivity of 1.674 g/l/h including with the highest productivity at 16 h of 3.04 g/l/h, which was even higher than that of a sterile fermentation. Moreover, high optical purities (approximately 99.85 %) of d-lactate were obtained under both conditions.
Conclusions
Given the use of a cheap nitrogen source and a non-sterile green fermentation process, this study provides a more valuable and favorable fermentation process for future polymer-grade d-lactate production.
doi:10.1186/s12934-015-0408-0
PMCID: PMC4709905  PMID: 26754255
Alkaliphilic; Bacillus sp.; d-lactate; Non-sterile fermentation; Peanut meal
3.  Using DNA Aptamer Probe for Immunostaining of Cancer Frozen Tissues 
Analytical Chemistry  2014;87(3):1919-1924.
Tissue immunostaining is critically important in clinical applications, and antibodies have been used extensively as the molecular probes. Recently, aptamer, as a new class of probes, have attracted much attention for their potential clinical and research value. Epithelial cell adhesion molecule (EpCAM) is a specific biomarker which is overexpressed in many cancers of epithelial origin. Here, a DNA-based EpCAM aptamer SYL3C is reported as a probe for the immunostaining of frozen and paraffin-embedded sections of colorectal cancer tissues. Commercialized EpCAM antibodies were also used as a standard control. EpCAM aptamer SYL3C specifically recognized and immunostained cancer nests of colorectal tumor sections, but it neither reacted with background cells within tumor sites nor exhibited cross-reaction to the benign lesions or inflammation of colorectal tissues. No cross-linking to EpCAM-negative malignant tumor sections occurred. Compared with standard antibody staining, our EpCAM aptamer SYL3C protocol is simpler to implement with a shorter reaction time. Moreover, SYL3C can specifically bind with either frozen or paraffin-embedded tissue sections. Since the histopathology of frozen tissue is closer to that of fresh tissue and since frozen sections can be produced more quickly than paraffin-embedded sections, SYL3C immunostaining of frozen sections is a quick protocol that is easy to implement.
doi:10.1021/ac504175h
PMCID: PMC4318623  PMID: 25536018
4.  Impaired Toll-like receptor 2-mediated Th1 and Th17/22 cytokines secretion in human peripheral blood mononuclear cells from patients with atopic dermatitis 
Background
Impaired Toll-like receptor 2 (TLR2) function has been associated with the pathogenesis of atopic dermatitis (AD). However, there are only few studies reporting on the TLR2-induced immunological responses of circulating leucocytes of AD patients. We thus investigated the expression and secretion of Th1, Th2 and Th17/22 cytokines triggered by TLR2 ligands in human peripheral blood mononuclear cells (PBMCs) from AD patients. Expression of TLR2, 1, 6 and high-affinity receptor for IgE (FcεRI) were further investigated to evaluate the outcome of immune response in AD.
Methods
Expression of TLR2, 1, 6 and FcεRI in PBMCs from AD patients and healthy individuals were measured by qPCR. Subsequent to stimulation with TLR2 ligands PGN and Pam3CSK4, expression and secretion of Th1, Th2 and Th17/22 cytokines were investigated by qPCR and ELISA.
Results
The levels of TLR2, 1, 6 mRNA were not altered in both groups of subjects while that of FcεRI was increased in AD patients. Subsequent to the activation by TLR2 ligands, PBMCs from AD patients significantly released less IFN-γ, IL-17F and IL-22 than those from healthy controls while no detectable level of release was observed with the other cytokines. In contrast, significantly higher levels of mRNA expression for TNF-α, IL5, IL-17A and IL-22 were observed in TLR2 activated PBMCs of AD patients than those of healthy control.
Conclusions
PBMCs from AD patients are defective in the secretion of Th1 and Th17/22 cytokines in response to TLR2 ligands. The inconsistent increased expression of the mRNA for the corresponding Th1 cytokines and the Th2 cytokines IL-5 suggested that there may be alterations of downstream signaling events in the cytokine release mechanisms of PBMCs that are associated with the development of AD.
