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1.  HCCS1-armed, quadruple-regulated oncolytic adenovirus specific for liver cancer as a cancer targeting gene-viro-therapy strategy 
Molecular Cancer  2011;10:133.
In previously published studies, oncolytic adenovirus-mediated gene therapy has produced good results in targeting cancer cells. However, safety and efficacy, the two most important aspects in cancer therapy, remain serious challenges. The specific expression or deletion of replication related genes in an adenovirus has been frequently utilized to regulate the cancer cell specificity of a virus. Accordingly, in this study, we deleted 24 bp in E1A (bp924-bp947) and the entirety of E1B, including those genes encoding E1B 55kDa and E1B19kDa. We used the survivin promoter (SP) to control E1A in order to construct a new adenovirus vector named Ad.SP.E1A(Δ24).ΔE1B (briefly Ad.SPDD). HCCS1 (hepatocellular carcinoma suppressor 1) is a novel tumor suppressor gene that is able to specifically induce apoptosis in cancer cells. The expression cassette AFP-HCCS1-WPRE-SV40 was inserted into Ad.SPDD to form Ad.SPDD-HCCS1, enabling us to improve the safety and efficacy of oncolytic-mediated gene therapy for liver cancer.
Ad.SPDD showed a decreased viral yield and less toxicity in normal cells but enhanced toxicity in liver cancer cells, compared with the cancer-specific adenovirus ZD55 (E1B55K deletion). Ad.SPDD-HCCS1 exhibited a potent anti-liver-cancer ability and decreased toxicity in vitro. Ad.SPDD-HCCS1 also showed a measurable capacity to inhibit Huh-7 xenograft tumor growth on nude mice. The underlying mechanism of Ad.SPDD-HCCS1-induced liver cancer cell death was found to be via the mitochondrial apoptosis pathway.
These results demonstrate that Ad.SPDD-HCCS1 was able to elicit reduced toxicity and enhanced efficacy both in vitro and in vivo compared to a previously constructed oncolytic adenovirus. Ad.SPDD-HCCS1 could be a promising candidate for liver cancer therapy.
PMCID: PMC3222618  PMID: 22040050
liver cancer; quadruple regulated adenovirus; HCCS1; mitochondrial apoptosis pathway
2.  Ligand Concentration Regulates the Pathways of Coupled Protein Folding and Binding 
Coupled ligand binding and conformational change plays a central role in biological regulation. Ligands often regulate protein function by modulating conformational dynamics, yet the order in which binding and conformational change occurs are often hotly debated. Here we show that the “conformational selection versus induced fit” on which this debate is based is a false dichotomy because the mechanism depends on ligand concentration. Using the binding of pyrophosphate (PPi) to B. subtilis RNase P protein as a model, we show that coupled reactions are best understood as a change in flux between competing pathways with distinct orders of binding and conformational change. The degree of partitioning through each pathway depends strongly on PPi concentration, with ligand binding redistributing the conformational ensemble toward the folded state by both increasing folding rates and decreasing unfolding rates. These results indicate that ligand binding induces marked and varied changes in protein conformational dynamics, and that the order of binding and conformational change is ligand concentration dependent.
PMCID: PMC3977005  PMID: 24364358
3.  The Effects of Tai Chi in Centrally Obese Adults with Depression Symptoms 
This study examined the effects of Tai Chi, a low-impact mind-body movement therapy, on severity of depression, anxiety, and stress symptoms in centrally obese people with elevated depression symptoms. In total, 213 participants were randomized to a 24-week Tai Chi intervention program or a wait-list control group. Assessments were conducted at baseline and 12 and 24 weeks. Outcomes were severity of depression, anxiety, and stress symptoms, leg strength, central obesity, and other measures of metabolic symptom. There were statistically significant between-group differences in favor of the Tai Chi group in depression (mean difference = −5.6 units, P < 0.001), anxiety (−2.3 units, P < 0.01), and stress (−3.6 units, P < 0.001) symptom scores and leg strength (1.1 units, P < 0.001) at 12 weeks. These changes were further improved or maintained in the Tai Chi group relative to the control group during the second 12 weeks of follow-up. Tai Chi appears to be beneficial for reducing severity of depression, anxiety, and stress and leg strength in centrally obese people with depression symptoms. More studies with longer follow-up are needed to confirm the findings. This trial is registered with ACTRN12613000010796.
PMCID: PMC4320798
4.  Ultrasound Molecular Imaging of Vascular Endothelial Growth Factor Receptor 2 Expression for Endometrial Receptivity Evaluation 
Theranostics  2015;5(2):206-217.
Purpose: Ultrasound (US) molecular imaging by examining the expression of vascular endothelial growth factor receptor 2 (VEGFR2) on uterus vascular endothelium was applied to evaluate the endometrial receptivity.
