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1.  Preventive effect of Qianggan-Rongxian Decoction on rat liver fibrosis 
AIM: To study the preventive effects of Qianggan-Rongxian Decoction on liver fibrosis induced by dimethylnitrosamine (DMN) in rats.
METHODS: Male Wistar rats were randomly divided into hepatic fibrosis model group, control group and 3 treatment groups (12 rats in each group). Except for the normal control group, all the rats received 1% DMN (10 μL/kg body weight, i.p), 3 times a week for 4 wk. The rats in the 3 treatment groups including a high-dose DMN group (10 mL/kg), a medium-dose DMN group (7 mL/kg), and a low-dose DMN group (4 mL/kg) were daily gavaged with Qianggan-Rongxian Decoction, and the rats in the model and normal control groups were given saline vehicle. Enzyme-linked immunosorbent assay (ELISA) was used to determine the changes in serum hyaluronic acid (HA), laminin (LN), and type IV collagen levels. Serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels were measured using routine laboratory methods. Pathologic changes, particularly fibrosis, were examined by hematoxylin and eosin (HE) and Sirius red staining. Hepatic stellate cells (HSC) were examined by transmission electron microscopy.
RESULTS: Compared with the model control group, the serum levels of HA, LN, type IV collagen, ALT and AST were decreased markedly in the other groups after treatment with Qianggan-Rongxian Decoction, especially in the medium-dose DMN group (P < 0.05). Moreover, the area-density percentage of collagen fibrosis was lower in the Qianggan-Rongxian Decoction treatment groups than in the model group, and a more significant drop was observed in the medium-dose DMN group (P < 0.05).
CONCLUSION: Qianggan-Rongxian Decoction can inhibit hepatic fibrosis due to chronic liver injury, delay the development of cirrhosis, and notably ameliorate liver function. It may be used as a safe and effective thera-peutic drug for patients with fibrosis.
doi:10.3748/wjg.14.3569
PMCID: PMC2716622  PMID: 18567088
Liver fibrosis; Qianggan-Rongxian Decoction; Prevention; Rat model; Dimethylnitrosamine
2.  Relationship of renin-angiotensin-aldosterone system polymorphisms and phenotypes to mortality in Chinese coronary atherosclerosis patients 
Scientific Reports  2014;4:4600.
We performed a large, long-term cohort study to evaluate the association of renin-angiotensin-aldosterone system gene polymorphisms and baseline phenotypes to all-cause mortality among patients with angiographically confirmed coronary atherosclerosis. The study included 1075 subjects who underwent coronary angiography. Patients were genotyped for eight polymorphisms (rs4343, rs5186, rs5182, rs5049, rs5051, rs699, rs4762, and rs1799998), and their baseline plasma angiotensin II and aldosterone levels were measured. The interval between baseline and follow-up time-points ranged from 6.39 to 9.59 years. The results of multivariate regression analysis further indicated that high baseline angiotensin II levels (1.226 (1.024–1.468), p = 0.027) were independently associated with all-cause death. Therefore, we found that an increased baseline plasma angiotensin II level was associated with higher long-term all-cause mortality, even after correcting for established cardiovascular risk factors.
doi:10.1038/srep04600
PMCID: PMC3983573  PMID: 24722536
3.  Reduced growth and proliferation dynamics of nasal epithelial stem/progenitor cells in nasal polyps in vitro 
Scientific Reports  2014;4:4619.
Basal cells in nasal epithelium have stemness/progenitor characters and play essential roles in the epithelial remodeling in nasal polyps (NP). We investigate whether the human nasal epithelial stem/progenitor cells (hNESPCs) from patients with NP are inherently distinct from those obtained from healthy controls. Epithelial basal cells were isolated and cultured for four passages from NP tissues and control nasal mucosa. hNESPCs from controls were stained positively with stem cell marker p63 and KRT5 and presented a consistent high Ki67 expression level over four passages. In contrast, hNESPCs from NP patients showed: i). a reduced growth and proliferation rate at each passage by evaluating colony-forming efficiency and doubling time; ii). a lower percentage of Ki67+ cells among p63+ cells in the colonies in late passages, which was also confirmed by immunostaining in the NP tissues. Thus reduced growth/proliferation dynamics in hNESPCs from NP could be an important pathological phenomenon in NP development.
doi:10.1038/srep04619
PMCID: PMC3980221  PMID: 24714674
4.  Spinal 5-HT3 receptors facilitate behavioral hypersensitivity induced by elevated calcium channel alpha-2-deltal-1 protein 
Background
Peripheral nerve injury induces upregulation of the calcium channel alpha-2-delta-1 proteins in the dorsal root ganglia and dorsal spinal cord that correlates with neuropathic pain development. Similar behavioral hypersensitivity was also observed in injury-free transgenic mice (TG) over-expressing the alpha-2-delta-1 proteins in neuronal tissues. To investigate pathways regulating alpha-2-delta-1 protein-mediated behavioral hypersensitivity, we examined whether spinal serotonergic 5-HT3 receptors are involved similarly in the modulation of behavioral hypersensitivity induced by either peripheral nerve injury in a nerve injury model or neuronal alpha-2-delta-1 over-expression in the TG model.