doi:10.1186/s12967-015-0744-1
PMCID: PMC4683963  PMID: 26682905
Atopic dermatitis; Toll-like receptor 2; Th1 cytokine; Th2 cytokine; Th17/22 cytokines
5.  Berberine Attenuates Myocardial Ischemia/Reperfusion Injury by Reducing Oxidative Stress and Inflammation Response: Role of Silent Information Regulator 1 
Berberine (BBR) exerts potential protective effect against myocardial ischemia/reperfusion (MI/R) injury. Activation of silent information regulator 1 (SIRT1) signaling attenuates MI/R injury by reducing oxidative damage and inflammation response. This study investigated the antioxidative and anti-inflammatory effects of BBR treatment in MI/R condition and elucidated its potential mechanisms. Sprague-Dawley rats were treated with BBR in the absence or presence of the SIRT1 inhibitor sirtinol (Stnl) and then subjected to MI/R injury. BBR conferred cardioprotective effects by improving postischemic cardiac function, decreasing infarct size, reducing apoptotic index, diminishing serum creatine kinase and lactate dehydrogenase levels, upregulating SIRT1, Bcl-2 expressions, and downregulating Bax and caspase-3 expressions. Stnl attenuated these effects by inhibiting SIRT1 signaling. BBR treatment also reduced myocardium superoxide generation, gp91phox expression, malondialdehyde (MDA) level, and cardiac inflammatory markers and increased myocardium superoxide dismutase (SOD) level. However, these effects were also inhibited by Stnl. Consistently, BBR conferred similar antioxidative and anti-inflammatory effects against simulated ischemia reperfusion injury in cultured H9C2 cardiomyocytes. SIRT1 siRNA administration also abolished these effects. In summary, our results demonstrate that BBR significantly improves post-MI/R cardiac function recovery and reduces infarct size against MI/R injury possibly due to its strong antioxidative and anti-inflammatory activity. Additionally, SIRT1 signaling plays a key role in this process.
doi:10.1155/2016/1689602
PMCID: PMC4691633  PMID: 26788242
6.  An integrated pathway interaction network for the combination of four effective compounds from ShengMai preparations in the treatment of cardio-cerebral ischemic diseases 
Acta Pharmacologica Sinica  2015;36(11):1337-1348.
Aim:
SMXZF (a combination of ginsenoside Rb1, ginsenoside Rg1, schizandrin and DT-13) derived from Chinese traditional medicine formula ShengMai preparations) is capable of alleviating cerebral ischemia-reperfusion injury in mice. In this study we used network pharmacology approach to explore the mechanisms of SMXZF in the treatment of cardio-cerebral ischemic diseases.
Methods:
Based upon the chemical predictors, such as chemical structure, pharmacological information and systems biology functional data analysis, a target-pathway interaction network was constructed to identify potential pathways and targets of SMXZF in the treatment of cardio-cerebral ischemia. Furthermore, the most related pathways were verified in TNF-α-treated human vascular endothelial EA.hy926 cells and H2O2-treated rat PC12 cells.
Results:
Three signaling pathways including the NF-κB pathway, oxidative stress pathway and cytokine network pathway were demonstrated to be the main signaling pathways. The results from the gene ontology analysis were in accordance with these signaling pathways. The target proteins were found to be associated with other diseases such as vision, renal and metabolic diseases, although they exerted therapeutic actions on cardio-cerebral ischemic diseases. Furthermore, SMXZF not only dose-dependently inhibited the phosphorylation of NF-κB, p50, p65 and IKKα/β in TNF-α-treated EA.hy926 cells, but also regulated the Nrf2/HO-1 pathway in H2O2-treated PC12 cells.
Conclusion:
NF-κB signaling pathway, oxidative stress pathway and cytokine network pathway are mainly responsible for the therapeutic actions of SMXZF against cardio-cerebral ischemic diseases.
doi:10.1038/aps.2015.70
PMCID: PMC4635328  PMID: 26456587
ShengMai San; cardio-cerebral ischemic diseases; network pharmacology; traditional Chinese medicines; target-pathway interaction network; gene ontology; NF-κB; oxidative stress; EA.hy926 cells; PC12 cells
7.  Roles of microRNA-34a targeting SIRT1 in mesenchymal stem cells 
Introduction
Mesenchymal stem cell (MSC)-based therapies have had positive outcomes both in animal models of cardiovascular diseases and in clinical patients. However, the number and function of MSCs decline during hypoxia and serum deprivation (H/SD), reducing their ability to contribute to endogenous injury repair. MicroRNA-34a (miR-34a) is originally identified as a TP53-targeted miRNA that modulates cell functions, including apoptosis, proliferation, and senescence via several signaling pathways, and hence is an appealing target for MSC-based therapy for myocardial infarction.
Methods
Bone marrow-derived MSCs were isolated from 60–80 g male donor rats. Expression levels of miR-34a were determined by qRT-PCR. The roles of miR-34a in regulating cell vitality, apoptosis and senescence were investigated using the cell counting kit (CCK-8) assay, flow cytometric analysis of Annexin V-FITC/PI staining and senescence-associated β-galactosidase (SA-β-gal) staining, respectively. The expression of silent information regulator 1 (SIRT1) and forkhead box class O 3a (FOXO3a) and of apoptosis- and senescence-associated proteins in MSCs were analyzed by western blotting.