Methods: VEGFR2-targeted ultrasound contrast agents (UCA) and the control UCA (without VEGFR2) were prepared and characterized. Adhesion experiment in vitro was performed with mouse microvascular endothelial cells (bEnd.3) and the ratio of the number of UCA to that of cells at the same field was compared. In vivo study, randomized boluses of targeted or control UCA were injected into the animals of non-pregnancy (D0), pregnancy on day 2 (D2) and day 4 (D4), respectively. Sonograms were acquired by an ultrasound equipment with a 40-MHz high-frequency transducer (Vevo 2100; VisualSonics, Toronto, Canada). The ultrasonic imaging signals were quantified as the video intensity amplitudes generated by the attachment of VEGFR2-targeted UCA. Immunoblotting and immunofluorescence assays were used for confirmation of VEGFR2 expression.
Results: Our results showed that VEGFR2-targeted UCA could bind to bEnd.3 cells with significantly higher affinity than the control UCA (9.8 ± 1.0 bubbles/cell versus 0.7 ± 0.3 bubbles/cell, P < 0.01) in vitro. The mean video intensity from the US backscattering of the retained VEGFR2-targeted UCA was significantly higher than that of the control UCA in D2 and D4 mice (D2, 10.5 ± 2.5 dB versus 1.5 ± 1.1 dB, P < 0.01; D4, 15.7 ± 4.0 dB versus 1.5 ± 1.2 dB, P < 0.01), but not significantly different in D0 mice (1.0 ± 0.8 dB versus 0.9 ± 0.6 dB, P > 0.05). Moreover, D4 mice showed the highest video intensity amplitude, indicating the highest VEGFR2 expression when compared with D2 and D0 mice (P < 0.01). This was further confirmed by our immunoblotting and immunofluorescence experiments.
Conclusion: Ultrasound molecular imaging with VEGFR2-targeted UCA may be used for noninvasive evaluation of endometrial receptivity in murine models.
PMCID: PMC4279005  PMID: 25553109
Endometrial receptivity; Ultrasound molecular imaging; Vascular endothelial growth factor receptor 2.
5.  Development of HIV Reservoir Targeted Long Acting Nanoformulated Antiretroviral Therapies 
Current medicinal chemistry  2014;21(36):4186-4198.
Human immunodeficiency virus (HIV) infection commonly results in a myriad of comorbid conditions secondary to immune deficiency. Infection also affects broad organ system function. Although current antiretroviral therapy (ART) reduces disease morbidity and mortality through effective control of peripheral viral load, restricted infection in HIV reservoirs including gut, lymphoid and central nervous system tissues, is not eliminated. What underlies these events is, in part, poor ART penetrance into each organ across tissue barriers, viral mutation and the longevity of infected cells. We posit that one means to improve these disease outcomes is through nanotechnology. To this end, this review discusses a broad range of cutting-edge nanomedicines and nanomedicine platforms that are or can be used to improve ART delivery. Discussion points include how polymer-drug conjugates, dendrimers, micelles, liposomes, solid lipid nanoparticles and polymeric nanoparticles can be harnessed to best yield cell-based delivery systems. When completely developed, such nanomedicine platforms have the potential to clear reservoirs of viral infection.
PMCID: PMC4281174  PMID: 25174930
Dendrimers; drug delivery systems; gut associated lymphoid tissue; HIV; HIV reservoir targeted ART; liposomes; lymphoid tissues; micelles; nanomedicine; polymeric nanoparticles
6.  Etomidate-Remifentanil is more Suitable for Monitored Anesthesia Care during Gastroscopy in Older Patients than Propofol-Remifentanil 
This prospective and randomized study was designed to compare safety, potential complications, and patient and examiner satisfaction of 2 anesthetic combinations – etomidate-remifentanil and propofol-remifentanil – in elderly patients undergoing diagnostic gastroscopy.
A group of 720 patients, aged 60–80 years, scheduled for diagnostic gastroscopy under sedation were prospectively randomized. After 0.4–0.6 μg kg−1 of remifentanil was infused, etomidate or propofol was administered. Patients in the etomidate group received doses of etomidate at 0.1–0.15 mg kg−1 followed by 4–6 mg. Patients in the propofol group received doses of propofol at 1–2 mg kg−1 followed by 20–40 mg. Physiological indexes were evaluated for the 715 of 720 patients that completed the treatment. The onset time, duration time, and discharge time were recorded. Physicians, anesthetists, and patients were surveyed to assess their satisfaction.
Systolic pressure and diastolic pressure decreased significantly after the procedure in the propofol group (P<0.001). The average heart rate was significantly lower in the propofol group (P<0.05). No periods of desaturation (SpO2 <95%) were observed in either group. The onset time was earlier in the etomidate group (P=0.00). All adverse events, with the exception of myoclonus, were greater in the propofol group, and physician and patient satisfaction in both groups was similar.
Etomidate-remifentanil administration for sedation and analgesia during gastroscopy resulted in more stable hemodynamic responses and less adverse events in older patients.
