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1.  Effect of Dan Hong injection on PON1, SOD activity and MDA levels in elderly patients with coronary heart disease 
Objective: To research the effect of Dan Hong injection (DHI) on PON1, SOD activity and MDA levels in elderly patients with coronary heart disease (CHD). Methods: 98 elderly patients with CHD diagnosed by coronary angiography were randomly divided into conventional treatment group and DHI treatment group, measured and analysis the serum PON1 activity, SOD and MDA levels before and after treatment in the two groups. Results: PON1 and SOD activity in elderly CHD patients were significantly lower than elderly non-coronary heart disease group, there was a significant difference between the two groups (P < 0.01); and MDA level in elderly CHD patients was significantly higher than elderly non-coronary heart disease group, there was a significant difference between the two groups (P < 0.01). There was a major change in PON1 activity, SOD and MDA after 4 weeks DHI treatment (P < 0.05). There was different degrees of change in PON activity, SOD and MDA after 4 weeks conventional treatment when compared with pre-administer DHI, but did not reach significant difference (P > 0.05); PON1 activity, SOD and MDA had significant different after 4 weeks treatment in DHI group compared with the conventional treatment group (P < 0.05). Conclusions: There is lipid peroxidation in the elderly patients with the coronary heart disease. DHI can raise serum PON1, SOD activity and lower MDA to improve the antioxidant effect in elderly patients with coronary heart disease.
PMCID: PMC4307573  PMID: 25664126
Dan Hong injection; elderly; coronary heart disease; paraoxonase; malondialdehyde; superoxide dismutase; lipid peroxidation
2.  Smart Soup, a Traditional Chinese Medicine Formula, Ameliorates Amyloid Pathology and Related Cognitive Deficits 
PLoS ONE  2014;9(11):e111215.
Alzheimer’s disease (AD) is a progressive neurodegenerative disease that causes substantial public health care burdens. Intensive efforts have been made to find effective and safe disease-modifying treatment and symptomatic intervention alternatives against AD. Smart Soup (SS), a Chinese medicine formula composed of Rhizoma Acori Tatarinowii (AT), Poria cum Radix Pini (PRP) and Radix Polygalae (RP), is a typical prescription against memory deficits. Here, we assessed the efficacy of SS against AD. Oral administration of SS ameliorated the cognitive impairment of AD transgenic mice, with reduced Aβ levels, retarded Aβ amyloidosis and reduced Aβ-induced gliosis and neuronal loss in the brains of AD mice. Consistently, SS treatment reduced amyloid-related locomotor dysfunctions and premature death of AD transgenic Drosophila. Mechanistic studies showed that RP reduced Aβ generation, whereas AT and PRP exerted neuroprotective effects against Aβ. Taken together, our study indicates that SS could be effective against AD, providing a practical therapeutic strategy against the disease.
PMCID: PMC4227681  PMID: 25386946
4.  Effects of synthetic colloid and crystalloid solutions on hemorheology in vitro and in hemorrhagic shock 
Plasma expanders are commonly used in the management of critically ill patients, which may exhibit altered hemorheology. We evaluated the effects of various synthetic colloids and Lactated Ringer’s (LR) solution on hemorheological parameters in vitro and in a rodent hemorrhagic shock model.
For the in vitro experiments, rat blood was incubated with hydroxyethyl starch (HES) 130/0.4, HES 200/0.5, succinylated gelatine (GEL), or LR at various ratios. The control consisted of blood without dilution. The hemorheological parameters were measured after a 15-min incubation. For the in vivo study, rats were subjected to a severe volume-controlled hemorrhage and were resuscitated using a colloid solution (HES 130/0.4, HES 200/0.5, or GEL) or LR. The hemorheological parameters were measured 2 h after resuscitation.
The GEL significantly elevated the plasma viscosity compared to the other groups. In the in vitro study, GEL and LR accelerated the erythrocyte aggregation. There was no significant difference between HES 130/0.4, HES 200/0.5, and control groups regarding the aggregation amplitude and index. In the in vivo study, the aggregation amplitude increased significantly in the GEL group compared to the HES 130/0.4, HES 200/0.5, LR, and sham groups. There was no significant difference between the groups with respect to the elongation index in vivo.
Hydroxyethyl starch did not change the erythrocyte aggregation compared to the control. GEL significantly accelerates the erythrocyte aggregation and elevates the plasma viscosity compared to hydroxyethyl starch. The in vitro hemorheological measurements most likely provide hints for the in vivo study.
PMCID: PMC4323036  PMID: 25649347
Plasma expander; Synthetic colloids; Hemorrhagic shock; Plasma viscosity; Erythrocyte aggregation
5.  Notch1 signaling regulates the epithelial–mesenchymal transition and invasion of breast cancer in a Slug-dependent manner 
Molecular Cancer  2015;14(1):28.
The epithelial–mesenchymal transition (EMT) is crucial for the invasion and metastasis of breast cancer. However, how Notch signaling regulates the EMT process and invasion in breast cancer remains largely unknown.
The impact of Notch1 silencing by specific shRNAs on the EMT and invasion of human breast cancer MCF-7 and MDA-MB-231 cells as well as xenografts was tested by western blot, real-time polymerase chain reaction (RT-PCR), immunofluorescence, transwell, and immunohistochemistry assays. The effect of Slug silencing or upregulation on the EMT and invasion of breast cancer cells was analyzed, and the effect of Notch1 signaling on Slug expression was determined by the luciferase reporter assay.