Results
The results of the current study showed that miR-34a was significantly up-regulated under H/SD conditions in MSCs, while overexpression of miR-34a was significantly associated with increased apoptosis, impaired cell vitality and aggravated senescence. Moreover, we found that the mechanism underlying the proapoptotic function of miR-34a involves activation of the SIRT1/FOXO3a pathway, mitochondrial dysfunction and finally, activation of the intrinsic apoptosis pathway. Further study showed that miR-34a can also aggravate MSC senescence, an effect which was partly abolished by the reactive oxygen species (ROS) scavenger, N-acetylcysteine (NAC).
Conclusions
Our study demonstrates for the first time that miR-34a plays pro-apoptotic and pro-senescence roles in MSCs by targeting SIRT1. Thus, inhibition of miR-34a might have important therapeutic implications in MSC-based therapy for myocardial infarction.
doi:10.1186/s13287-015-0187-x
PMCID: PMC4597437  PMID: 26446137
8.  Berberine regulates proliferation, collagen synthesis and cytokine secretion of cardiac fibroblasts via AMPK-mTOR-p70S6K signaling pathway 
Objective: The traditional Chinese medicinal berberine has long been used to treat cardiovascular diseases; however, the mechanism underlying its effects remains unclear. Here, this study would to investigate the effects of berberine on proliferation, collagen synthesis and cytokine secretion of cardiac fibroblasts. Methods: We assessed proliferation, collagen synthesis and cytokine secretion in cardiac fibroblasts subjected to angiotensin II (Ang II) subsequent to the consumption of berberine or a control treatment. And then we detected the role of AMPK/mTOR signaling pathway in berberine treatment of cardiac fibroblasts. Results: In the present study, the cellular behaviors of cardiac fibroblasts induced by Ang II were significantly activated including proliferation, transformation into myofibroblasts and collagen synthesis. Additionally, the ability of cytokine secretion was enhanced obviously. It was demonstrated that treatment of cardiac fibroblasts with berberine resulted in deceased proliferation, and attenuated fibroblast α-smooth muscle actin expression and collagen synthesis. And the protein secretion of TGFβ1 was inhibited; however, the protein secretion of IL-10 was increased in cardiac fibroblasts with berberine treatment. Mechanistically, the phosphorylation level of AMPK was increased; and the phosphorylation levels of mTOR and p70S6K were decreased in berberine treatment group. Conclusion: These results illustrated that the protective effects of berberine on cellular behaviors of cardiac fibroblasts were at least in part due to activate AMPK signaling pathway and downregulate mTOR/p70S6K signaling pathway. Berberine might become a new strategy for treating cardiac fibrosis in the future.
PMCID: PMC4680383  PMID: 26722438
Berberine; cardiac fibroblasts; proliferation; collagen synthesis; cytokine secretion
9.  The D-Lactate Dehydrogenase from Sporolactobacillus inulinus Also Possessing Reversible Deamination Activity 
PLoS ONE  2015;10(9):e0139066.
Hydroxyacid dehydrogenases are responsible for the conversion of 2-keto acids to 2-hydroxyacids and have a wide range of biotechnological applications. In this study, a D-lactate dehydrogenase (D-LDH) from a Sporolactobacillus inulinus strain was experimentally verified to have both the D-LDH and glutamate dehydrogenase (GDH) activities (reversible deamination). The catalytic mechanism was demonstrated by identification of key residues from the crystal structure analysis and site-directed mutagenesis. The Arg234 and Gly79 residues of this enzyme play a significant role in both D-LDH and GDH activities. His295 and Phe298 in DLDH744 were identified to be key residues for lactate dehydrogenase (LDH) activity only whereas Tyr101 is a unique residue that is critical for GDH activity. Characterization of the biochemical properties contributes to understanding of the catalytic mechanism of this novel D-lactate dehydrogenase enzyme.
doi:10.1371/journal.pone.0139066
PMCID: PMC4580590  PMID: 26398356
10.  PubChem Substance and Compound databases 
Nucleic Acids Research  2015;44(Database issue):D1202-D1213.
PubChem (https://pubchem.ncbi.nlm.nih.gov) is a public repository for information on chemical substances and their biological activities, launched in 2004 as a component of the Molecular Libraries Roadmap Initiatives of the US National Institutes of Health (NIH). For the past 11 years, PubChem has grown to a sizable system, serving as a chemical information resource for the scientific research community. PubChem consists of three inter-linked databases, Substance, Compound and BioAssay. The Substance database contains chemical information deposited by individual data contributors to PubChem, and the Compound database stores unique chemical structures extracted from the Substance database. Biological activity data of chemical substances tested in assay experiments are contained in the BioAssay database. This paper provides an overview of the PubChem Substance and Compound databases, including data sources and contents, data organization, data submission using PubChem Upload, chemical structure standardization, web-based interfaces for textual and non-textual searches, and programmatic access. It also gives a brief description of PubChem3D, a resource derived from theoretical three-dimensional structures of compounds in PubChem, as well as PubChemRDF, Resource Description Framework (RDF)-formatted PubChem data for data sharing, analysis and integration with information contained in other databases.