PMCID: PMC4288392  PMID: 25553506
Etomidate; Gastroscopy; Propofol
7.  Relationship between red blood cell distribution width and intermediate-term mortality in elderly patients after percutaneous coronary intervention 
Large-scale clinical research on the relationship between red blood cell distribution width (RDW) and intermediate-term prognosis in elderly patients with coronary artery disease (CAD) is lacking. Thus, this study investigated the effects of RDW on the intermediate-term mortality of elderly patients who underwent elective percutaneous coronary intervention (PCI).
Data from 1891 patients ≥ 65 years old underwent elective PCI from July 2009 to September 2011 were collected. Based on preoperative median RDW (12.3%), the patients were divided into two groups. The low RDW group (RDW < 12.3%) had 899 cases; the high RDW group (RDW ≥ 12.3%) had 992 cases. The all-cause mortality rates of the two groups were compared.
Patients in the high RDW group were more likely to be female and accompanied with diabetes, had lower hemoglobin level. The mean follow-up period was 527 days. During follow-up, 61 patients died (3.2%). The postoperative mortality of the high RDW group was significantly higher than that of the low RDW group (4.3% vs. 2.0%, P = 0.004). After adjusting other factors, multivariate Cox regression analysis revealed that preoperative high RDW was significantly associated with postoperative all-cause mortality (hazard ratio: 2.301, 95% confidence interval: 1.106–4.785, P = 0.026).
Increased RDW was an independent predictor of the increased intermediate-term all-cause mortality in elderly CAD patients after elective PCI.
PMCID: PMC4308454
Coronary artery disease; Elderly patients; Percutaneous coronary intervention; Red blood cell distribution width
8.  Oxidative Stress-Related Genetic Polymorphisms Are Associated with the Prognosis of Metastatic Gastric Cancer Patients Treated with Epirubicin, Oxaliplatin and 5-Fluorouracil Combination Chemotherapy 
PLoS ONE  2014;9(12):e116027.
Oxidative stress genes are related to cancer development and treatment response. In this study, we aimed to determine the predictive and prognostic roles of oxidative stress-related genetic polymorphisms in metastatic gastric cancer (MGC) patients treated with chemotherapy.
In this retrospective study, we genotyped nine oxidative stress-related single nucleotide polymorphisms (SNPs) in NQO1, SOD2, SOD3, PON1, GSTP1, GSTT1, and NOS3 (rs1800566, rs10517, rs4880, rs1799895, rs662, rs854560, rs1695, rs2266637, rs1799983, respectively) in 108 consecutive MGC patients treated with epirubicin, oxaliplatin, and 5-fluorouracil (EOF) regimen as the first-line chemotherapy and analyzed the association between the genotypes and the disease control rate (DCR), progression-free survival (PFS), and overall survival (OS).
We found that, in addition to a lower pathological grade (p = 0.017), NQO1 rs1800566 CT/TT genotype was an independent predictive factor of poor PFS (hazard ratio [HR] = 1.97, 95% confidence interval [CI] = 1.23–3.16; p = 0.005). PON1 rs662 AA/AG genotype was significantly associated with poor OS (HR = 1.95, 95% CI = 1.07–3.54; p = 0.029). No associations were detected between the nine SNPs and DCR.
NQO1 rs1800566 is an independent predictive factor of PFS for MGC patients treated with EOF chemotherapy, and PON1 rs662 is a noteworthy prognostic factor of OS. Information on oxidative stress-related genetic variants may facilitate optimization of individualized chemotherapy in clinical practice.
PMCID: PMC4278770  PMID: 25545243
9.  Noise alters guinea pig’s blood-labyrinth barrier ultrastructure and permeability along with a decrease of cochlear Claudin-5 and Occludin 
BMC Neuroscience  2014;15(1):136.
Noise exposure (NE) is a severe modern health hazard that induces hearing impairment. However, the noise-induced ultrastructural changes of blood-labyrinth barrier (BLB) and the potential involvements of tight junction proteins (TJP) remain inconclusive.
We investigated the effects of NE on not only the ultrastructure of cochlea and permeability of BLB but also the expression of TJP within the guinea pig cochlea.
Male albino guinea pigs were exposed to white noise for 4 h or 2 consecutive days (115 dB sound pressure level, 6 hours per day) and the hearing impairments and light microscopic change of BLB were evaluated with auditory brainstem responses (ABR) and the cochlear sensory epithelia surface preparation, respectively. The cochlear ultrastructure and BLB permeability after NE 2d were revealed with transmission electron microscope (TEM) and lanthanum nitrate-tracing techniques, respectively. The potential alterations of TJPs Claudin-5 and Occludin were quantified with immunohistochemistry and western blot. NE induced significant hearing impairment and NE 2d contributed to significant outer hair cell (OHC) loss that is most severe in the first row of outer hair cells. Furthermore, the loosen TJ and an obvious leakage of lanthanum nitrate particles beneath the basal lamina were revealed with TEM. Moreover, a dose-dependent decrease of Claudin-5 and Occludin was observed in the cochlea after NE.