The Notch1 intracellular domain (N1ICD) and Jagged1 were expressed in breast cancer cells. Notch1 silencing reversed the spontaneous EMT process and inhibited the migration and invasion of breast cancer cells and the growth of xenograft breast cancers. The expression of N1ICD was upregulated significantly by Jagged1-mediated Notch signaling activation. Moreover, Jagged1-mediated Notch signaling promoted the EMT process, migration, and invasion of breast cancer cells, which were abrogated by Notch silencing. Furthermore, the N1ICD positively regulated the Slug expression by inducing Slug promoter activation. Importantly, the knockdown of Slug weakened the invasion ability of breast cancer cells and reversed the Jagged1-induced EMT process with significantly decreased expression of vimentin and increased expression of E-cadherin. In addition, Slug overexpression restored the Notch1 knockdown-suppressed EMT process.
Our novel data indicate that Notch signaling positively regulates the EMT, invasion, and growth of breast cancer cells by inducing Slug expression. The Notch1–Slug signaling axis may represent a potential therapeutic target for breast cancer therapy.
Electronic supplementary material
The online version of this article (doi:10.1186/s12943-015-0295-3) contains supplementary material, which is available to authorized users.
PMCID: PMC4322803  PMID: 25645291
Breast cancer; Notch1 signaling; Invasion; Epithelial-mesenchymal transition; Slug
6.  Related Factors and Adverse Neonatal Outcomes in Women with Preterm Premature Rupture of Membranes Complicated by Histologic Chorioamnionitis 
The aim of this study was to identify factors predicting histologic chorioamnionitis (HCA) in women with preterm premature rupture of membranes (PPROM).
We retrospectively enrolled 371 women diagnosed with PPROM at less than 34 weeks of gestation at the Second Affiliated Hospital of Wenzhou Medical University between January 2008 and December 2012. HCA was diagnosed by placental histopathology in 70% of participants. Binary logistic regression was used to identify factors associated with HCA and neonatal outcomes.
Patient age, rate of parity, tocolysis, cesarean section, serum C reactive protein (CRP) level at admission, white blood cell count, and latency duration did not significantly differ between the 2 groups. Binary logistic regression revealed that oligohydramnios at admission, gestational age at PPROM, and serum CRP >8 mg/L before delivery were significantly associated with HCA. Gestational age at delivery and birth weight were significantly lower in HCA patients than control patients. The rate of 1-min Apgar score <7, abnormal neonatal intracranial ultrasound findings, neonatal pneumonia, bronchopulmonary dysplasia, early-onset neonatal sepsis, and mortality were higher in HCA patients, but no significant difference was observed in the incidence of neonatal respiratory distress syndrome, necrotizing enterocolitis, hyperbilirubinemia, or hypoglycemia.
Younger gestational age at time of PPROM, higher CRP level before delivery, and oligohydramnios at admission in women with PPROM are associated with HCA, and HCA is associated with some adverse neonatal outcomes.
PMCID: PMC4325828  PMID: 25644559
Chorioamnionitis; Gestational Age; Neonatal Abstinence Syndrome
7.  Direct Interaction between the WD40 Repeat Protein WDR-23 and SKN-1/Nrf Inhibits Binding to Target DNA 
Molecular and Cellular Biology  2014;34(16):3156-3167.
SKN-1/Nrf transcription factors activate cytoprotective genes in response to reactive small molecules and strongly influence stress resistance, longevity, and development. The molecular mechanisms of SKN-1/Nrf regulation are poorly defined. We previously identified the WD40 repeat protein WDR-23 as a repressor of Caenorhabditis elegans SKN-1 that functions with a ubiquitin ligase to presumably target the factor for degradation. However, SKN-1 activity and nuclear accumulation are not always correlated, suggesting that there could be additional regulatory mechanisms. Here, we integrate forward genetics and biochemistry to gain insights into how WDR-23 interacts with and regulates SKN-1. We provide evidence that WDR-23 preferentially regulates one of three SKN-1 variants through a direct interaction that is required for normal stress resistance and development. Homology modeling predicts that WDR-23 folds into a β-propeller, and we identify the top of this structure and four motifs at the termini of SKN-1c as essential for the interaction. Two of these SKN-1 motifs are highly conserved in human Nrf1 and Nrf2 and two directly interact with target DNA. Lastly, we demonstrate that WDR-23 can block the ability of SKN-1c to interact with DNA sequences of target promoters identifying a new mechanism of regulation that is independent of the ubiquitin proteasome system, which can become occupied with damaged proteins during stress.
PMCID: PMC4135592  PMID: 24912676
8.  Novel Outer Membrane Protein Involved in Cellulose and Cellooligosaccharide Degradation by Cytophaga hutchinsonii 
Applied and Environmental Microbiology  2014;80(15):4511-4518.
