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1.  Response to comment on ‘TAp63 suppress metastasis via miR-133b in colon cancer cells' 
Lin, C W | Li, X R | Zhang, Y | Hu, G | Guo, Y H | Zhou, J Y | Du, J | Lv, L | Gao, K | Zhang, Y | Deng, H
British Journal of Cancer  2014;111(12):2369-2370.
PMCID: PMC4264430  PMID: 25490679
2.  Histone demethylase Kdm4b functions as a co-factor of C/EBPβ to promote mitotic clonal expansion during differentiation of 3T3-L1 preadipocytes 
Cell Death and Differentiation  2012;19(12):1917-1927.
CCAAT/enhancer-binding protein (C/EBP) β is required for both mitotic clonal expansion (MCE) and terminal adipocyte differentiation of 3T3-L1 preadipocytes. Although the role of C/EBPβ in terminal adipocyte differentiation is well defined, its mechanism of action during MCE is not. In this report, histone demethylase Kdm4b, as well as cell cycle genes Cdc45l (cell division cycle 45 homolog), Mcm3 (mini-chromosome maintenance complex component 3), Gins1 (GINS complex subunit 1) and Cdc25c (cell division cycle 25 homolog c), were identified as potential C/EBPβ target genes during MCE by utilizing promoter-wide chromatin immunoprecipitation (ChIP)-on-chip analysis combined with gene expression microarrays. The expression of Kdm4b is induced during MCE and its induction is dependent on C/EBPβ. ChIP, Electrophoretic Mobility Shift Assay (EMSA) and luciferase assay confirmed that the promoter of Kdm4b is bound and activated by C/EBPβ. Knockdown of Kdm4b impaired MCE. Furthermore, Kdm4b interacted with C/EBPβ and was recruited to the promoters of C/EBPβ-regulated cell cycle genes, including Cdc45l, Mcm3, Gins1, and Cdc25c, demethylated H3K9me3 and activated their transcription. These findings suggest a novel feed forward mechanism involving a DNA binding transcription factor (C/EBPβ) and a chromatin regulator (Kdm4b) in the regulation of MCE by controlling cell cycle gene expression.
PMCID: PMC3504706  PMID: 22722334
3T3-L1 preadipocytes; adipocyte differentiation; mitotic clonal expansion; C/EBPβ; Kdm4b; ChIP-on-chip
3.  Acute atrial arrhythmogenesis in murine hearts following enhanced extracellular Ca2+ entry depends on intracellular Ca2+ stores 
Acta Physiologica (Oxford, England)  2010;198(2):143-158.
To investigate the effect of increases in extracellular Ca2+ entry produced by the L-type Ca2+ channel agonist FPL-64176 (FPL) upon acute atrial arrhythmogenesis in intact Langendorff-perfused mouse hearts and its dependence upon diastolic Ca2+ release from sarcoplasmic reticular Ca2+ stores.
Confocal microscope studies of Fluo-3 fluorescence in isolated atrial myocytes were performed in parallel with electrophysiological examination of Langendorff-perfused mouse hearts.
Atrial myocytes stimulated at 1 Hz and exposed to FPL (0.1 μm) initially showed (<10 min) frequent, often multiple, diastolic peaks following the evoked Ca2+ transients whose amplitudes remained close to control values. With continued pacing (>10 min) this reverted to a regular pattern of evoked transients with increased amplitudes but in which diastolic peaks were absent. Higher FPL concentrations (1.0 μm) produced sustained and irregular patterns of cytosolic Ca2+ activity, independent of pacing. Nifedipine (0.5 μm), and caffeine (1.0 mm) and cyclopiazonic acid (CPA) (0.15 μm) pre-treatments respectively produced immediate and gradual reductions in the F/F0 peaks. Such nifedipine and caffeine, or CPA pre-treatments, abolished, or reduced, the effects of 0.1 and 1.0 μm FPL on cytosolic Ca2+ signals. FPL (1.0 μm) increased the incidence of atrial tachycardia and fibrillation in intact Langendorff-perfused hearts without altering atrial effective refractory periods. These effects were inhibited by nifedipine and caffeine, and reduced by CPA.
Enhanced extracellular Ca2+ entry exerts acute atrial arrhythmogenic effects that is nevertheless dependent upon diastolic Ca2+ release. These findings complement reports that associate established, chronic, atrial arrhythmogenesis with decreased overall inward Ca2+ current.
PMCID: PMC3763207  PMID: 19886909
atrial arrhythmogenesis; Ca2+ homeostasis; calcium entry; murine hearts; store calcium
4.  Inhibition of 12/15-lipoxygenase by baicalein induces microglia PPARβ/δ: a potential therapeutic role for CNS autoimmune disease 
Xu, J | Zhang, Y | Xiao, Y | Ma, S | Liu, Q | Dang, S | Jin, M | Shi, Y | Wan, B | Zhang, Y
Cell Death & Disease  2013;4(4):e569-.