Methods
The effects of blocking behavioral hypersensitivity in these two models by intrathecal or systemic injections of 5-HT3 receptor antagonist, ondansetron, were compared.
Results
Our data indicated that the TG mice displayed similar behavioral hypersensitivities to non-painful mechanical stimulation (tactile allodynia) and painful thermal stimulation (thermal hyperalgesia) as that observed in the nerve injury model. Interestingly, tactile allodynia and thermal hyperalgesia in both models can be blocked similarly by intrathecal, but not systemic, injection of ondansetron.
Conclusions
Our data suggest that spinal 5-HT3 receptors are likely play a role in alpha-2-delta-1-mediated behavioral hypersensitivities through a descending serotonergic facilitation.
doi:10.1002/j.1532-2149.2012.00221.x
PMCID: PMC3548964  PMID: 23065867
5.  Real-Time Light Scattering Tracking of Gold Nanoparticles- bioconjugated Respiratory Syncytial Virus Infecting HEp-2 Cells 
Scientific Reports  2014;4:4529.
Real-time tracking of virus invasion is crucial for understanding viral infection mechanism, which, however, needs simple and efficient labeling chemistry with improved signal-to-noise ratio. For that purpose, herein we investigated the invasion dynamics of respiratory syncytial virus (RSV) through dark-field microscopic imaging (iDFM) technique by using Au nanoparticles (AuNPs) as light scattering labels. RSV, a ubiquitous, non-segmented, pleiomorphic and negative-sense RNA virus, is an important human pathogen in infants, the elderly, and the immunocompromised. In order to label the enveloped virus of paramyxoviridae family, an efficient streptavidin (SA)-biotin binding chemistry was employed, wherein AuNPs and RSV particles modified with SA and biotin, respectively, allowing the AuNP-modified RSVs to maintain their virulence without affecting the native activities of RSV, making the long dynamic visualization successful for the RSV infections into human epidermis larynx carcinoma cells.
doi:10.1038/srep04529
PMCID: PMC3970125  PMID: 24681709
6.  Role of Nitric Oxide Synthases in Early Blood-Brain Barrier Disruption following Transient Focal Cerebral Ischemia 
PLoS ONE  2014;9(3):e93134.
The role of nitric oxide synthases (NOSs) in early blood-brain barrier (BBB) disruption was determined using a new mouse model of transient focal cerebral ischemia. Ischemia was induced by ligating the middle cerebral artery (MCA) at its M2 segment and reperfusion was induced by releasing the ligation. The diameter alteration of the MCA, arterial anastomoses and collateral arteries were imaged and measured in real time. BBB disruption was assessed by Evans Blue (EB) and sodium fluorescein (Na-F) extravasation at 3 hours of reperfusion. The reperfusion produced an extensive vasodilation and a sustained hyperemia. Although expression of NOSs was not altered at 3 hours of reperfusion, L-NAME (a non-specific NOS inhibitor) abolished reperfusion-induced vasodilation/hyperemia and significantly reduced EB and Na-F extravasation. L-NIO (an endothelial NOS (eNOS) inhibitor) significantly attenuated cerebral vasodilation but not BBB disruption, whereas L-NPA and 7-NI (neuronal NOS (nNOS) inhibitors) significantly reduced BBB disruption but not cerebral vasodilation. In contrast, aminoguanidine (AG) (an inducible NOS (iNOS) inhibitor) had less effect on either cerebral vasodilation or BBB disruption. On the other hand, papaverine (PV) not only increased the vasodilation/hyperemia but also significantly reduced BBB disruption. Combined treatment with L-NAME and PV preserved the vasodilation/hyperemia and significantly reduced BBB disruption. Our findings suggest that nNOS may play a major role in early BBB disruption following transient focal cerebral ischemia via a hyperemia-independent mechanism.
doi:10.1371/journal.pone.0093134
PMCID: PMC3966853  PMID: 24671193
7.  Predicting the Severity and Prognosis of Trismus after Intensity-Modulated Radiation Therapy for Oral Cancer Patients by Magnetic Resonance Imaging 
PLoS ONE  2014;9(3):e92561.