Cytophaga hutchinsonii is an aerobic cellulolytic soil bacterium which was reported to use a novel contact-dependent strategy to degrade cellulose. It was speculated that cellooligosaccharides were transported into the periplasm for further digestion. In this study, we reported that most of the endoglucanase and β-glucosidase activity was distributed on the cell surface of C. hutchinsonii. Cellobiose and part of the cellulose could be hydrolyzed to glucose on the cell surface. However, the cell surface cellulolytic enzymes were not sufficient for cellulose degradation by C. hutchinsonii. An outer membrane protein, CHU_1277, was disrupted by insertional mutation. Although the mutant maintained the same endoglucanase activity and most of the β-glucosidase activity, it failed to digest cellulose, and its cellooligosaccharide utilization ability was significantly reduced, suggesting that CHU_1277 was essential for cellulose degradation and played an important role in cellooligosaccharide utilization. Further study of cellobiose hydrolytic ability of the mutant on the enzymatic level showed that the β-glucosidase activity in the outer membrane of the mutant was not changed. It revealed that CHU_1277 played an important role in assisting cell surface β-glucosidase to exhibit its activity sufficiently. Studies on the outer membrane proteins involved in cellulose and cellooligosaccharide utilization could shed light on the mechanism of cellulose degradation by C. hutchinsonii.
PMCID: PMC4148786  PMID: 24837387
9.  Macrophage Mitochondrial Oxidative Stress Promotes Atherosclerosis and NF-κB-Mediated Inflammation in Macrophages 
Circulation research  2013;114(3):421-433.
Mitochondrial oxidative stress (mitoOS) has been shown to correlate with the progression of human atherosclerosis. However, definitive cell-type specific causation studies in vivo are lacking, and the molecular mechanisms of potential pro-atherogenic effects remain to be determined.
To assess the importance of macrophage mitoOS in atherogenesis and explore the underlying molecular mechanisms.
Methods & Results
We first validated Western-type diet-fed Ldlr-/- mice as a model of human mitoOS-atherosclerosis association by showing that a marker of mitoOS in lesional macrophages, non-nuclear oxidative DNA damage, correlates with aortic root lesion development. To investigate the importance of macrophage-mitoOS, we used a genetic engineering strategy in which the OS suppressor catalase was ectopically expressed in mitochondria (mCAT) in macrophages. MitoOS in lesional macrophages was successfully suppressed in these mice, and this led to a significant reduction in aortic root lesional area. The mCAT lesions had less monocyte-derived cells, less Ly6chi monocyte infiltration into lesions, and lower levels of the monocyte chemotactic protein-1 (MCP-1). The decrease in lesional MCP-1 was associated with suppression of other markers of inflammation and with decreased phosphorylation of RelA (NF-κB p65), indicating decreased activation of the pro-inflammatory NF-κB pathway. Using models of mitoOS in cultured macrophages, we showed that mCAT suppressed MCP-1 expression by decreasing activation of the Iκ-kinase-RelA NF-κB pathway.
MitoOS in lesional macrophages amplifies atherosclerotic lesion development by promoting NF-κB-mediated entry of monocytes and other inflammatory processes. In view of the mitoOS-atherosclerosis link in human atheromata, these findings reveal a potentially new therapeutic target to prevent the progression of atherosclerosis.
PMCID: PMC3946745  PMID: 24297735
Mitochondrial oxidative stress; atherosclerosis; macrophage; reactive oxygen species (ROS); NF-κB
10.  Global Deletion of Trp53 Reverts Ovarian Tumor Phenotype of the Germ Cell–Deficient White Spotting Variant (Wv) Mice1 
Neoplasia (New York, N.Y.)  2015;17(1):89-100.
White spotting variant (Wv) mice are spontaneous mutants attributed to a point mutation in the c-Kit gene, which reduces the tyrosine kinase activity to around 1% and affects the development of melanocytes, mast cells, and germ cells. Homozygous mutant mice are sterile but can live nearly a normal life span. The female Wv mice have a greatly reduced ovarian germ cell and follicle reserve at birth, and the remaining follicles are largely depleted soon after the females reach reproductive stage at around 7 weeks of age. Consequently, ovarian epithelial tumors develop in 100% of Wv females by 3 to 4 months of age. These tumors, called tubular adenomas, are benign but can become invasive in older Wv mice.
We tested if additional genetic mutation(s) could convert the benign ovarian epithelial tumors to malignant tumors by crossing the Wv mutant into the Trp53 knockout background. Surprisingly, we found that global deletion of Trp53 suppressed the development of ovarian tubular adenomas in Wv mice. The ovaries of Wv/Wv; Trp53 (−/−) mice were covered by a single layer of surface epithelium and lacked excessive epithelial proliferation. Rather, the ovaries contained a small number of follicles. The presence of ovarian follicles and granulosa cells, as indicated by Pgc7 and inhibin-alpha expression, correlated with the absence of epithelial lesions. A reduction of Pten gene dosage, as in Wv/Wv; Pten (+/−) mice, produced a similar, though less dramatic, phenotype. We conclude that deletion of Trp53 prolongs the survival of ovarian follicles in Wv mice and consequently prevents the proliferation of ovarian epithelial cells and development of ovarian tubular adenomas. The results suggest that various cell types within the ovary communicate and mutually modulate, and an intact tissue environment is required to ensure homeostasis of ovarian surface epithelial cells. Especially, the current finding emphasizes the importance of ovarian follicles in suppressing the hyperplastic growth of ovarian epithelial cells, dominating over the loss of p53.