12/15-Lipoxygenase (12/15-LO) is an enzyme that converts polyunsaturated fatty acids into bioactive lipid derivatives. In this study, we showed that inhibition of 12/15-LO by baicalein (BA) significantly attenuated clinical severity of experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS). Inhibited migration of autoimmune T cells into the central nervous system (CNS) by BA treatment could be attributed to reduced activation of microglia, which was indicated by suppressed phagocytosis, and decreased production of proinflammatory cytokines and chemokines in the CNS. We further observed that inhibition of 12/15-LO with BA led to increased expression of peroxisome proliferator-activated receptor (PPAR)β/δ in microglia of EAE mice. This was confirmed in vitro in primary microglia and a microglia cell line, BV2. In addition, we demonstrated that BA did not affect 12/15-LO or 5-lipoxygenase (5-LO) expression in microglia, but significantly decreased 12/15-LO products without influencing the levels of 5-LO metabolites. Moreover, among these compounds only 12/15-LO metabolite 12-hydroxyeicosatetraenoic acid was able to reverse BA-mediated upregulation of PPARβ/δ in BV2 cells. We also showed that inhibition of microglia activation by PPARβ/δ was associated with repressed NF-κB and MAPK activities. Our findings indicate that inhibition of 12/15-LO induces PPARβ/δ, demonstrating important regulatory properties of 12/15-LO in CNS inflammation. This reveals potential therapeutic applications for MS.
PMCID: PMC3668632  PMID: 23559003
12/15-LO; PPARβ/δ; baicalein; microglia; EAE
5.  QTL mapping in outbred half-sib families using Bayesian model selection 
Heredity  2011;107(3):265-276.
In this article, we propose a model selection method, the Bayesian composite model space approach, to map quantitative trait loci (QTL) in a half-sib population for continuous and binary traits. In our method, the identity-by-descent-based variance component model is used. To demonstrate the performance of this model, the method was applied to map QTL underlying production traits on BTA6 in a Chinese half-sib dairy cattle population. A total of four QTLs were detected, whereas only one QTL was identified using the traditional least square (LS) method. We also conducted two simulation experiments to validate the efficiency of our method. The results suggest that the proposed method based on a multiple-QTL model is efficient in mapping multiple QTL for an outbred half-sib population and is more powerful than the LS method based on a single-QTL model.
PMCID: PMC3183946  PMID: 21487433
Bayesian model selection; variance component model; Markov chain Monte Carlo algorithm; QTL mapping
6.  A functionalized single-walled carbon nanotube-induced autophagic cell death in human lung cells through Akt–TSC2-mTOR signaling 
Cell Death & Disease  2011;2(5):e159-.
Nanoparticles are now emerging as a novel class of autophagy activators. Functionalized single-walled carbon nanotubes (f-SWCNTs) are valuable nanomaterials in many industries. This article is designed to assess the autophagic response for f-SWCNTs exposure in vitro and in vivo. A few types of f-SWCNTs were screened in human lung adenocarcinoma A549 cells for the autophagic response and related pathways in vitro. Formation of autophagosomes and LC3-II upregulation were confirmed on the basis of electron microscopy and LC3 western blotting for COOH-CNT, but not for PABS-CNT and PEG-CNT. MTT assay showed marked increase in cell viability, when COOH-CNT was added to cells in the presence of autophagy inhibitor 3MA, ATG6 or TSC2 siRNA. Consistent with the involvement of the Akt–TSC1/2–mTOR pathway, the phosphorylation levels of mTOR, mTOR's substrate S6 and Akt were shown significantly decreased in A549 cells on treatment with COOH-CNT using western blotting. What's more, autophagy inhibitor 3MA significantly reduced the lung edema in vivo. In a word, COOH-CNT induced autophagic cell death in A549 cells through the AKT–TSC2–mTOR pathway and caused acute lung injury in vivo. Inhibition of autophagy significantly reduced COOH-CNT-induced autophagic cell death and ameliorated acute lung injury in mice, suggesting a potential remedy to address the growing concerns on the safety of nanomaterials.
PMCID: PMC3122114  PMID: 21593791
SWCNT; autophagy; mTOR; acute lung injury
7.  Electronic Structures of S-Doped Capped C-SWNT from First Principles Study 
Nanoscale Research Letters  2010;5(6):1027-1031.
The semiconducting single-walled carbon nanotube (C-SWNT) has been synthesized by S-doping, and they have extensive potential application in electronic devices. We investigated the electronic structures of S-doped capped (5, 5) C-SWNT with different doping position using first principles calculations. It is found that the electronic structures influence strongly on the workfunction without and with external electric field. It is considered that the extended wave functions at the sidewall of the tube favor for the emission properties. With the S-doping into the C-SWNT, the HOMO and LUMO charges distribution is mainly more localized at the sidewall of the tube and the presence of the unsaturated dangling bond, which are believed to enhance workfunction. When external electric field is applied, the coupled states with mixture of localized and extended states are presented at the cap, which provide the lower workfunction. In addition, the wave functions close to the cap have flowed to the cap as coupled states and to the sidewall of the tube mainly as extended states, which results in the larger workfunction. It is concluded that the S-doped C-SWNT is not incentive to be applied in field emitter fabrication. The results are also helpful to understand and interpret the application in other electronic devices.