doi:10.1093/nar/gkv951
PMCID: PMC4702940  PMID: 26400175
11.  Two case reports of bilateral adrenal myelolipomas 
Primary adrenal myelolipoma is a rare, non-functioning adrenal benign tumor that is composed of mature adipose tissue and a variable amount of haemopoietic elements. Clinically, it is difficult to get diagnosed with adrenal myelolipoma because the patient usually doesn’t have obvious symptoms and signs in early stage. In the present study, two cases of primary bilateral adrenal myelolipomas are reported. Clinical presentation, imaging diagnostic features, histopathological changes and surgical treatments of the two patients are discussed. Preoperative diagnostic imaging examinations (B-mode ultrasonography, computed tomography and magnetic resonance imaging sans) assisted getting a prediction diagnosis of bilateral adrenal myelolipomas. A two-stage surgery was used to successfully excise bilateral adrenal myelolipomas in the two patients. Conventional open adrenalectomy was applied to remove the adrenal myelolipomas greater than 6 cm, and laparoscopic adrenalectomy was performed to excise the adrenal tumors smaller than 6 cm. Bilateral adrenal myelolipomas of the two patients were finally confirmed by postoperative histopathological examinations. Understanding clinical, imaging diagnostic and histopathological features of bilateral adrenal myelolipomas will facilitate timely diagnosis and treatment of this condition. Surgical removal of bilateral adrenal myelolipomas is safe, curative and beneficial. The two-stage surgery appears to be the best treatment option for the patients with bilateral adrenal myelolipomas because it achieves optimal treatment effectiveness with minimized sequelae.
doi:10.12998/wjcc.v3.i9.853
PMCID: PMC4568537  PMID: 26380835
Bilateral adrenal myelolipomas; Magnetic resonance imaging scan; Imaging diagnosis; B-mode ultrasonography; Computed tomography scan; Two-stage surgery; Histopathological examination
12.  The Complex Pre-Execution Stage of Auditory Cognitive Control: ERPs Evidence from Stroop Tasks 
PLoS ONE  2015;10(9):e0137649.
Cognitive control has been extensively studied from Event-Related Potential (ERP) point of view in visual modality using Stroop paradigms. Little work has been done in auditory Stroop paradigms, and inconsistent conclusions have been reported, especially on the conflict detection stage of cognitive control. This study investigated the early ERP components in an auditory Stroop paradigm, during which participants were asked to identify the volume of spoken words and ignore the word meanings. A series of significant ERP components were revealed that distinguished incongruent and congruent trials: two declined negative polarity waves (the N1 and the N2) and three declined positive polarity wave (the P1, the P2 and the P3) over the fronto-central area for the incongruent trials. These early ERP components imply that both a perceptual stage and an identification stage exist in the auditory Stroop effect. A 3-stage cognitive control model was thus proposed for a more detailed description of the human cognitive control mechanism in the auditory Stroop tasks.
doi:10.1371/journal.pone.0137649
PMCID: PMC4569364  PMID: 26368570
13.  Long noncoding RNA AK056155 involved in the development of Loeys-Dietz syndrome through AKT/PI3K signaling pathway 
Loeys-Dietz syndrome (LDS) is an autosomal dominant genetic connective tissue disorder, and most of LDS patients will develop into aortic aneurysm. Unfortunately, there is no known cure, and a high risk of death from aortic aneurysm rupture. However the detailed mechanism is still unknown. In order to explore the mechanism, we firstly used bioinformatics to predict, and then verified with biology methods. Firstly, we found that LncRNA AK056155 was differentially expressed in peripheral blood circulating endothelial cells between normal patients and LDS patients by bioinformatics. Then we further verified that AK056155 was also overexpressed in aortic aneurysm patients by RT-PCR. Moreover, we demonstrated that the expression of AK056155 can be enhanced by TGF-β1 in a concentration or time depended manner in HUVECs by RT-PCR. Furthermore, the expression of AK056155 was reduced with treatment of PI3K inhibitor (LY294002) or AKT inhibitor (GDC-0068) in combination with TGF-β1. These results indicate that AK056155 involved in the development of Loeys-Dietz syndrome through AKT/PI3K signaling pathway, it may provide a promising target gene to prevent LDS develop in to aortic aneurysm.