All these findings suggest that both decrease of Claudin-5 and Occludin and increased BLB permeability are involved in the pathologic process of noise-induced hearing impairment; however, the causal relationship and underlying mechanisms should be further investigated.
Electronic supplementary material
The online version of this article (doi:10.1186/s12868-014-0136-0) contains supplementary material, which is available to authorized users.
PMCID: PMC4299297  PMID: 25539640
Blood-labyrinth barrier; Noise exposure; Tight-junction proteins
10.  Altered expression of T cell Immunoglobulin-Mucin (Tim) molecules in peripheral blood mononuclear cells in aplastic anemia 
Cancer Cell International  2014;14(1):144.
To evaluate the balance between T-cell immunoglobulin and mucin domain (Tim) molecules(Tim)-1 and Tim-3 in patients with aplastic anemia (AA), plasma IFN-γ and IL-4 levels were measured in patients with active AA (n = 41), AA in remission (n = 29) and in healthy subjects (n = 40) by enzyme linked immunosorbent assay (ELISA). Using real-time quantitative polymerase chain reaction (RT-PCR), the mRNA expression of IFN-γ, IL-4, Tim-1 and Tim-3 were studied in all subjects. The results showed that the expression of Tim-3 in newly diagnosed patients was significantly deceased, compared with the controls. Meanwhile, Tim-1 mRNA expression in the active AA group was not significantly reduced, which resulted in a declined ratio of Tim-3/Tim-1 in patients with active disease. During the remission stages, the levels of these transcription factors were comparable with those observed in the healthy controls. These findings are the first data on the expression of the Tim-1 and Tim-3 molecules in AA. The reduced levels of Tim-3/Tim-1 in PBMCs during the active stages of disease suggest that they may play a possible role in the pathogenesis and course of AA.
PMCID: PMC4278261  PMID: 25548541
Aplastic anemia; T-cell immunoglobulin and mucin domain; IFN-γ; Interleukin 4; Cytokines; RT-PCR
11.  Cloning and expression of visfatin and screening of oligopeptides binding with visfatin 
Purpose: In the present study, we constructed an efficient expression system for visfatin and identified the peptide sequences which binding to visfatin. Methods and results: The fusion protein was identified by SDS-PAGE and Western blot. The yield of visfatin was 300 mg/L culture medium with optimal conditions. The recombinant visfatin binds with insulin receptor with a dose-dependent effect. All of the 24 sequence identified by ELISA were able to bind to visfatin specifically. Among the 24 DNA sequences, there were 8 clones of AAKTPTE, 4 clones of ATTVPAS and 4 clones of MSLQQEH. Conclusion: The sequence of AA(X)TPT(X) was the most frequently existed sequence in all of sequences analyzed, which suggests that AA(X)TPT(X) is likely to be the essential motif in peptides which visfatin could bind with.
PMCID: PMC4307426  PMID: 25663979
Visfatin; adipokine; gene engineering; fusion expression; phage display
12.  The Sheep Genome Illuminates Biology of the Rumen and Lipid Metabolism 
Science (New York, N.Y.)  2014;344(6188):1168-1173.
Sheep (Ovis aries) are a major source of meat, milk and fiber in the form of wool, and represent a distinct class of animals that have a specialized digestive organ, the rumen, which carries out the initial digestion of plant material. We have developed and analyzed a high quality reference sheep genome and transcriptomes from 40 different tissues. We identified highly expressed genes encoding keratin cross-linking proteins associated with rumen evolution. We also identified genes involved in lipid metabolism that had been amplified and/or had altered tissue expression patterns. This may be in response to changes in the barrier lipids of the skin, an interaction between lipid metabolism and wool synthesis, and an increased role of volatile fatty acids in ruminants, compared to non-ruminant animals.
PMCID: PMC4157056  PMID: 24904168
13.  Locally Linear Embedding (LLE) for MRI based Alzheimer’s Disease Classification 
NeuroImage  2013;83:10.1016/j.neuroimage.2013.06.033.
Modern machine learning algorithms are increasingly being used in neuroimaging studies, such as the prediction of Alzheimer’s disease (AD) from structural MRI. However, finding a good representation for multivariate brain MRI features in which their essential structure is revealed and easily extractable has been difficult. We report a successful application of a machine learning framework that significantly improved the use of brain MRI for predictions. Specifically, we used the unsupervised learning algorithm of locally linear embedding (LLE) to transform multivariate MRI data of regional brain volume and cortical thickness to a locally linear space with fewer dimensions, while also utilizing the global nonlinear data structure. The embedded brain features were then used to train a classifier for predicting future conversion to AD based on a baseline MRI. We tested the approach on 413 individuals from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) who had baseline MRI scans and complete clinical follow-ups over 3 years with following diagnoses: Cognitive normal (CN; n= 137), stable mild cognitive impairment (s-MCI; n=93), MCI converters to AD (c-MCI, n=97), and AD (n=86). We found classifications using embedded MRI features generally outperformed (p < 0.05) classifications using the original features directly. Moreover, the improvement from LLE was not limited to a particular classifier but worked equally well for regularized logistic regressions, support vector machines, and linear discriminant analysis. Most strikingly, using LLE significantly improved (p = 0.007) predictions of MCI subjects who converted to AD and those who remained stable (accuracy/sensitivity/specificity: = 0.68/0.80/0.56). In contrast, predictions using the original features performed not better than by chance (accuracy/sensitivity/specificity: = 0.56/0.65/0.46). In conclusion, LLE is a very effective tool for classification studies of AD using multivariate MRI data. The improvement in predicting conversion to AD in MCI could have important implications for health management and for powering therapeutic trials by targeting non-demented subjects who later convert to AD.