PMCID: PMC4309726  PMID: 25622902
11.  Hormonal regulators of muscle and metabolism in aging (HORMA): design and conduct of a complex, double masked multicenter trial 
Older persons often lose muscle mass, strength, and physical function. This report describes the challenges of conducting a complex clinical investigation assessing the effects of anabolic hormones on body composition, physical function, and metabolism during aging.
HORMA is a multicenter, randomized double masked study of 65–90-year-old community dwelling men with testosterone levels of 150–550 ng/dL and IGF-1 < 167 ng/dL. Subjects were randomized to transdermal testosterone (5 or 10 g/day) and rhGH (0, 3, or 5 μg/kg/day) for 16 weeks. Outcome measures included body composition by DEXA, MRI, and 2H2O dilution; muscle performance (strength, power, and fatigability), VO2peak, measures of physical function, synthesis/breakdown of myofibrillar proteins, other measures of metabolism, and quality of life.
Major challenges included delay in startup caused by need for 7 institutional contracts, creating a 142-page manual of operations, orientation and training, creating a 121-page CRF; enrollment inefficiencies; scheduling 16 evaluations/subject; overnight admissions for invasive procedures and isotope infusions; large data and image management and transfer; quality control at multiples sites; staff turnover; and replacement of a clinical testing site. Impediments were largely solved by implementation of a web-based data entry and eligibility verification; electronic scheduling for multiple study visits; availability of research team members to educate and reassure subjects; more frequent site visits to validate all source documents and reliability of data entry; and intensifying quality control in testing and imaging. The study exceeded the target goal of 108 (n =112) completely evaluable cases. Two interim DSMB meetings confirmed the lack of excessive adverse events, lack of center effects, comparability of subjects, and that distribution of subjects and enrollment will not jeopardize outcomes or generalizability of results.
Flexibility and rapidly solving evolving problems is critical when conducting highly complex multicenter metabolic studies.
PMCID: PMC4301418  PMID: 17942471
12.  T cell-NF-κB activation is required for tumor control in vivo 
T cells have the capacity to eliminate tumors but the signaling pathways by which they do so are incompletely understood. T cell priming requires activation of the transcription factors AP-1, NFAT and NF-κB downstream of the TCR, but whether activation of T cell-NF-κB in vivo is required for tumor control has not been addressed. In humans and mice with progressively growing tumors, the activity of T cell-intrinsic NF-κB is often reduced. However, it is not clear if this is causal for an inability to reject transformed cells, or if it is a consequence of tumor growth. T cell-NF-κB is important for T cell survival and effector differentiation and plays an important role in enabling T cells to reject cardiac and islet allografts, suggesting the possibility that it may also be required for tumor elimination. In this study, we tested whether normal T cell-NF-κB activation is necessary for the rejection of tumors whose growth is normally controlled by the immune system.
Mice with genetically impaired T cell-NF-κB activity were subcutaneously injected with MC57-SIY tumor cells. Tumor growth was measured over time, and the anti-tumor immune response was evaluated using flow cytometry and cytokine detection assays.
Mice with impaired T cell-NF-κB activity were unable to reject tumors that were otherwise eliminated by wildtype mice, despite equal accumulation of tumor-reactive T cells. In addition, specific impairment of NF-κB signaling downstream of the TCR was sufficient to prevent tumor rejection. Tumor antigen-specific T cell-IFN-γ and TNF-α production, as well as cytotoxic ability, were all reduced in mice with impaired T cell-NF-κB, suggesting an important role for this transcription factor in the effector differentiation of tumor-specific effector T cells.
Our results have identified the NF-κB pathway as an important signaling axis in T cells, required for the elimination of growing tumors in vivo. Maintaining or enhancing T cell-NF-κB activity may be a promising avenue for anti-tumor immunotherapy.
Electronic supplementary material
The online version of this article (doi:10.1186/s40425-014-0045-x) contains supplementary material, which is available to authorized users.
PMCID: PMC4308877  PMID: 25648675
T cell; NF-κB; Tumor rejection; Priming; Effector function; Cytokine production; Cytotoxicity
13.  Tuning LeSPL-CNR expression by SlymiR157 affects tomato fruit ripening 
Scientific Reports  2015;5:7852.
In plants, microRNAs (miRNAs) play essential roles in growth, development, yield, stress response and interactions with pathogens. However no miRNA has been experimentally documented to be functionally involved in fruit ripening although many miRNAs have been profiled in fruits. Here we show that SlymiR157 and SlymiR156 differentially modulate ripening and softening in tomato (Solanum lycopersicum). SlymiR157 is expressed and developmentally regulated in normal tomato fruits and in those of the Colourless non-ripening (Cnr) epimutant. It regulates expression of the key ripening gene LeSPL-CNR in a likely dose-dependent manner through miRNA-induced mRNA degradation and translation repression. Viral delivery of either pre-SlymiR157 or mature SlymiR157 results in delayed ripening. Furthermore, qRT-PCR profiling of key ripening regulatory genes indicates that the SlymiR157-target LeSPL-CNR may affect expression of LeMADS-RIN, LeHB1, SlAP2a and SlTAGL1. However SlymiR156 does not affect the onset of ripening, but it impacts fruit softening after the red ripe stage. Our findings reveal that working together with a ripening network of transcription factors, SlymiR157 and SlymiR156 form a critical additional layer of regulatory control over the fruit ripening process in tomato.