PMCID: PMC2894202  PMID: 20672070
Single-walled carbon nanotube (C-SWNT); Electronic properties; Workfunctions
8.  CD44 targets Na+/H+ exchanger 1 to mediate MDA-MB-231 cells' metastasis via the regulation of ERK1/2 
Chang, G | Wang, J | Zhang, H | Zhang, Y | Wang, C | Xu, H | Zhang, H | Lin, Y | Ma, L | Li, Q | Pang, T
British Journal of Cancer  2014;110(4):916-927.
CD44, a transmembrane glycoprotein expressed in a variety of cells and tissues, has been implicated in tumour metastasis. But the molecular mechanisms of CD44-mediated tumour cell metastasis remain to be elucidated.
The downregulation of CD44 was determined by immunofluorescence. Moreover, the motility of breast cancer cells was detected by wound-healing and transwell experiments. Then the spontaneous metastasis of CD44-silenced MDA-MB-231 cells was tested by histology with BALB/c nude mice.
A positive correlation between CD44 and Na+/H+ exchanger isoform 1 (NHE1) was found in two breast cancer cells. CD44 downregulation could inhibit the metastasis of MDA-MB-231 cells and the expressions of Na+/H+ exchanger 1. Moreover, CD44 overexpression upregulated the metastasis of MCF-7 cells, but the elevated metastatic ability was then inhibited by Cariporide. Interestingly, during these processes only the p-ERK1/2 was suppressed by CD44 downregulation and the expression of matrix metalloproteinases and metastatic capacity of MDA-MB-231 cells were greatly inhibited by the MEK1 inhibitor PD98059, which even had a synergistic effect with Cariporide. Furthermore, CD44 downregulation inhibits breast tumour outgrowth and spontaneous lung metastasis.
Taken together, this work indicates that CD44 regulates the metastasis of breast cancer cells through regulating NHE1 expression, which could be used as a novel strategy for breast cancer therapy.
PMCID: PMC3929887  PMID: 24434427
CD44; Na+/H+ exchanger 1; matrix metalloproteinase; breast cancer; metastasis
9.  Regulation of Autophagy by miR-30d Impacts Sensitivity of Anaplastic Thyroid Carcinoma to Cisplatin* 
Biochemical pharmacology  2013;87(4):562-570.
miR-30d has been observed to be significantly down-regulated in human anaplastic thyroid carcinoma (ATC), and is believed to be an important event in thyroid cell transformation. In this study, we found that miR-30d has a critical role in modulating sensitivity of ATC cells to cisplatin, a commonly used chemotherapeutic drug for treatment of this neoplasm. Using a mimic of miR-30d, we demonstrated that miR-30d could negatively regulate the expression of beclin 1, a key autophagy gene, leading to suppression of the cisplatin-activated autophagic response that protects ATC cells from apoptosis. A reporter gene assay demonstrated that the binding sequences of miR-30d in the beclin 1-3′ UTR was the region required for the inhibition of beclin 1 expression by this miRNA. We further showed that inhibition of the beclin 1-mediated autophagy by the miR-30d mimic sensitized ATC cells to cisplatin both in vitro (cell culture) and in vivo (animal xenograft model). These results suggest that dysregulation of miR-30d in ATC cells is responsible for the insensitivity to cisplatin by promoting autophagic survival. Thus, miR-30d may be exploited as a potential target for therapeutic intervention in the treatment of ATC.
PMCID: PMC3926201  PMID: 24345332
miR-30d; autophagy; apoptosis; Beclin1; cisplatin; Anaplastic thyroid cancer
10.  Real-space anisotropic dielectric response in a multiferroic skyrmion lattice 
Scientific Reports  2015;5:8318.
A magnetic skyrmion lattice is a microstructure consisting of hexagonally aligned skyrmions. While a skyrmion as a topologically protected carrier of information promises a number of applications, an easily accessible probe of the skyrmion and skyrmion lattice at mesoscopic scale is of significance. It is known that neutron scattering, Lorentz transmission electron microscopy, and spin-resolved STM as effective probes of skyrmions have been established. In this work, we propose that the spatial contour of dielectric permittivity in a skyrmion lattice with ferromagnetic interaction and in-plane (xy) Dzyaloshinskii-Moriya (DM) interaction can be used to characterize the skyrmion lattice. The phase field and Monte Carlo simulations are employed to develop the one-to-one correspondence between the magnetic skyrmion lattice and dielectric dipole lattice, both exhibiting the hexagonal symmetry. Under excitation of in-plane electric field in the microwave range, the dielectric permittivity shows the dumbbell-like pattern with the axis perpendicular to the electric field, while it is circle-like for the electric field along the z-axis. The dependences of the spatial contour of dielectric permittivity on external magnetic field along the z-axis and dielectric frequency dispersion are discussed.
PMCID: PMC4321174  PMID: 25661786
11.  Local structure order in Pd78Cu6Si16 liquid 
Scientific Reports  2015;5:8277.