PMCID: PMC3815961  PMID: 23792982
Alzheimer’s disease; locally linear embedding; statistical learning; classification of AD; MRI
14.  Developing an in vitro model of T cell type of large granular lymphocyte leukemia 
Leukemia research  2013;37(12):10.1016/j.leukres.2013.10.002.
We developed a strategy that can prolong in vitro growth of T cell type of large granular lymphocyte (T-LGL) leukemia cells. Primary CD8+ lymphocytes from T-LGL leukemia patients were stably transduced with the retroviral tax gene derived from human T cell leukemia virus type 2. Expression of Tax overrode replicative senescence and promoted clonal expansion of the leukemic CD8+ T cells. These cells exhibit features characteristic of leukemic LGL, including resistance to FasL-mediated apoptosis, sensitivity to the inhibitors of sphingosine-1-phosphate receptor and IκB kinases as well as expression of cytotoxic gene products such as granzyme B, perforin and IFNγ. Collectively, these results indicate that this leukemia cell model can duplicate the main phenotype and pathophysiological characteristics of the clinical isolates of T-LGL leukemia. This model should be useful for investigating molecular pathogenesis of the disease and for developing new therapeutics targeting T-LGL leukemia.
PMCID: PMC3865428  PMID: 24183305
T-LGLL; Stat3; NF-κB; retroviral Tax oncoprotein
15.  Pharmacokinetics, Biodistribution, and Toxicity of Folic Acid-Coated Antiretroviral Nanoformulations 
Antimicrobial Agents and Chemotherapy  2014;58(12):7510-7519.
The drug delivery platform for folic acid (FA)-coated nanoformulated ritonavir (RTV)-boosted atazanavir (FA-nanoATV/r) using poloxamer 407 was developed to enhance cell and tissue targeting for a range of antiretroviral drugs. Such formulations would serve to extend the drug half-life while improving the pharmacokinetic profile and biodistribution to reservoirs of human immunodeficiency virus (HIV) infection. To this end, we now report enhanced pharmacokinetics and drug biodistribution with limited local and systemic toxicities of this novel nanoformulation. The use of FA as a targeting ligand for nanoATV/r resulted in plasma and tissue drug concentrations up to 200-fold higher compared to equimolar doses of native drug. In addition, ATV and RTV concentrations in plasma from mice on a folate-deficient diet were up to 23-fold higher for mice administered FA-nanoATV/r than for mice on a normal diet. Compared to earlier nanoATV/r formulations, FA-nanoATV/r resulted in enhanced and sustained plasma and tissue ATV concentrations. In a drug interaction study, ATV plasma and tissue concentrations were up to 5-fold higher in mice treated with FA-nanoATV/r than in mice treated with FA-nanoATV alone. As observed in mice, enhanced and sustained plasma concentrations of ATV were observed in monkeys. NanoATV/r was associated with transient local inflammation at the site of injection. There were no systemic adverse reactions associated with up to 10 weeks of chronic exposure of mice or monkeys to FA-nanoATV/r.
PMCID: PMC4249580  PMID: 25288084
16.  RNA Polymerase II Transcription: Structure and Mechanism 
Biochimica et biophysica acta  2012;1829(1):2-8.
A minimal RNA polymerase II (pol II) transcription system comprises the polymerase and five general transcription factors (GTFs) TFIIB, -D, -E, -F, and -H. The addition of Mediator enables a response to regulatory factors. The GTFs are required for promoter recognition and the initiation of transcription. Following initiation, pol II alone is capable of RNA transcript elongation and of proofreading. Structural studies reviewed here reveal roles of GTFs in the initiation process and shed light on the transcription elongation mechanism.
PMCID: PMC4244541  PMID: 23000482
17.  The Prevalence of Antinuclear Antibodies in the General Population of China: A Cross-Sectional Study 
The incidence of autoimmune diseases such as systemic lupus erythematosus, rheumatoid arthritis, and primary biliary cirrhosis has increased significantly in China. Information about the susceptibility or potential of autoimmune diseases in the general population is lacking.
To explore the prevalence of antinuclear antibody (ANA) and its specificities in the general population in China.
Twenty thousand nine hundred seventy sera samples were taken from the physical examination center in Baoding, China. Indirect immunofluorescence and line immunoassays were used to detect ANA and its specificities, respectively.