To develop magnetic resonance imaging (MRI) indicators to predict trismus outcome for post-operative oral cavity cancer patients who received adjuvant intensity-modulated radiation therapy (IMRT), 22 patients with oral cancer treated with IMRT were studied over a two-year period. Signal abnormality scores (SA scores) were computed from Likert-type ratings of the abnormalities of nine masticator structures and compared with the Mann-Whitney U-test and Kruskal–Wallis one-way ANOVA test between groups. Seventeen patients (77.3%) experienced different degrees of trismus during the two-year follow-up period. The SA score correlated with the trismus grade (r = 0.52, p<0.005). Patients having progressive trismus had higher mean doses of radiation to multiple structures, including the masticator and lateral pterygoid muscles, and the parotid gland (p<0.05). In addition, this group also had higher SA-masticator muscle dose product at 6 months and SA scores at 12 months (p<0.05). At the optimum cut-off points of 0.38 for the propensity score, the sensitivity was 100% and the specificity was 93% for predicting the prognosis of the trismus patients. The SA score, as determined using MRI, can reflect the radiation injury and correlate to trismus severity. Together with the radiation dose, it could serve as a useful biomarker to predict the outcome and guide the management of trismus following radiation therapy.
doi:10.1371/journal.pone.0092561
PMCID: PMC3962418  PMID: 24658376
8.  In Vivo and In Vitro Studies of Th17 Response to Specific Immunotherapy in House Dust Mite-Induced Allergic Rhinitis Patients 
PLoS ONE  2014;9(3):e91950.
T helper (Th)17 cells have been implicated in the development of allergic rhinitis (AR), but their response to specific immunotherapy (SIT) remains unclear. We investigated the impact of SIT on Th17 response and Th1/Th2 changes in AR patients. Blood samples from AR patients (n = 20) who were monosensitized to house dust mite (HDM) were collected before the initiation of SIT (SIT-untreated) and after the end of 2-year SIT (SIT-treated) treatment. Twenty healthy volunteers were recruited as controls. In vitro HDM stimulation in peripheral blood mononuclear cells (PBMCs) was also performed. Expression levels of Th17 associated genes were determined in both PBMCs and plasma by PCR and ELISA, while Th17/Th1/Th2/IL10 producing cell proportions were evaluated in PBMCs by flow cytometry. The SIT effect was evaluated by assessing clinical symptoms. mRNA levels of Th17 specific genes (IL17 and RORC) were increased in SIT-untreated AR versus controls, and decreased following SIT treatment. SIT can change the production of Th17 associated genes (reduction of IL17, IL6, and IL23, but increase of IL27) in plasma from AR patients. Th2/Th1 ratio and proportions of Th17 cells were suppressed while IL10 producing CD4+ T cells were elevated after SIT. In vitro HDM challenge presents concordant patterns with in vivo findings: 1) increase of Th2 and Th17 response in AR patients; 2) suppression of IL10 producing CD4+ T cells in SIT-untreated AR but elevation in SIT-treated AR patients. Most importantly, a positive correlation between IL17 mRNA/protein levels and clinical symptom scores was observed. SIT significantly inhibits Th17 mediated inflammation in AR and IL17 may be a useful biomarker for both AR severity and SIT therapeutic effect.
Trial Registration
Australian New Zealand Clinical Trials Registry (ANZCTR) ACTRN12613000445774
doi:10.1371/journal.pone.0091950
PMCID: PMC3960160  PMID: 24647473
9.  Neuroprotective Effects of Sevoflurane against Electromagnetic Pulse-Induced Brain Injury through Inhibition of Neuronal Oxidative Stress and Apoptosis 
PLoS ONE  2014;9(3):e91019.
Electromagnetic pulse (EMP) causes central nervous system damage and neurobehavioral disorders, and sevoflurane protects the brain from ischemic injury. We investigated the effects of sevoflurane on EMP-induced brain injury. Rats were exposed to EMP and immediately treated with sevoflurane. The protective effects of sevoflurane were assessed by Nissl staining, Fluoro-Jade C staining and electron microscopy. The neurobehavioral effects were assessed using the open-field test and the Morris water maze. Finally, primary cerebral cortical neurons were exposed to EMP and incubated with different concentration of sevoflurane. The cellular viability, lactate dehydrogenase (LDH) release, superoxide dismutase (SOD) activity and malondialdehyde (MDA) level were assayed. TUNEL staining was performed, and the expression of apoptotic markers was determined. The cerebral cortexes of EMP-exposed rats presented neuronal abnormalities. Sevoflurane alleviated these effects, as well as the learning and memory deficits caused by EMP exposure. In vitro, cell viability was reduced and LDH release was increased after EMP exposure; treatment with sevoflurane ameliorated these effects. Additionally, sevoflurane increased SOD activity, decreased MDA levels and alleviated neuronal apoptosis by regulating the expression of cleaved caspase-3, Bax and Bcl-2. These findings demonstrate that Sevoflurane conferred neuroprotective effects against EMP radiation-induced brain damage by inhibiting neuronal oxidative stress and apoptosis.
doi:10.1371/journal.pone.0091019
PMCID: PMC3948751  PMID: 24614080
10.  Quantitative Assessment of the Presence and Severity of Cirrhosis in Patients with Hepatitis B Using Right Liver Lobe Volume and Spleen Size Measured at Magnetic Resonance Imaging 
PLoS ONE  2014;9(3):e89973.