The short-range order (SRO) in Pd78Cu6Si16 liquid was studied by high energy x-ray diffraction and ab initio molecular dynamics (MD) simulations. The calculated pair correlation functions at different temperatures agree well with the experimental results. The partial pair correlation functions from ab intio MD simulations indicate that Si atoms prefer to be uniformly distributed while Cu atoms tend to aggregate. By performing structure analysis using Honeycutt-Andersen index, Voronoi tessellation, and atomic cluster alignment method, we show that the icosahedron and face-centered cubic SRO increase upon cooling. The dominant SRO is the Pd-centered Pd9Si2 motif, namely the structure of which motif is similar to the structure of Pd-centered clusters in the Pd9Si2 crystal. The study further confirms the existence of trigonal prism capped with three half-octahedra that is reported as a structural unit in Pd-based amorphous alloys. The majority of Cu-centered clusters are icosahedra, suggesting that the presence of Cu is benefit to promote the glass forming ability.
PMCID: PMC4317692  PMID: 25652079
12.  Daclizumab reduces CD25 levels on T cells through monocyte- mediated trogocytosis 
Daclizumab is a humanized monoclonal antibody that prevents IL-2 binding to CD25, blocking interleukin-2 (IL-2) signaling by cells that require high-affinity IL-2 receptors to mediate IL-2 signaling. The phase 2a CHOICE study evaluating daclizumab as a treatment for MS included longitudinal analysis of activated T cell counts. Whereas an exposure-dependent relationship was observed between daclizumab and reductions in HLA-DR+-activated T cells, a similar relationship was not observed for reductions in CD25 levels.
Objective and Methods
Determine the mechanism daclizumab reduces CD25 levels on peripheral blood mononuclear cells (PBMC) using cytometric techniques
Daclizumab reduced T cell CD25 levels through a mechanism that required the daclizumab-Fc domain interaction with FcR on monocytes, but not on natural killer (NK) cells, and was unrelated to internalization or cell killing. Activated CD4+ T cells and FoxP3+ Treg cells showed evidence of trogocytosis of the CD25 antigen in the presence of monocytes. A daclizumab variant that retained affinity for CD25 but lacked FcR binding did not induce trogocytosis and was significantly less potent as an inhibitor of IL-2-induced proliferation of peripheral blood mononuclear cells.
Daclizumab-induced monocyte-mediated trogocytosis of CD25 from T cells appears to be an additional mechanism contributing to daclizumab inhibition of IL-2 signaling.
PMCID: PMC4184423  PMID: 23846354
daclizumab; multiple sclerosis; trogocytosis; CD25; Treg; HLA-DR; regulatory T cell
13.  Depletion of white adipocyte progenitors induces beige adipocyte differentiation and suppresses obesity development 
Cell Death and Differentiation  2014;22(2):351-363.
Overgrowth of white adipose tissue (WAT) in obesity occurs as a result of adipocyte hypertrophy and hyperplasia. Expansion and renewal of adipocytes relies on proliferation and differentiation of white adipocyte progenitors (WAP); however, the requirement of WAP for obesity development has not been proven. Here, we investigate whether depletion of WAP can be used to prevent WAT expansion. We test this approach by using a hunter-killer peptide designed to induce apoptosis selectively in WAP. We show that targeted WAP cytoablation results in a long-term WAT growth suppression despite increased caloric intake in a mouse diet-induced obesity model. Our data indicate that WAP depletion results in a compensatory population of adipose tissue with beige adipocytes. Consistent with reported thermogenic capacity of beige adipose tissue, WAP-depleted mice display increased energy expenditure. We conclude that targeting of white adipocyte progenitors could be developed as a strategy to sustained modulation of WAT metabolic activity.
PMCID: PMC4291494  PMID: 25342467
14.  Gambogic acid synergistically potentiates cisplatin-induced apoptosis in non-small-cell lung cancer through suppressing NF-κB and MAPK/HO-1 signalling 
British Journal of Cancer  2013;110(2):341-352.
Gambogic acid (GA) has been reported to have potent anticancer activity and is authorised to be tested in phase II clinical trials for treatment of non-small-cell lung cancer (NSCLC). The present study aims to investigate whether GA would be synergistic with cisplatin (CDDP) against the NSCLC.
1-(4,5-Dimethylthiazol-2-yl)-3,5-diphenylformazan (MTT), combination index (CI) isobologram, western blot, quantitative PCR, flow cytometry, electrophoretic mobility shift assay, xenograft tumour models and terminal deoxynucleotide transferase-mediated dUTP nick-end labelling analysis were used in this study.
The cell viability results showed that sequential CDDP-GA treatment resulted in a strong synergistic action in A549, NCI-H460, and NCI-H1299 cell lines, whereas the reverse sequence and simultaneous treatments led to a slight synergistic or additive action. Increased sub-G1 phase cells and enhanced PARP cleavage demonstrated that the sequence of CDDP-GA treatment markedly increased apoptosis in comparison with other treatments. Furthermore, the sequential combination could enhance the activation of caspase-3, -8, and 9, increase the expression of Fas and Bax, and decrease the expression of Bcl-2, survivin and X-inhibitor of apoptosis protein (X-IAP) in A549 and NCI-H460 cell lines. In addition, increased apoptosis was correlated with enhanced reactive oxygen species generation. Importantly, it was found that, followed by CDDP treatment, GA could inhibit NF-κB and mitogen-activated protein kinase (MAPK)/heme oxygenase-1 (HO-1) signalling pathways, which have been validated to reduce ROS release and confer CDDP resistance. The roles of NF-κB and MAPK pathways were further confirmed by using specific inhibitors, which significantly increased ROS release and apoptosis induced by the sequential combination of CDDP and GA. Moreover, our results indicated that the combination of CDDP and GA exerted increased antitumour effects on A549 xenograft models through inhibiting NF-κB, HO-1, and subsequently inducing apoptosis.