Samples from females had a higher prevalence of ANA than samples from males (χ2 = 278.55; P < 0.01). For both sexes, the prevalence of ANA positively correlated with age and there were significant differences among different age groups at 10-year intervals, except the 80 years group (P < 0.05). One thousand two hundred forty-three ANA-positive samples were further analyzed with line immunoassays. There was a significant difference among age groups and between sex groups in terms of the specific autoantibodies (P < 0.01). The autoantibodies with the top-3 positive frequencies were anti-Ro-52, anti-M2, and anti-SSA.
There was a high prevalence of ANA positivity in the general Chinese population that seemed to be influenced by sex and age and correlated with specific autoantibodies.
PMCID: PMC4245690  PMID: 25473438
antinuclear antibody; autoimmune diseases; Chinese; prevalence
18.  Requirement of HIV-1 Vif C-terminus for Vif-CBF-β interaction and assembly of CUL5-containing E3 ligase 
BMC Microbiology  2014;14(1):290.
Human immunodeficiency virus type 1 (HIV-1) Vif hijacks an E3 ligase to suppress natural APOBEC3 restriction factors, and core binding factor β (CBF-β) is required for this process. Although an extensive region of Vif spanning most of its N-terminus is known to be critical for binding with CBF-β, involvement of the Vif C-terminus in the interaction with CBF-β has not been fully investigated.
Here, through immunoprecipitation analysis of Vif C-terminal truncated mutants of various lengths, we identified that CBF-β binding requires not only certain amino acids (G126A, E134A, Y135A and G138A) in the HCCH region but also the HCCH motif itself, which also affects the Vif-mediated suppression of APOBEC3G/APOBEC3F (A3G/A3F). These mutants still maintained interactions with substrate A3G or A3F as well as other cellular factors ElonginB/C (ELOB/C), indicating that their structures were not functionally affected. Moreover, by determining that the BC box also is necessary for CBF-β interaction in vivo, we speculate that binding to ELOB/C induces conformational changes in Vif, facilitating its interaction with CBF-β and consequent interaction with CUL5.
These results provide important information on the assembly of the Vif-CUL5-E3 ubiquitin ligase. Identification of the new binding interface with CBF-β at the C-terminus of HIV-1 Vif also provides novel targets for the development of HIV-1 inhibitors.
PMCID: PMC4265484  PMID: 25424878
HIV-1 Vif; CBF-β; C-terminus; APOBEC3
19.  A numerical study of the effect of varied blood pressure on the stability of carotid atherosclerotic plaque 
Blood pressure (BP) is associated with early atherosclerosis and plaque rupture because the BP variability can significantly affect the blood flow velocity and shear stress over the plaque. However, the mechanical response of BP variability to the plaque remains unclear. Therefore, we investigated the correlation between different maximum systolic blood pressure (SBP) and the stress distribution on plaque, as well as the stress over the plaque and blood velocity around the plaque using different BP variations, which are the BP variability in different phases during one cardiac cycle and beat-to-beat BP variability.
We established a two-dimensional artery model with stenosis at the degree of 62.5%. Eight combinations of pulsatile pressure gradients between the inflow and outflow were implemented at the model. Three levels of fibrous cap thickness were taken into consideration to investigate the additional effect on the BP variability. Wall shear stress and stress/strain distribution over the plaque were derived as well as the oscillation shear index (OSI) to analyze the impact of the changing rate of BP.
The stresses at diastole were 2.5% ± 1.8% lower than that at systole under the same pressure drop during one cycle. It was also found that elevated SBP might cause the immediate increment of stress in the present cycle (292% ± 72.3%), but slight reduction in the successive cycle (0.48% ± 0.4%).
The stress/strain distribution over the plaque is sensitive to the BP variability during one cardiac cycle, and the beat-to-beat BP variability could cause considerable impact on the progression of atherosclerosis in long-term.
PMCID: PMC4277844  PMID: 25413300
Atherosclerotic plaque vulnerability; Stress distribution; Blood pressure; Computational mechanical analysis
20.  Synthesis and discovery of 18α-GAMG as anticancer agent in vitro and in vivo via down expression of protein p65 
Scientific Reports  2014;4:7106.
Glycyrrhizic acid (GA) is a natural product with favorable antitumor activity. But, glycyrrhetinic acid monoglucuronide (GAMG) showed stronger antitumor activity than GA. It is of our interest to generate and identify novel compounds with regulation telomerase for cancer therapy. So, in this study, 18α-GAMG was synthesized via biotransformation. In vitro studies showed that it displayed potent anticancer activity and high selectivity on tumor liver cell SMMC-7721 versus human normal liver cell L-02. The further results in vivo confirmed that it could significantly improve pathological changes of N,N-diethylnitrosamine (DEN)-induced rat hepatic tumor. Western blot and immunofluorescence results indicated that the expression of p65-telomerase reverse transcriptase (TERT) was clearly down-regulated treated with it. Taken together, this study for the first time identified an active compound with high selectivity on tumor liver cell in mice. Furthermore, the title compound could inhibit the expression of protein p65 and TERT. These data support further studies to assess the rational design of more efficient p65 modulators in the future.