PMCID: PMC4637603  PMID: 26617788
Loeys-Dietz syndrome (LDS); aortic aneurysm; AK056155; TGF-β1; PI3K/AKT
14.  Levels of plasma Epstein-Barr virus DNA prior and subsequent to treatment predicts the prognosis of nasopharyngeal carcinoma 
Oncology Letters  2015;10(5):2888-2894.
The level of Epstein-Barr virus DNA (EBV-DNA) in the plasma prior and subsequent to treatment is a reliable biomarker for the screening, diagnosis, monitoring and prognosis of nasopharyngeal carcinoma (NPC). The present retrospective study aimed to determine whether pre- and post-treatment levels of plasma EBV-DNA were predictive of survival in a large sample of patients with NPC. The level of plasma EBV-DNA in 637 NPC patients prior and subsequent to treatment was determined by quantitative polymerase chain reaction. The value of pre- and post-treatment plasma EBV-DNA in predicting the survival of NPC patients was then analyzed. The results revealed that pre-treatment plasma EBV-DNA loads were significantly higher in patients with NPC than those in healthy controls (P<0.001). The percentage of patients with positive plasma EBV-DNA was markedly higher prior to treatment (70.64%; median, 1150 copies/ml; range, 0–9.75×106 copies/ml) than following treatment (25.99%; median, 0 copies/ml; range, 0–3.83×106 copies/ml) (P<0.001). Patients with a high plasma EBV-DNA load presented with a higher clinical tumor classification, lymph node status, metastatic status and overall cancer stage. The risk of NPC relapse and mortality was higher in patients with pre-treatment plasma EBV-DNA levels of ≥1,500 copies/ml than that in patients with <1,500 copies/ml. Furthermore, the risk of relapse and mortality was higher in patients with positive post-treatment plasma EBV-DNA than in patients with negative post-treatment plasma EBV-DNA. Detectable post-treatment plasma EBV-DNA was the most significant prognostic factor to affect relapse-free survival, whilst metastasis was the prognostic factor with the greatest effect on overall survival. These data indicated that pre- and post-treatment levels of plasma EBV-DNA were able to predict the prognosis of NPC. This finding may provide novel references for research and clinical practice.
doi:10.3892/ol.2015.3628
PMCID: PMC4665674  PMID: 26722258
nasopharyngeal carcinoma; Epstein-Barr virus DNA; prognosis
15.  A microfluidic method for synthesis of transferrin-lipid nanoparticles loaded with siRNA LOR-1284 for therapy of acute myeloid leukemia 
Nanoscale  2014;6(16):9742-9751.
siRNA LOR-1284 targets the R2 subunit of ribonucleotide reductase (RRM2) and has shown promise in cancer therapy. In this study, transferrin (Tf) conjugated lipid nanoparticles (Tf-NP-LOR-1284) were synthesized by microfluidic hydrodynamic focusing (MHF) and evaluated for targeted delivery of LOR-1284 siRNA to acute myeloid leukemia (AML) cells. In vitro study showed that Tf-NP-LOR-1284 can protect LOR-1284 from serum nuclease degradation. Selective uptake of Tf-NP-LOR-1284 was observed in MV4–11 cells. In addition, qRT-PCR and Western blot results revealed that Tf-NP-LOR-1284 was more effective than free LOR-1284 in reducing the R2 mRNA and protein levels. Tf-NP-LOR-1284 showed prolonged circulation time and increased AUC after i.v. administration relative to free LOR-1284. Furthermore, Tf-NP-LOR-1284 facilitated increased accumulation at the tumor site along with decreased R2 mRNA and protein expression in a murine xenograft model. These results suggest that Tf-conjugated NPs prepared by MHF provide a suitable platform for efficient and specific thereapeutic delivery of LOR-1284 to AML.
doi:10.1039/c4nr01510j
PMCID: PMC4312591  PMID: 25003978
Microfluidics; Lipid nanoparticles; Transferrin; siRNA; Acute myeloid leukemia
16.  Detection of circulating IgG antibodies to apolipoprotein B100 in acute myocardial infarction 
FEBS Open Bio  2015;5:712-716.
Highlights
•Anti-ApoB IgG is involved in the development of acute myocardial infarction (AMI).•We looked for biomarkers for the prediction of acute myocardial infarction.•An ELISA antibody test was developed to detect anti-ApoB IgG.•The test was used in clinical screening for anti-ApoB IgG in patients with AMI.