Gambogic acid sensitises lung cancer cells to CDDP in vitro and in vivo in NSCLC through inactivation of NF-κB and MAPK/HO-1 signalling pathways, providing a rationale for the combined use of CDDP and GA in lung cancer chemotherapy.
PMCID: PMC3899775  PMID: 24300974
gambogic acid; cisplatin; lung cancer; NF-κB; apoptosis; heme oxygenase-1
15.  The role of KCNQ1 in mouse and human gastrointestinal cancers 
Oncogene  2013;33(29):3861-3868.
Kcnq1, which encodes for the pore-forming alpha subunit of a voltage-gated potassium channel, was identified as a gastrointestinal (GI) tract cancer susceptibility gene in multiple Sleeping Beauty DNA transposon-based forward genetic screens in mice. To confirm that Kcnq1 has a functional role in GI tract cancer we created ApcMin mice that carried a targeted deletion mutation in Kcnq1. Results demonstrated that Kcnq1 is a tumor suppressor gene as Kcnq1 mutant mice developed significantly more intestinal tumors, especially in the proximal small intestine and colon, some of these tumors progressed to become aggressive adenocarcinomas. Gross tissue abnormalities were also observed in the rectum, pancreas and stomach. Colon organoid formation was significantly increased in organoids created from Kcnq1 mutant mice compared with wildtype littermate controls, suggesting a role for Kcnq1 in regulation of the intestinal crypt stem cell compartment. To identify gene expression changes due to loss of Kcnq1 we carried out microarray studies in colon and proximal small intestine. We identified altered genes involved in innate immune responses, goblet and Paneth cell function, ion channels, intestinal stem cells, EGFR and other growth regulatory signaling pathways. We also found genes implicated in inflammation and in cellular detoxification. Pathway analysis using Ingenuity Pathway Analysis (IPA) and gene set enrichment analysis (GSEA) confirmed the importance of these gene clusters and further identified significant overlap with genes regulated by MUC2 and CFTR, two important regulators of intestinal homeostasis. To investigate the role of KCNQ1 in human colorectal cancer (CRC) we measured protein levels of KCNQ1 by immunohistochemistry in tissue microarrays containing samples from CRC patients with liver metastases who had undergone hepatic resection. Results showed that low expression of KCNQ1 expression was significantly associated with poor overall survival (OS).
PMCID: PMC3935979  PMID: 23975432
colorectal cancer; KCNQ1; tumor suppressor
16.  Sulphoxythiocarbamates modify cysteine residues in HSP90 causing degradation of client proteins and inhibition of cancer cell proliferation 
British Journal of Cancer  2013;110(1):71-82.
Heat shock protein 90 (HSP90) has a key role in the maintenance of the cellular proteostasis. However, HSP90 is also involved in stabilisation of oncogenic client proteins and facilitates oncogene addiction and cancer cell survival. The development of HSP90 inhibitors for cancer treatment is an area of growing interest as such agents can affect multiple pathways that are linked to all hallmarks of cancer. This study aimed to test the hypothesis that targeting cysteine residues of HSP90 will lead to degradation of client proteins and inhibition of cancer cell proliferation.
Combining chemical synthesis, biological evaluation, and structure–activity relationship analysis, we identified a new class of HSP90 inhibitors. Click chemistry and protease-mass spectrometry established the sites of modification of the chaperone.
The mildly electrophilic sulphoxythiocarbamate alkyne (STCA) selectively targets cysteine residues of HSP90, forming stable thiocarbamate adducts. Without interfering with the ATP-binding ability of the chaperone, STCA destabilises the client proteins RAF1, HER2, CDK1, CHK1, and mutant p53, and decreases proliferation of breast cancer cells. Addition of a phenyl or a tert-butyl group in tandem with the benzyl substituent at nitrogen increased the potency. A new compound, S-4, was identified as the most robust HSP90 inhibitor within a series of 19 derivatives.
By virtue of their cysteine reactivity, sulphoxythiocarbamates target HSP90, causing destabilisation of its client oncoproteins and inhibiting cell proliferation.
PMCID: PMC3887302  PMID: 24322890
Hsp90; NRF2; cysteine; HSF1
17.  Pharmacokinetics and pharmacodynamics of levofloxacin injection in healthy Chinese volunteers and dosing regimen optimization 
Cao, G | Zhang, J | Wu, X | Yu, J | Chen, Y | Ye, X | Zhu, D | Zhang, Y | Guo, B | Shi, Y
What is known and objective
The pharmacokinetics (PK) and pharmacodynamics (PD) of levofloxacin were investigated following administration of levofloxacin injection in healthy Chinese volunteers for optimizing dosing regimen.