PMCID: PMC4236752  PMID: 25407586
21.  The Positive Regulatory Roles of the TIFY10 Proteins in Plant Responses to Alkaline Stress 
PLoS ONE  2014;9(11):e111984.
The TIFY family is a novel plant-specific protein family, and is characterized by a conserved TIFY motif (TIFF/YXG). Our previous studies indicated the potential roles of TIFY10/11 proteins in plant responses to alkaline stress. In the current study, we focused on the regulatory roles and possible physiological and molecular basis of the TIFY10 proteins in plant responses to alkaline stress. We demonstrated the positive function of TIFY10s in alkaline responses by using the AtTIFY10a and AtTIFY10b knockout Arabidopsis, as evidenced by the relatively lower germination rates of attify10a and attify10b mutant seeds under alkaline stress. We also revealed that ectopic expression of GsTIFY10a in Medicago sativa promoted plant growth, and increased the NADP-ME activity, citric acid content and free proline content but decreased the MDA content of transgenic plants under alkaline stress. Furthermore, expression levels of the stress responsive genes including NADP-ME, CS, H+-ppase and P5CS were also up-regulated in GsTIFY10a transgenic plants under alkaline stress. Interestingly, GsTIFY10a overexpression increased the jasmonate content of the transgenic alfalfa. In addition, we showed that neither GsTIFY10a nor GsTIFY10e exhibited transcriptional activity in yeast cells. However, through Y2H and BiFc assays, we demonstrated that GsTIFY10a, not GsTIFY10e, could form homodimers in yeast cells and in living plant cells. As expected, we also demonstrated that GsTIFY10a and GsTIFY10e could heterodimerize with each other in both yeast and plant cells. Taken together, our results provided direct evidence supporting the positive regulatory roles of the TIFY10 proteins in plant responses to alkaline stress.
PMCID: PMC4222965  PMID: 25375909
22.  Automated Detection Framework of the Calcified Plaque with Acoustic Shadowing in IVUS Images 
PLoS ONE  2014;9(11):e109997.
Intravascular Ultrasound (IVUS) is one ultrasonic imaging technology to acquire vascular cross-sectional images for the visualization of the inner vessel structure. This technique has been widely used for the diagnosis and treatment of coronary artery diseases. The detection of the calcified plaque with acoustic shadowing in IVUS images plays a vital role in the quantitative analysis of atheromatous plaques. The conventional method of the calcium detection is manual drawing by the doctors. However, it is very time-consuming, and with high inter-observer and intra-observer variability between different doctors. Therefore, the computer-aided detection of the calcified plaque is highly desired. In this paper, an automated method is proposed to detect the calcified plaque with acoustic shadowing in IVUS images by the Rayleigh mixture model, the Markov random field, the graph searching method and the prior knowledge about the calcified plaque. The performance of our method was evaluated over 996 in-vivo IVUS images acquired from eight patients, and the detected calcified plaques are compared with manually detected calcified plaques by one cardiology doctor. The experimental results are quantitatively analyzed separately by three evaluation methods, the test of the sensitivity and specificity, the linear regression and the Bland-Altman analysis. The first method is used to evaluate the ability to distinguish between IVUS images with and without the calcified plaque, and the latter two methods can respectively measure the correlation and the agreement between our results and manual drawing results for locating the calcified plaque in the IVUS image. High sensitivity (94.68%) and specificity (95.82%), good correlation and agreement (>96.82% results fall within the 95% confidence interval in the Student t-test) demonstrate the effectiveness of the proposed method in the detection of the calcified plaque with acoustic shadowing in IVUS images.
PMCID: PMC4220935  PMID: 25372784
23.  A genome-wide association study of limb bone length using a Large White × Minzhu intercross population 
In pig, limb bone length influences ham yield and body height to a great extent and has important economic implications for pig industry. In this study, an intercross population was constructed between the indigenous Chinese Minzhu pig breed and the western commercial Large White pig breed to examine the genetic basis for variation in limb bone length. The aim of this study was to detect potential genetic variants associated with porcine limb bone length.
A total of 571 F2 individuals from a Large White and Minzhu intercross population were genotyped using the Illumina PorcineSNP60K Beadchip, and phenotyped for femur length (FL), humerus length (HL), hipbone length (HIPL), scapula length (SL), tibia length (TL), and ulna length (UL). A genome-wide association study was performed by applying the previously reported approach of genome-wide rapid association using mixed model and regression. Statistical significance of the associations was based on Bonferroni-corrected P-values.