A number of studies have reported an association between increased levels of antibodies against oxidized low-density lipoprotein (oxLDL) and cardiovascular disease, but the anti-oxLDL antibody has not been confirmed to serve as an effective biomarker for prediction of acute myocardial infarction (AMI). Apolipoprotein B100 (ApoB100)-derived peptide fragments generated by proteolytic degradation and aldehyde modification are the major antigens in oxLDL, and so the present work was undertaken to detect circulating IgG for Apo-B100-derived peptide antigens. An in-house enzyme-linked immunosorbent assay (ELISA) was developed with eight ApoB100-derived peptide antigens (Ag1–Ag8) to detect circulating anti-ApoB100 IgG levels in 267 patients with AMI and 201 control subjects. Binary logistic regression analysis revealed that circulating IgG for Ag1 was significantly higher in the patient group than the control group (P < 0.001) after adjustment for age, gender, smoking, hypertension, diabetes and circulating levels of cholesterol, HDL, LDL, ApoA and ApoB100. None of the other seven antigens detected an increase in IgG levels in AMI patients compared with control subjects. Spearman correlation analysis showed no correlation between IgG antibody for Ag1 and clinical characteristics. In conclusion, the linear peptide antigens derived from ApoB100 may be suitable for the development of an ELISA antibody test for prediction of AMI, although further confirmation is still needed in large-scale clinical studies.
doi:10.1016/j.fob.2015.08.006
PMCID: PMC4564368  PMID: 26425439
AMI, acute myocardial infarction; ApoB100, apolipoprotein B100; cAg, control antigen; ELISA, enzyme-linked immunosorbent assay; hAgs, human antigens; HLA, human leukocyte antigen; IgG, immunoglobulin G; LDL, low-density lipoprotein; oxLDL, oxidized low-density lipoprotein; Acute myocardial infarction; ApoB100; oxLDL; Antibody; Atherosclerosis
17.  Application of eupatilin in the treatment of osteosarcoma 
Oncology Letters  2015;10(4):2505-2510.
5,7-dihydroxy-3′,4′,6-trimethoxyflavone, commonly known as eupatilin, is a traditional Asian medicinal plant, which is mainly used for the treatment of gastritis, as well as its use as an anti-inflammatory agent. Eupatilin is a bioactive compound; however, its effects on osteosarcoma (OS) have remained to be elucidated. Therefore, the present study aimed to investigate the effects of eupatilin on this malignant bone tumor, using the U-2 OS cell line. The experimental results revealed that eupatilin inhibited U-2 OS cell growth in a concentration-dependent manner and induced G2/M phase cell cycle arrest and apoptosis. Additionally, western blot analysis indicated that eupatilin was able to trigger the mitochondrial apoptotic pathway, demonstrated by the enhanced Bax/B cell lymphoma-2 ratio, decrease in mitochondrial membrane potential, release of cytochrome c, caspase-3 and -9 activation and poly(ADP-ribose)polymerase cleavage detected in the U-2 OS cells. These results indicated that eupatilin was able to inhibit U-2 OS cancer cell proliferation by the induction of apoptosis via the mitochondrial intrinsic pathway. Eupatilin may therefore represent a novel anticancer drug for use in the treatment of osteosarcoma.
doi:10.3892/ol.2015.3563
PMCID: PMC4580008  PMID: 26622880
eupatilin; osteosarcoma; apoptosis; anticancer activity
18.  Cost-Effectiveness Analysis Comparing Continuation of ART with Conversion to IUI in Patients with Low Follicle Numbers 
Fertility and sterility  2014;102(2):435-439.
Objective
To compare the cost-effectiveness of proceeding with oocyte retrieval versus conversion to intrauterine insemination (IUI) in patients with 4 or fewer mature follicles during assisted reproductive technology (ART) cycles.
Design
Probabilistic decision analysis. The cost-effectiveness of completing ART cycles in poor responders was compared to converting the cycles to IUI.
Setting
Analysis of published data.
Patient(s)
Not applicable.
Interventions
Cost-effectiveness analysis.
Main Outcome Measure(s)
Cost-effectiveness, which was defined as the average direct medical costs per ongoing pregnancy.
Results
In patients with 1 to 3 mature follicles, completing ART was more cost-effective if the cost of a single ART cycle was between $10,000 – $25,000. For patients with 4 mature follicles, if an ART cycle cost less than $18,025, it was more cost effective to continue with oocyte retrieval than to convert to IUI.
Conclusion(s)
In patients with 4 or fewer mature follicles following ovarian stimulation in ART cycles, it was on average more cost effective to proceed to oocyte retrieval, rather than converting to IUI. However, important factors such as age, prior ART failures, other fertility factors, and medications used in each individual case, need to be considered before this analysis model can be adapted by individual practices.
doi:10.1016/j.fertnstert.2014.05.015
PMCID: PMC4119511  PMID: 24951366
Poor responders; intrauterine insemination; assisted reproductive technologies; cost effectiveness
19.  Tumor antigen ROR1 targeted drug delivery mediated selective leukemic but not normal B cell cytotoxicity in chronic lymphocytic leukemia 
Leukemia  2014;29(2):346-355.