PMCID: PMC4297963  PMID: 25597857
14.  Genetic Architecture of a Hormonal Response to Gene Knockdown in Honey Bees 
Journal of Heredity  2015;106(2):155-165.
Variation in endocrine signaling is proposed to underlie the evolution and regulation of social life histories, but the genetic architecture of endocrine signaling is still poorly understood. An excellent example of a hormonally influenced set of social traits is found in the honey bee (Apis mellifera): a dynamic and mutually suppressive relationship between juvenile hormone (JH) and the yolk precursor protein vitellogenin (Vg) regulates behavioral maturation and foraging of workers. Several other traits cosegregate with these behavioral phenotypes, comprising the pollen hoarding syndrome (PHS) one of the best-described animal behavioral syndromes. Genotype differences in responsiveness of JH to Vg are a potential mechanistic basis for the PHS. Here, we reduced Vg expression via RNA interference in progeny from a backcross between 2 selected lines of honey bees that differ in JH responsiveness to Vg reduction and measured JH response and ovary size, which represents another key aspect of the PHS. Genetic mapping based on restriction site-associated DNA tag sequencing identified suggestive quantitative trait loci (QTL) for ovary size and JH responsiveness. We confirmed genetic effects on both traits near many QTL that had been identified previously for their effect on various PHS traits. Thus, our results support a role for endocrine control of complex traits at a genetic level. Furthermore, this first example of a genetic map of a hormonal response to gene knockdown in a social insect helps to refine the genetic understanding of complex behaviors and the physiology that may underlie behavioral control in general.
PMCID: PMC4323067  PMID: 25596612
Apis mellifera; complex trait genetics; genetic architecture juvenile hormone; social evolution; vitellogenin
15.  Sit-to-stand test: Performance and determinants across the age-span 
Isokinetics and exercise science  2010;18(4):235-240.
Although the validity of the sit-to-stand (STS) test as a measure of lower limb strength has been questioned, it is widely used as such among older adults. The purposes of this study were: 1) to describe five-repetition STS test (FRSTST) performance (time) by adolescents and adults and 2) to determine the relationship of isometric knee extension strength (force and torque), age, gender, weight, and stature with that performance. Participants were 111 female and 70 male (14–85 years) community-dwelling enrollees in the NIH Toolbox Assessment of Neurological and Behavioral Function. The FRSTST was conducted using a standard armless chair. Knee extension force was measured using a belt-stabilized hand-held dynamometer; knee extension torque was measured using a Biodex dynamometer. The mean times for the FRSTST ranged from 6.0 sec (20–29 years) to 10.8 sec (80–85 years). For both the entire sample and a sub-sample of participants 50–85 years, knee extension strength (r = −0.388 to −0.634), age (r = 0.561 and 0.466), and gender (r = 0.182 and 0.276) were correlated significantly with FRSTST times. In all multiple regression models, knee extension strength provided the best explanation of FRSTST performance, but age contributed as well. Bodyweight and stature were less consistent in explaining FRSTST performance. Gender did not add to the explanation of FRSTST performance. Our findings suggest, therefore, that FRSTST time reflects lower limb strength, but that performance should be interpreted in light of age and other factors.
PMCID: PMC4293702  PMID: 25598584
Muscle strength; measurement; mobility; aging
16.  Detection of Herb-Symptom Associations from Traditional Chinese Medicine Clinical Data 
Background. Traditional Chinese medicine (TCM) is an individualized medicine by observing the symptoms and signs (symptoms in brief) of patients. We aim to extract the meaningful herb-symptom relationships from large scale TCM clinical data. Methods. To investigate the correlations between symptoms and herbs held for patients, we use four clinical data sets collected from TCM outpatient clinical settings and calculate the similarities between patient pairs in terms of the herb constituents of their prescriptions and their manifesting symptoms by cosine measure. To address the large-scale multiple testing problems for the detection of herb-symptom associations and the dependence between herbs involving similar efficacies, we propose a network-based correlation analysis (NetCorrA) method to detect the herb-symptom associations. Results. The results show that there are strong positive correlations between symptom similarity and herb similarity, which indicates that herb-symptom correspondence is a clinical principle adhered to by most TCM physicians. Furthermore, the NetCorrA method obtains meaningful herb-symptom associations and performs better than the chi-square correlation method by filtering the false positive associations. Conclusions. Symptoms play significant roles for the prescriptions of herb treatment. The herb-symptom correspondence principle indicates that clinical phenotypic targets (i.e., symptoms) of herbs exist and would be valuable for further investigations.
PMCID: PMC4305614  PMID: 25650023
17.  Preparation of novel (-)-gossypol nanoparticles and the effect on growth inhibition in human prostate cancer PC-3 cells in vitro 
The aim of the present study was to investigate the antitumor effects and possible mechanism of (-)-gossypol nanoparticles, loaded with vv polyethylene glycol-maleimide (mPEG-Mal), in vitro. Emulsification-volatilization was used to prepare the loaded (-)-gossypol nanoparticles. The toxicity of blank nanoparticles on human prostate cancer PC-3 cells and human prostate RWPE-1 cells was measured. The antitumor effects of the nanoparticles on PC-3 cells were evaluated by an MTT assay, acridine orange staining and transmission electron microscopy in vitro, and the results were compared with those of free (-)-gossypol. In addition, the mRNA expression levels of Bcl-2 and Bak were measured using semi-quantitative reverse transcription polymerase chain reaction. The growth inhibition activity of the loaded (-)-gossypol nanoparticles was found to be dose- and time-dependent, and similar to the activity of free (-)-gossypol. The nanoparticles induced apoptotic morphological changes on the PC-3 cells, downregulating the mRNA expression level of Bcl-2 and upregulating the mRNA expression level of Bak. Blank nanoparticles exhibited no evident toxicity on PC-3 and RWPE-1 cells at a high dose. Therefore, the mPEG-Mal loaded (-)-gossypol nanoparticles demonstrated a favorable antitumor activity and no toxicity. The nanoparticles were able to induce the apoptosis of prostate cancer cells; thus, may be a potential antitumor nanodrug.