The PK study included single-dose (750 mg/150 mL) and multiple-dose (750 mg/150 mL once daily for 7 days) phases. The concentration of levofloxacin in blood and urine was determined using HPLC method. Both non-compartmental and compartmental analyses were performed to estimate PK parameters. Taking fCmax/MIC ≥5 and fAUC24 h/MIC ≥30 as a target, the cumulative fraction of response (CFR) of levofloxacin 750 mg for treatment of community-acquired pneumonia (CAP) was calculated using Monte Carlo simulation. The probability of target attainment (PTA) of levofloxacin at various minimal inhibitory concentrations (MICs) was also evaluated.
Results and discussion
The results of PK study showed that the Cmax and AUC0–∞ of levofloxacin were 14·94 μg/mL and 80·14 μg h/mL following single-dose infusion of levofloxacin. The half-life and average cumulative urine excretion ratio within 72 h post-dosing were 7·75 h and 86·95%, respectively. The mean Css,max, Css,min and AUC0–τ of levofloxacin at steady state following multiple doses were 13·31 μg/mL, 0·031 μg/mL and 103·7 μg h/mL, respectively. The accumulation coefficient was 1·22. PK/PD analysis revealed that the CFR value of levofloxacin 750-mg regimen against Streptococcus pneumoniae was 96·2% and 95·4%, respectively, in terms of fCmax/MIC and fAUC/MIC targets.
What is new and conclusion
The regimen of 750-mg levofloxacin once daily provides a satisfactory PK/PD profile against the main pathogenic bacteria of CAP, which implies promising clinical and bacteriological efficacy for patients with CAP. A large-scale clinical study is warranted to confirm these results.
PMCID: PMC4285945  PMID: 23701411
healthy volunteer; levofloxacin; Monte Carlo simulation; pharmacodynamics; pharmacokinetics
Neuroscience  2013;254:10.1016/j.neuroscience.2013.09.014.
We have previously shown that anti-hyperalgesic effects of cannabinoid agonists under inflammatory condition are much greater in male than female, and that inflammatory cytokines upregulate cannabinoid receptor type 1 (CB1) expression in male, but not female, trigeminal ganglia (TG) in a testosterone-dependent manner. In this study, we investigated the mechanisms underlying the testosterone-mediated regulation of peripheral CB1 expression. We hypothesized that testosterone upregulates CB1 through transcriptional modulation by androgen receptor (AR). Interleukin-1 beta (IL-1β), a proinflammatory cytokine, upregulated CB1 mRNA expression in TG of male rats. The cytokine-induced upregulation was prevented by the pre-treatment with flutamide, a specific antagonist for AR, but not by ICI 182,780, a specific antagonist for estrogen receptor, suggesting that the effects of testosterone are not mediated by estradiol, a testosterone metabolite. The expression levels of AR and IL-1β receptors were comparable between male and female TG, suggesting that the male specific IL-1β effects on CB1 upregulation occurs downstream to these receptors. The chromatin immunoprecipitation assay showed AR binding to the CB1 promoter in the rat TG. Furthermore, luciferase reporter assay revealed that AR activated the CB1 gene in response to testosterone or dihydrotestosterone treatment. These experiments provided compelling evidence that testosterone regulates CB1 gene transcription in TG through AR following cytokine stimulation. These results should provide mechanistic bases for understanding cytokine–hormone–neuron interactions in peripheral cannabinoid systems, and have important clinical implications for pain patients in whom testosterone level is naturally low, gradually declining or pharmacologically compromised.
PMCID: PMC3870904  PMID: 24055403
testosterone; inflammation; cytokines; sensory neurons; rat
19.  On the failure load and mechanism of polycrystalline graphene by nanoindentation 
Scientific Reports  2014;4:7437.
Nanoindentation has been recently used to measure the mechanical properties of polycrystalline graphene. However, the measured failure loads are found to be scattered widely and vary from lab to lab. We perform molecular dynamics simulations of nanoindentation on polycrystalline graphene at different sites including grain center, grain boundary (GB), GB triple junction, and holes. Depending on the relative position between the indenter tip and defects, significant scattering in failure load is observed. This scattering is found to arise from a combination of the non-uniform stress state, varied and weakened strengths of different defects, and the relative location between the indenter tip and the defects in polycrystalline graphene. Consequently, the failure behavior of polycrystalline graphene by nanoindentation is critically dependent on the indentation site, and is thus distinct from uniaxial tensile loading. Our work highlights the importance of the interaction between the indentation tip and defects, and the need to explicitly consider the defect characteristics at and near the indentation site in polycrystalline graphene during nanoindentation.
PMCID: PMC4262822  PMID: 25500732
20.  Transcriptome profiling of the whitefly Bemisia tabaci reveals stage-specific gene expression signatures for thiamethoxam resistance 
Yang, N | Xie, W | Jones, CM | Bass, C | Jiao, X | Yang, X | Liu, B | Li, R | Zhang, Y
Insect Molecular Biology  2013;22(5):485-496.