Selective cytotoxicity to cancer cells without compromising their normal counterparts pose a huge challenge for traditional drug design. Here we developed a tumor antigen targeted delivery of immunonanoparticle carrying a novel non-immunosuppressive FTY720 derivative OSU-2S with potent cytotoxicity against leukemic B cells. OSU-2S induces activation of protein phosphatase 2A, phosphorylation and nuclear translocation of SHP1S591 and deregulation of multiple cellular processes in chronic lymphocytic leukemia (CLL) resulting in potent cytotoxicity. To preclude OSU-2S mediated effects on these ubiquitous phosphatases in unintended cells and avoid potential adverse effects we developed a OSU-2S targeted delivery immunonanoparticles (2A2-OSU-2S-ILP), that mediated selective cytotoxicity of CLL but not normal B cells through targeting receptor tyrosine kinase ROR1 expressed in leukemic but not normal B cells. Developing a novel spontaneous CLL mouse model expressing human ROR1 (hROR1) in all leukemic B cells, we demonstrate the therapeutic benefit of enhanced survival with 2A2-OSU-2S-ILP in-vivo. The newly developed non-immunosuppressive OSU-2S, its delivery using human CLL directed immunonanoparticles and the novel transgenic mouse model of CLL that expresses hROR1 exclusively in leukemic B cell surface are highly innovative and can be applied to CLL and other ROR1+ malignancies including mantle cell lymphoma and acute lymphoblastic leukemia.
doi:10.1038/leu.2014.199
PMCID: PMC4272672  PMID: 24947019
CLL; OSU-2S; phosphatases; ROR1; immunonanoparticle; ROR1 transgenic mice
20.  TGF-β1-509C/T polymorphism and the risk of ESCC in a Chinese Han population 
Background: The studies investigating whether transforming growth factor (TGF)-β1-509C/T polymorphism is associated with the risk of ESCC is inconsistent. Methods: The TGF-β1-509C/T genotypes were determined by using a polymerase chain reaction (PCR)-restriction fragment length polymorphism assay and DNA sequencing analysis. The differences in demographic variables and genotype distributions of TGF-β1-509C/T polymorphism between ESCC patients and controls were calculated by Pearson’s Chi square test. Associations between TGF-β1-509C/T polymorphism genotypes and ESCC risk were estimated by OR and their 95% CIs computed using unconditional logistic regression model. Results: There was a significant difference of TGF-β1-509C/T polymorphism genotype distribution between ESCC group and control group (P<0.001). With the CC genotype as reference, the adjusted OR for CT genotype reached to 0.78 (95% CI: 0.65-0.89; P=0.041), and the adjusted OR for TT homozygous carriers was 0.52 (95% CI: 0.33-0.78; P=0.017). The T allele carriage also presented a lower risk for ESCC (adjusted OR=0.43; 95% CI, 0.29-0.71; P=0.009). Conclusion: TGF-β1-509C/T polymorphism may contributes to ESCC susceptibility in Chinese population.
PMCID: PMC4565357  PMID: 26379974
TGF-β1; polymorphism; ESCC; risk
21.  PubChem structure–activity relationship (SAR) clusters 
Background
Developing structure–activity relationships (SARs) of molecules is an important approach in facilitating hit exploration in the early stage of drug discovery. Although information on millions of compounds and their bioactivities is freely available to the public, it is very challenging to infer a meaningful and novel SAR from that information.
Results
Research discussed in the present paper employed a bioactivity-centered clustering approach to group 843,845 non-inactive compounds stored in PubChem according to both structural similarity and bioactivity similarity, with the aim of mining bioactivity data in PubChem for useful SAR information. The compounds were clustered in three bioactivity similarity contexts: (1) non-inactive in a given bioassay, (2) non-inactive against a given protein, and (3) non-inactive against proteins involved in a given pathway. In each context, these small molecules were clustered according to their two-dimensional (2-D) and three-dimensional (3-D) structural similarities. The resulting 18 million clusters, named “PubChem SAR clusters”, were delivered in such a way that each cluster contains a group of small molecules similar to each other in both structure and bioactivity.
Conclusions
The PubChem SAR clusters, pre-computed using publicly available bioactivity information, make it possible to quickly navigate and narrow down the compounds of interest. Each SAR cluster can be a useful resource in developing a meaningful SAR or enable one to design or expand compound libraries from the cluster. It can also help to predict the potential therapeutic effects and pharmacological actions of less-known compounds from those of well-known compounds (i.e., drugs) in the same cluster.