PMCID: PMC4316968  PMID: 25667612
(-)-gossypol; nanoparticle; apoptosis; prostate cancer
18.  Cinnabar-Induced Subchronic Renal Injury Is Associated with Increased Apoptosis in Rats 
BioMed Research International  2015;2015:278931.
The aim of this study was to explore the role of apoptosis in cinnabar-induced renal injury in rats. To test this role, rats were dosed orally with cinnabar (1 g/kg/day) for 8 weeks or 12 weeks, and the control rats were treated with 5% carboxymethylcellulose solution. Levels of urinary mercury (UHg), renal mercury (RHg), serum creatinine (SCr), and urine kidney injury molecule 1 (KIM-1) were assessed, and renal pathology was analyzed. Apoptotic cells were identified and the apoptotic index was calculated. A rat antibody array was used to analyze expression of cytokines associated with apoptosis. Results from these analyses showed that UHg, RHg, and urine KIM-1, but not SCr, levels were significantly increased in cinnabar-treated rats. Renal pathological changes in cinnabar-treated rats included vacuolization of tubular cells, formation of protein casts, infiltration of inflammatory cells, and increase in the number of apoptotic tubular cells. In comparison to the control group, expression of FasL, Fas, TNF-α, TRAIL, activin A, and adiponectin was upregulated in the cinnabar-treated group. Collectively, our results suggest that prolonged use of cinnabar results in kidney damage due to accumulation of mercury and that the underlying mechanism involves apoptosis of tubular cells via a death receptor-mediated pathway.
PMCID: PMC4300031  PMID: 25629042
19.  The risk factors of neurologic deficits of one-stage posterior vertebral column resection for patients with severe and rigid spinal deformities 
European Spine Journal  2013;23(1):149-156.
To determine the risk factors of neurologic deficits during PVCR correction, so as to help improve safety during and after surgery.
A consecutive series of 76 patients with severe and rigid spinal deformities who were treated with PVCR at a single institution between October 2004 and July 2011 were included in our study. Of the 76 patients, 37 were male and 39 female, with an average age of 17.5 years (range 10–48 years). There were 52 adolescent patients (with an age <18 years) and 24 adult patients (with an age ≥18 years). Preoperatively, postoperatively and 6 months after surgery, we performed systemically neurologic function evaluations of each patients through meticulous physical examination. Any new abnormality or deterioration in evaluation of neurologic function than preoperative is reckoned postoperative neurologic deficits. Ten variables that might affect the safety of neurologic deficits during PVCR procedures, including imaging factors, clinical factors and operational factors, were analyzed using univariate analysis. Then the variables with statistical difference were analyzed by using multi-factor unconditional logistic regression analysis.
No patient in this series had permanent paraplegia and nerve root injury due to operation. Change of neurologic status was found in six patients after surgery. Results of single-factor comparison demonstrated that the following seven variables were statistically different (P < 0.05): location of apex at main curve (X3), Cobb angle at the main curve at the coronal plane (X4), scoliosis associated with thoracic hyperkyphosis (X5), level of vertebral column resected (X6), number of segmental vessels ligated (X7), preexisting neurologic dysfunction (X8), and associated with intraspinal and brain stem anomalies (X9). The multi-factor unconditional logistic regression analysis revealed that X8 (OR = 49.322), X9 (OR = 18.423), X5 (OR = 11.883), and X6 (OR = 8.769) were independent and positively correlated with the neurologic deficit.
Preexisting neurologic dysfunction, associated with intraspinal and brain stem anomalies, scoliosis associated with thoracic hyperkyphosis and level of vertebral column resected are independent risk factors for neurologic deficits during PVCR procedure.
PMCID: PMC3897813  PMID: 23619771
Spinal deformity; Vertebral column resection; Surgical procedures; Neurologic deficits; Risk factor
20.  CD45 ligation expands Tregs by promoting interactions with DCs 
The Journal of Clinical Investigation  2014;124(10):4603-4613.