Bemisia tabaci has developed high levels of resistance to many insecticides including the neonicotinoids and there is strong evidence that for some compounds resistance is stage-specific. To investigate the molecular basis of B. tabaci resistance to the neonicotinoid thiamethoxam we used a custom whitefly microarray to compare gene expression in the egg, nymph and adult stages of a thiamethoxam-resistant strain (TH-R) with a susceptible strain (TH-S). Gene ontology and bioinformatic analyses revealed that in all life stages many of the differentially expressed transcripts encoded enzymes involved in metabolic processes and/or metabolism of xenobiotics. Several of these are candidate resistance genes and include the cytochrome P450 CYP6CM1, which has been shown to confer resistance to several neonicotinoids previously, a P450 belonging to the Cytochrome P450s 4 family and a glutathione S-transferase (GST) belonging to the sigma class. Finally several ATP-binding cassette transporters of the ABCG subfamily were highly over-expressed in the adult stage of the TH-R strain and may play a role in resistance by active efflux. Here, we evaluated both common and stage-specific gene expression signatures and identified several candidate resistance genes that may underlie B. tabaci resistance to thiamethoxam.
PMCID: PMC4229068  PMID: 23889345
Bemisia tabaci; metabolic resistance; thiamethoxam; microarray; stage specific
21.  Interleukin-17 enhances immunosuppression by mesenchymal stem cells 
Han, X | Yang, Q | Lin, L | Xu, C | Zheng, C | Chen, X | Han, Y | Li, M | Cao, W | Cao, K | Chen, Q | Xu, G | Zhang, Y | Zhang, J | Schneider, R J | Qian, Y | Wang, Y | Brewer, G | Shi, Y
Cell Death and Differentiation  2014;21(11):1758-1768.
IL-17 is one of the most potent and most actively investigated proinflammatory cytokines. In this study, we examined the effect of IL-17 on mesenchymal stem cells (MSCs) under the influence of inflammatory cytokines. Ironically, IL-17 dramatically enhanced the immunosuppressive effect of MSCs induced by IFNγ and TNFα, revealing a novel role of IL-17 in immunosuppression. Interestingly, we found that this action of IL-17 was dependent on the promoted expression of a key immune suppressive molecule, inducible nitric oxide synthase (iNOS), in MSCs. In a concanavalin A (ConA)-induced hepatitis mouse model, we found that IL-17 also enhanced the in vivo immunosuppressive effect of MSCs in an iNOS-dependent manner. Moreover, this promoting effect of IL-17 was found to be exerted through enhancing mRNA stability by modulating the protein level of ARE/poly(U)-binding/degradation factor 1 (AUF1), a well-known factor that promotes mRNA decay. In auf1−/− MSCs, IFNγ and TNFα could induce maximal immunosuppressive effect, both in vitro and in vivo, without the need for IL-17. Thus, our studies demonstrated that in the presence of MSCs, IL-17 promotes immunosuppression.
PMCID: PMC4211372  PMID: 25034782
22.  IFN-γ induces aberrant CD49b+ NK cell recruitment through regulating CX3CL1: a novel mechanism by which IFN-γ provokes pregnancy failure 
Cell Death & Disease  2014;5(11):e1512-.
Interferon-γ (IFN-γ), a pleiotropic lymphokine, has important regulatory effects on many cell types. Although IFN-γ is essential for the initiation of uterine vascular modifications and maintenance of decidual integrity, IFN-γ administration can also cause pregnancy failure in many species. However, little is known about the effector mechanisms involved. In this study, using an IFN-γ-induced abortion mouse model, we reported that no Dolichos biflorus agglutinin lectin-positive uterine natural killer (uNK) cells were observed in the uteri from IFN-γ-induced abortion mice. By contrast, the percentage of CD3−CD49b+ NK cells in the uterus and blood from a foetal resorption group was significantly higher than that of the control group. Similarly, significantly upregulated expression of CD49b (a pan-NK cell marker), CX3CL1 and CX3CR1 (CX3CL1 receptor) was detected in the uteri of IFN-γ-induced abortion mice. Using isolated uterine stromal cells, we showed that upregulated expression of CX3CL1 by IFN-γ was dependent on a Janus family kinase 2-signal transducers and activators of transcription 1 (JAK2-STAT1) pathway. We further demonstrated the chemotactic activity of CX3CL1 in uterine stromal cell conditioned medium on primary splenic NK cells. Finally, we observed increased recruitment of CD49b+ NK cells into the endometrium after exogenous CX3CL1 administration. Collectively, our findings indicate that IFN-γ can significantly increase uterine CX3CL1 expression via activation of the JAK2-STAT1 pathway, thus inducing CD49b+ NK cell uterine homing, and eventually provoke foetal loss. Thus, we provide a new line of evidence correlating the deleterious effects of IFN-γ on pregnancy with the aberrant regulation of CX3CL1 and CD49b+ NK cells.
PMCID: PMC4260728  PMID: 25375377
23.  Mitochondrial dysfunction-associated OPA1 cleavage contributes to muscle degeneration: preventative effect of hydroxytyrosol acetate 
Wang, X | Li, H | Zheng, A | Yang, L | Liu, J | Chen, C | Tang, Y | Zou, X | Li, Y | Long, J | Liu, J | Zhang, Y | Feng, Z
Cell Death & Disease  2014;5(11):e1521-.