Graphical abstract
Electronic supplementary material
The online version of this article (doi:10.1186/s13321-015-0070-x) contains supplementary material, which is available to authorized users.
doi:10.1186/s13321-015-0070-x
PMCID: PMC4492103  PMID: 26150895
PubChem; PubChem3D; Structure–activity relationship (SAR); Cluster analysis; Molecular similarity; BioSystems; MeSH
22.  PubChem structure–activity relationship (SAR) clusters 
Background
Developing structure–activity relationships (SARs) of molecules is an important approach in facilitating hit exploration in the early stage of drug discovery. Although information on millions of compounds and their bioactivities is freely available to the public, it is very challenging to infer a meaningful and novel SAR from that information.
Results
Research discussed in the present paper employed a bioactivity-centered clustering approach to group 843,845 non-inactive compounds stored in PubChem according to both structural similarity and bioactivity similarity, with the aim of mining bioactivity data in PubChem for useful SAR information. The compounds were clustered in three bioactivity similarity contexts: (1) non-inactive in a given bioassay, (2) non-inactive against a given protein, and (3) non-inactive against proteins involved in a given pathway. In each context, these small molecules were clustered according to their two-dimensional (2-D) and three-dimensional (3-D) structural similarities. The resulting 18 million clusters, named “PubChem SAR clusters”, were delivered in such a way that each cluster contains a group of small molecules similar to each other in both structure and bioactivity.
Conclusions
The PubChem SAR clusters, pre-computed using publicly available bioactivity information, make it possible to quickly navigate and narrow down the compounds of interest. Each SAR cluster can be a useful resource in developing a meaningful SAR or enable one to design or expand compound libraries from the cluster. It can also help to predict the potential therapeutic effects and pharmacological actions of less-known compounds from those of well-known compounds (i.e., drugs) in the same cluster.
Graphical abstract
Electronic supplementary material
The online version of this article (doi:10.1186/s13321-015-0070-x) contains supplementary material, which is available to authorized users.
doi:10.1186/s13321-015-0070-x
PMCID: PMC4492103  PMID: 26150895
PubChem; PubChem3D; Structure–activity relationship (SAR); Cluster analysis; Molecular similarity; BioSystems; MeSH
23.  Crystallization and preliminary X-ray study of the deaminase AmnE from Pseudomonas sp. AP-3 
The deaminase AmnE from Pseudomonas sp. AP-3 was expressed in E. coli and purified. Crystallization and preliminary X-ray crystallographic analysis were performed for this recombinant enzyme.
The amnE gene from Pseudomonas sp. AP-3 has been verified as encoding a deaminase with 142 amino-acid residues. In order to change the substrate specificity via structure-based protein engineering, the amnE gene, after gene-code optimization, was chemically synthesized and cloned into the expression vector pET-28a. The protein was expressed in Escherichia coli BL21 (DE3) and purified by Ni2+-chelating affinity chromatography. Diffraction-quality crystals were obtained using the hanging-drop vapour-diffusion method and diffracted to a resolution of 2.09 Å. The crystals belonged to the orthorhombic space group C2221, with unit-cell parameters a = 63.23, b = 88.93, c = 137.83 Å.
doi:10.1107/S1744309113016709
PMCID: PMC3702332  PMID: 23832215
AmnE; Pseudomonas sp. AP-3
25.  Efficacy of Laparoscopic Mini Gastric Bypass for Obesity and Type 2 Diabetes Mellitus: A Systematic Review and Meta-Analysis 
Background. Controversies on the utility of laparoscopic mini gastric bypass (LMGB) in weight loss and type 2 diabetes mellitus (T2DM) control still exist. Methods. We conducted a comprehensive literature search of PubMed, EMBASE, and Cochrane Library. Review Manager was used to perform the meta-analysis and the weighted mean difference (WMD) and/or odds ratio with 95% confidence interval (95% CI) were used to evaluate the overall size effect. Results. The literature search identified 16 studies for systematic review and 15 articles for meta-analysis. Compared with LAGB, LSG, and LRYGB, LMGB showed significant weight loss [WMD, −6.58 (95% CI, −9.37, −3.79), P < 0.01 (LAGB); 2.86 (95% CI, 1.40, 5.83), P = 0.004 (LSG); 10.33 (95% CI, 4.30, 16.36), P < 0.01 (LRYGB)] and comparable/higher T2DM remission results [86.2% versus 55.6%, P = 0.06 (LAGB); 89.1% versus 76.3%, P = 0.004 (LAGB); 93.4% versus 77.6%, P = 0.006 (LAGB)]; LMGB also had shorter learning curve and less operation time than LRYGB [WMD, −35.2 (95% CI, −46.94, −23.46)]. Conclusions. LMGB appeared to be effective in weight loss and T2DM remission and noninferior to other bariatric surgeries. However, clinical utility of LMGB needs to be further validated by future prospective randomized controlled trials.
doi:10.1155/2015/152852
PMCID: PMC4488176  PMID: 26167173

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