Regulatory T cells (Tregs), which express CD4 and FOXP3, are critical for modulating the immune response and promoting immune tolerance. Consequently, methods to expand Tregs for therapeutic use are of great interest. While transfer of Tregs after massive ex vivo expansion can be achieved, in vivo expansion of Tregs would be more practical. Here, we demonstrate that targeting the CD45 tyrosine phosphatase with a tolerogenic anti-CD45RB mAb acutely increases Treg numbers in WT mice, even in absence of exogenous antigen. Treg expansion occurred through substantial augmentation of homeostatic proliferation in the preexisting Treg population. Moreover, anti-CD45RB specifically increased Treg proliferation in response to cognate antigen. Compared with conventional T cells, Tregs differentially regulate their conjugation with DCs. Therefore, we determined whether CD45 ligation could alter interactions between Tregs and DCs. Live imaging showed that CD45 ligation specifically reduced Treg motility in an integrin-dependent manner, resulting in enhanced interactions between Tregs and DCs in vivo. Increased conjugate formation, in turn, augmented nuclear translocation of nuclear factor of activated T cells (NFAT) and Treg proliferation. Together, these results demonstrate that Treg peripheral homeostasis can be specifically modulated in vivo to promote Treg expansion and tolerance by increasing conjugation between Tregs and DCs.
PMCID: PMC4191025  PMID: 25202978
21.  Effects of rapamycin against paraquat-induced pulmonary fibrosis in mice*  
Background and aims: Ingestion of paraquat (PQ), a widely used herbicide, can cause severe toxicity in humans, leading to a poor survival rate and prognosis. One of the main causes of death by PQ is PQ-induced pulmonary fibrosis, for which there are no effective therapies. The aim of this study was to evaluate the effects of rapamycin (RAPA) on inhibiting PQ-induced pulmonary fibrosis in mice and to explore its possible mechanisms. Methods: Male C57BL/6J mice were exposed to either saline (control group) or PQ (10 mg/kg body weight, intraperitoneally; test group). The test group was divided into four subgroups: a PQ group (PQ-exposed, non-treated), a PQ+RAPA group (PQ-exposed, treated with RAPA at 1 mg/kg intragastrically), a PQ+MP group (PQ-exposed, treated with methylprednisolone (MP) at 30 mg/kg intraperitoneally), and a PQ+MP+RAPA group (PQ-exposed, treated with MP at 30 mg/kg intraperitoneally and with RAPA at 1 mg/kg intragastrically). The survival rate and body weight of all the mice were recorded every day. Three mice in each group were sacrificed at 14 d and the rest at 28 d after intoxication. Lung tissues were excised and stained with hematoxylin-eosin (H&E) and Masson’s trichrome stain for histopathological analysis. The hydroxyproline (HYP) content in lung tissues was detected using an enzyme-linked immunosorbent assay (ELISA) kit. The expression of transforming growth factor-β1 (TGF-β1) and α-smooth muscle actin (α-SMA) in lung tissues was detected by immunohistochemical staining and Western blotting. Results: A mice model of PQ-induced pulmonary fibrosis was established. Histological examination of lung tissues showed that RAPA treatment moderated the pathological changes of pulmonary fibrosis, including alveolar collapse and interstitial collagen deposition. HYP content in lung tissues increased soon after PQ intoxication but had decreased significantly by the 28th day after RAPA treatment. Immunohistochemical staining and Western blotting showed that RAPA treatment significantly down-regulated the enhanced levels of TGF-β1 and α-SMA in lung tissues caused by PQ exposure. However, RAPA treatment alone could not significantly ameliorate the lower survival rate and weight loss of treated mice. MP treatment enhanced the survival rate, but had no significant effects on attenuating PQ-induced pulmonary fibrosis or reducing the expression of TGF-β1 and α-SMA. Conclusions: This study demonstrates that RAPA treatment effectively suppresses PQ-induced alveolar collapse and collagen deposition in lung tissues through reducing the expression of TGF-β1 and α-SMA. Thus, RAPA has potential value in the treatment of PQ-induced pulmonary fibrosis.
PMCID: PMC4288945  PMID: 25559956
Paraquat; Pulmonary fibrosis; Rapamycin; Transforming growth factor-β1; α-Smooth muscle actin; Methylprednisolone
22.  Comprehensive Transcriptome Analysis Reveals Accelerated Genic Evolution in a Tibet Fish, Gymnodiptychus pachycheilus 
Genome Biology and Evolution  2014;7(1):251-261.
Elucidating the genetic mechanisms of organismal adaptation to the Tibetan Plateau at a genomic scale can provide insights into the process of adaptive evolution. Many highland species have been investigated and various candidate genes that may be responsible for highland adaptation have been identified. However, we know little about the genomic basis of adaptation to Tibet in fishes. Here, we performed transcriptome sequencing of a schizothoracine fish (Gymnodiptychus pachycheilus) and used it to identify potential genetic mechanisms of highland adaptation. We obtained totally 66,105 assembled unigenes, of which 7,232 were assigned as putative one-to-one orthologs in zebrafish. Comparative gene annotations from several species indicated that at least 350 genes lost and 41 gained since the divergence between G. pachycheilus and zebrafish. An analysis of 6,324 orthologs among zebrafish, fugu, medaka, and spotted gar identified consistent evidence for genome-wide accelerated evolution in G. pachycheilus and only the terminal branch of G. pachycheilus had an elevated Ka/Ks ratio than the ancestral branch. Many functional categories related to hypoxia and energy metabolism exhibited rapid evolution in G. pachycheilus relative to zebrafish. Genes showing signature of rapid evolution and positive selection in the G. pachycheilus lineage were also enriched in functions associated with energy metabolism and hypoxia. The first genomic resources for fish in the Tibetan Plateau and evolutionary analyses provided some novel insights into highland adaptation in fishes and served as a foundation for future studies aiming to identify candidate genes underlying the genetic bases of adaptation to Tibet in fishes.