Mitochondrial dysfunction contributes to the development of muscle disorders, including muscle wasting, muscle atrophy and degeneration. Despite the knowledge that oxidative stress closely interacts with mitochondrial dysfunction, the detailed mechanisms remain obscure. In this study, tert-butylhydroperoxide (t-BHP) was used to induce oxidative stress on differentiated C2C12 myotubes. t-BHP induced significant mitochondrial dysfunction in a time-dependent manner, accompanied by decreased myosin heavy chain (MyHC) expression at both the mRNA and protein levels. Consistently, endogenous reactive oxygen species (ROS) overproduction triggered by carbonyl cyanide 4-(trifluoromethoxy) phenylhydrazone (FCCP), a mitochondrial oxidative phosphorylation inhibitor, was accompanied by decreased membrane potential and decreased MyHC protein content. However, the free radical scavenger N-acetyl-L-cysteine (NAC) efficiently reduced the ROS level and restored MyHC content, suggesting a close association between ROS and MyHC expression. Meanwhile, we found that both t-BHP and FCCP promoted the cleavage of optic atrophy 1 (OPA1) from the long form into short form during the early stages. In addition, the ATPase family gene 3-like 2, a mitochondrial inner membrane protease, was also markedly increased. Moreover, OPA1 knockdown in myotubes was accompanied by decreased MyHC content, whereas NAC failed to prevent FCCP-induced MyHC decrease with OPA1 knockdown, suggesting that ROS might affect MyHC content by modulating OPA1 cleavage. In addition, hydroxytyrosol acetate (HT-AC), an important compound in virgin olive oil, could significantly prevent t-BHP-induced mitochondrial membrane potential and cell viability loss in myotubes. Specifically, HT-AC inhibited t-BHP-induced OPA1 cleavage and mitochondrial morphology changes, accompanied by improvement on mitochondrial oxygen consumption capacity, ATP productive potential and activities of mitochondrial complex I, II and V. Moreover, both t-BHP- and FCCP-induced MyHC decrease was sufficiently inhibited by HT-AC. Taken together, our data provide evidence indicating that mitochondrial dysfunction-associated OPA1 cleavage may contribute to muscle degeneration, and olive oil compounds could be effective nutrients for preventing the development of muscle disorders.
PMCID: PMC4260731  PMID: 25393477
24.  More than 10 years survival with sequential therapy in a patient with advanced renal cell carcinoma: a case report 
Although radical nephrectomy alone is widely accepted as the standard of care in localized treatment for renal cell carcinoma (RCC), it is not sufficient for the treatment of metastatic RCC (mRCC), which invariably leads to an unfavorable outcome despite the use of multiple therapies. Currently, sequential targeted agents are recommended for the management of mRCC, but the optimal drug sequence is still debated. This case was a 57-year-old man with clear-cell mRCC who received multiple therapies following his first operation in 2003 and has survived for over 10 years with a satisfactory quality of life. The treatments given included several surgeries, immunotherapy, and sequentially administered sorafenib, sunitinib, and everolimus regimens. In the course of mRCC treatment, well-planned surgeries, effective sequential targeted therapies and close follow-up are all of great importance for optimal management and a satisfactory outcome.
PMCID: PMC4288490  PMID: 25493380
Metastatic renal cell carcinoma; Sequential therapy; Targeted anticancer agents; Sorafenib; Sunitinib; Immunotherapy
25.  Nerve growth factor/p75 neurotrophin receptor–mediated sensitization of rat sensory neurons depends on membrane cholesterol 
Neuroscience  2013;0:562-570.
Nerve growth factor (NGF) is an important mediator in the initiation of the inflammatory response and NGF via activation of the p75 neurotrophin receptor (p75NTR) and downstream sphingomyelin signaling leads to significant enhancement of the excitability of small diameter sensory neurons. Because of the interaction between sphingomyelin and cholesterol in creating membrane liquid-ordered domains known as membrane or lipid rafts, we examined whether neuronal NGF-induced sensitization via p75NTR was dependent on the integrity of membrane rafts. Here, we demonstrate that the capacity of NGF to enhance the excitability of sensory neurons may result from the interaction of p75NTR with its downstream signaling partner(s) in membrane rafts. Two agents known to disrupt membrane rafts, edelfosine and methyl-β-cyclodextrin (MβCD), block the increase in excitability produced by NGF. In contrast, treatment with MβCD containing saturated amounts of cholesterol does not alter the capacity of NGF to augment excitability. In addition, adding back MβCD with cholesterol restored the NGF-induced sensitization in previously cholesterol-depleted neurons, suggesting that cholesterol and the structural integrity of rafts are key in promoting NGF-mediated sensitization. Using established protocols to isolate detergent-resistant membranes, both p75NTR and the neuronal membrane raft marker, flotillin, localize to raft fractions. These results suggest that downstream signaling partners interacting with p75NTR in sensory neurons are associated with membrane raft signaling platforms.
PMCID: PMC3883999  PMID: 23811397
NGF; excitability; sensitization; membrane raft; dorsal root ganglia

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