A total of 39 significant SNPs were mapped to a 11.93 Mb long region on pig chromosome 7 (SSC7). Linkage analysis of these significant SNPs revealed three haplotype blocks of 495 kb, 376 kb and 492 kb, respectively, in the 11.93 Mb region. Annotation based on the pig reference genome identified 15 genes that were located near or contained the significant SNPs in these linkage disequilibrium intervals. Conditioned analysis revealed that four SNPs, one on SSC2 and three on SSC4, showed significant associations with SL and HL, respectively.
Analysis of the 15 annotated genes that were identified in these three haplotype blocks indicated that HMGA1 and PPARD, which are expressed in limbs and influence chondrocyte cell growth and differentiation, could be considered as relevant biological candidates for limb bone length in pig, with potential applications in breeding programs. Our results may also be useful for the study of the mechanisms that underlie human limb length and body height.
Electronic supplementary material
The online version of this article (doi:10.1186/s12711-014-0056-6) contains supplementary material, which is available to authorized users.
PMCID: PMC4219012  PMID: 25366846
24.  Macrophage Folate Receptor-Targeted Antiretroviral Therapy Facilitates Drug Entry, Retention, Antiretroviral Activities and Biodistribution for Reduction of Human Immunodeficiency Virus Infections 
Nanomedicine : nanotechnology, biology, and medicine  2013;9(8):10.1016/j.nano.2013.05.003.
Macrophages serve as vehicles for the carriage and delivery of polymer-coated nanoformulated antiretroviral therapy (nanoART). Although superior to native drug, high drug concentrations are required for viral inhibition. Herein, folate-modified atazanavir/ritonavir (ATV/r)-encased polymers facilitated macrophage receptor targeting for optimizing drug dosing. Folate coating of nanoART ATV/r significantly enhanced cell uptake, retention and antiretroviral activities without altering cell viability. Enhanced retentions of folate-coated nanoART within recycling endosomes provided a stable subcellular drug depot. Importantly, five-fold enhanced plasma and tissue drug levels followed folate-coated formulation injection in mice. Folate polymer encased ATV/r improves nanoART pharmacokinetics bringing the technology one step closer to human use.
PMCID: PMC3779529  PMID: 23680933
human immunodeficiency virus; nanoART; ATV/r; targeted drug delivery; folate; poloxamer 407; macrophages
25.  Natural product agonists of peroxisome proliferator-activated receptor gamma (PPARγ): a review 
Biochemical Pharmacology  2014;92(1):73-89.
Graphical abstract
Agonists of the nuclear receptor PPARγ are therapeutically used to combat hyperglycaemia associated with the metabolic syndrome and type 2 diabetes. In spite of being effective in normalization of blood glucose levels, the currently used PPARγ agonists from the thiazolidinedione type have serious side effects, making the discovery of novel ligands highly relevant.
Natural products have proven historically to be a promising pool of structures for drug discovery, and a significant research effort has recently been undertaken to explore the PPARγ-activating potential of a wide range of natural products originating from traditionally used medicinal plants or dietary sources. The majority of identified compounds are selective PPARγ modulators (SPPARMs), transactivating the expression of PPARγ-dependent reporter genes as partial agonists. Those natural PPARγ ligands have different binding modes to the receptor in comparison to the full thiazolidinedione agonists, and on some occasions activate in addition PPARα (e.g. genistein, biochanin A, sargaquinoic acid, sargahydroquinoic acid, resveratrol, amorphastilbol) or the PPARγ-dimer partner retinoid X receptor (RXR; e.g. the neolignans magnolol and honokiol). A number of in vivo studies suggest that some of the natural product activators of PPARγ (e.g. honokiol, amorfrutin 1, amorfrutin B, amorphastilbol) improve metabolic parameters in diabetic animal models, partly with reduced side effects in comparison to full thiazolidinedione agonists. The bioactivity pattern as well as the dietary use of several of the identified active compounds and plant extracts warrants future research regarding their therapeutic potential and the possibility to modulate PPARγ activation by dietary interventions or food supplements.
PMCID: PMC4212005  PMID: 25083916
PPAR gamma; Nuclear receptor; Natural product; Nutrition; Diabetes; 9-(S)-HODE, (9S,10E,12Z)-9-hydroxyoctadeca-10,12-dienoic acid; AF-2, activation function-2; CAP, c-Cbl-associated protein; Cdk5, cyclin-dependent kinase 5; DCM, dichloromethane; DIO, diet-induced obesity; DPP-4, dipeptidylpeptidase 4; EMA, European Medicines Agency; FDA, Food and Drug Administration; Glut4, glucose transporter type 4; HDL, high-density lipoprotein; HUVEC, human umbilical vein endothelial cells; LBD, ligand-binding domain; LDL, low-density lipoprotein; MAPK, mitogen-activated protein kinase; MeOH, methanol; NF-κB, nuclear factor-kappaB; PPAR, peroxisome proliferator-activated receptor; RXR, retinoid X receptor; PDB, protein data bank; PPRE, peroxisome proliferator response element; SPPARMs, selective PPARγ modulators; TCM, traditional Chinese medicine; TNF-α, tumor necrosis factor alpha

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