PMCID: PMC4316632  PMID: 25543049
Tibetan Plateau; adaptation; positive selection; schizothoracine fish; transcriptome
23.  Mutation Profiling in Cholangiocarcinoma: Prognostic and Therapeutic Implications 
PLoS ONE  2014;9(12):e115383.
Cholangiocarcinoma (CCA) is clinically heterogeneous; intra and extrahepatic CCA have diverse clinical presentations. Next generation sequencing (NGS) technology may identify the genetic differences between these entities and identify molecular subgroups for targeted therapeutics.
We describe successful NGS-based testing of 75 CCA patients along with the prognostic and therapeutic implications of findings. Mutation profiling was performed using either a) NGS panel of hotspot regions in 46 cancer-related genes using a 318-chip on Ion PGM Sequencer or b) Illumina HiSeq 2000 sequencing platform for 3,769 exons of 236 cancer-related genes plus 47 introns from 19 genes to an average depth of 1000X. Clinical data was abstracted and correlated with clinical outcome. Patients with targetable mutations were referred to appropriate clinical trials.
There were significant differences between intrahepatic (n = 55) and extrahepatic CCA (n = 20) in regard to the nature and frequency of the genetic aberrations (GAs). IDH1 and DNA repair gene alterations occurred more frequently in intrahepatic CCA, while ERBB2 GAs occurred in the extrahepatic group. Commonly occurring GAs in intrahepatic CCA were TP53 (35%), KRAS (24%), ARID1A (20%), IDH1 (18%), MCL1 (16%) and PBRM1 (11%). Most frequent GAs in extrahepatic CCA (n = 20) were TP53 (45%), KRAS (40%), ERBB2 (25%), SMAD4 (25%), FBXW7 (15%) and CDKN2A (15%). In intrahepatic CCA, KRAS, TP53 or MAPK/mTOR GAs were significantly associated with a worse prognosis while FGFR GAs correlated with a relatively indolent disease course. IDH1 GAs did not have any prognostic significance. GAs in the chromatin modulating genes, BAP1 and PBRM1 were associated with bone metastases and worse survival in extrahepatic CCA. Radiologic responses and clinical benefit was noted with EGFR, FGFR, C-met, B-RAF and MEK inhibitors.
There are significant genetic differences between intra and extrahepatic CCA. NGS can potentially identify disease subsets with distinct prognostic and therapeutic implications.
PMCID: PMC4275227  PMID: 25536104
24.  Dimensionality-dependent charge transport in close-packed nanoparticle arrays: from 2D to 3D 
Scientific Reports  2014;4:7565.
Charge transport properties in close-packed nanoparticle arrays with thickness crossing over from two dimensions to three dimensions have been studied. The dimensionality transition of nanoparticle arrays was realized by continually printing spatially well-defined nanoparticle monolayers on top of the device in situ. The evolution of charge transport properties depending on the dimensionality has been investigated in both the Efros-Shaklovskii variable-range-hopping (ES-VRH) (low temperature) regime and the sequential hopping (SH) (medium temperature) regime. We find that the energy barriers to transport decrease when the thickness of nanoparticle arrays increases from monolayer to multilayers, but start to level off at the thickness of 4–5 monolayers. The energy barriers are characterized by the coefficient βD at ES-VRH regime and the activation energy Ea at SH regime. Moreover, a turning point for the temperature coefficient of conductance was observed in multilayer nanoparticle arrays at high temperature, which is attributed to the increasing mobility with decreasing temperature of hopping transport in three dimensions.
PMCID: PMC4271260  PMID: 25523836
25.  Polymorphisms in the feline TNFA and CD209 genes are associated with the outcome of feline coronavirus infection 
Veterinary Research  2014;45(1):123.
Feline infectious peritonitis (FIP), caused by feline coronavirus (FCoV) infection, is a highly lethal disease without effective therapy and prevention. With an immune-mediated disease entity, host genetic variant was suggested to influence the occurrence of FIP. This study aimed at evaluating cytokine-associated single nucleotide polymorphisms (SNPs), i.e., tumor necrosis factor alpha (TNF-α), receptor-associated SNPs, i.e., C-type lectin DC-SIGN (CD209), and the five FIP-associated SNPs identified from Birman cats of USA and Denmark origins and their associations with the outcome of FCoV infection in 71 FIP cats and 93 FCoV infected non-FIP cats in a genetically more diverse cat populations. A promoter variant, fTNFA - 421 T, was found to be a disease-resistance allele. One SNP was identified in the extracellular domain (ECD) of fCD209 at position +1900, a G to A substitution, and the A allele was associated with FIP susceptibility. Three SNPs located in the introns of fCD209, at positions +2276, +2392, and +2713, were identified to be associated with the outcome of FCoV infection, with statistical relevance. In contrast, among the five Birman FIP cat-associated SNPs, no genotype or allele showed significant differences between our FIP and non-FIP groups. As disease resistance is multifactorial and several other host genes could involve in the development of FIP, the five genetic traits identified in this study should facilitate in the future breeding of the disease-resistant animal to reduce the occurrence of cats succumbing to FIP.
Electronic supplementary material
The online version of this article (doi:10.1186/s13567-014-0123-6) contains supplementary material, which is available to authorized users.
PMCID: PMC4267428  PMID: 25512064

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