Objective
To determine whether right liver lobe volume (RV) and spleen size measured utilizing magnetic resonance (MR) imaging could identify the presence and severity of cirrhosis in patients with hepatitis B.
Methods
Two hundred and five consecutive patients with clinically confirmed diagnosis of cirrhosis due to hepatitis B and 40 healthy control individuals were enrolled in this study and underwent abdominal triphasic enhanced scans using MR imaging. Spleen maximal width (W), thickness (T) and length (L), together with RV and spleen volume (SV), were measured utilizing MR imaging. Spleen multidimensional index (SI) was obtained by multiplying previously acquired parameters W×T×L. Then statistical assessment was performed to evaluate the ability of these parameters, including RV, SV, RV/SV and SI, to identify the presence of cirrhosis and define Child-Pugh class of this disease.
Results
SV and SI tended to increase (r = 0.557 and 0.622, respectively; all P<0.001), and RV and RV/SV tended to decrease (r = −0.749 and −0.699, respectively; all P<0.001) with increasing Child-Pugh class of cirrhosis. All the parameters, including RV, SV, RV/SV and SI, might be the indicators used to discriminate the patients with liver cirrhosis from the control group, and to distinguish these patients between Child-Pugh class A and B, between B and C, and between A and C (area under receiver operating characteristic curve [AUC] = 0.609–0.975, all P<0.05). Among these parameters, RV/SV was the best noninvasive factor for the discrimination of liver cirrhosis between Child-Pugh class A and B (AUC = 0.725), between A and C (AUC = 0.975), and between B and C (AUC = 0.876), while SI was the best variable to distinguish the cirrhosis patients from the control group (AUC = 0.960, P<0.05).
Conclusion
RV/SV should be used to identify the severity of cirrhosis, while SI can be recommended to determine the presence of this disease.
doi:10.1371/journal.pone.0089973
PMCID: PMC3942406  PMID: 24594920
11.  DanQi Pill protects against heart failure through the arachidonic acid metabolism pathway by attenuating different cyclooxygenases and leukotrienes B4 
Background
Chinese herbal formulae are composed of complex components and produce comprehensive pharmacological effects. Unlike chemical drugs that have only one clear single target, the components of Chinese herbal formulae have multiple channels and targets. How to discover the pharmacological targets of Chinese herbal formulae and their underlying molecular mechanism are still under investigation.
Methods
DanQi pill (DQP), which is one of the widely prescribed traditional Chinese medicines, is applied as an example drug. In this study, we used the drug target prediction model (DrugCIPHER-CS) to examine the underlying molecular mechanism of DQP, followed by experimental validation.
Results
A novel therapeutic effect pattern of DQP was identified. After determining the compounds in DQP, we used DrugCIPHER-CS to predict their potential targets. These potential targets were significantly enriched in well-known cardiovascular disease-related pathways. For example, the biological processes of neuroactive ligand–receptor interaction, calcium-signaling pathway, and aminoacyl–tRNA biosynthesis were involved. A new and significant pathway, arachidonic acid (AA) metabolism, was also identified in this study. This predicted pathway alteration was validated with an animal model of heart failure (HF). Results show that DQP had effect both on thromboxane B2 (TXB2) and Prostaglandin I2 (PGI2) in different patterns. It can down-regulate the TXB2 and up-regulate the PGI2 in diverse way. Remarkably, it also had effect on cyclooxygenase (COX)-1 and COX2 by suppressing their levels, which may be the critical and novel mechanism of cardiacprotective efficacy for DQP. Furthermore, leukotrienes B4 (LTB4) receptor, another key molecule of AA metabolism which finally mediated gastrotoxic leukotrienes, was also reduced by DQP.
Conclusions
The combination of drug target prediction and experimental validation provides new insights into the complicated mechanism of DQP.
doi:10.1186/1472-6882-14-67
PMCID: PMC3933388  PMID: 24555740
12.  Anticipation, anti-glaucoma drug treatment response and phenotype of a Chinese family with glaucoma caused by the Pro370Leu myocilin mutation 
AIM
To describe the anticipation and anti-glaucoma drugs response of a Chinese family with juvenile-onset open angle glaucoma (JOAG) caused by the Pro370Leu myocilin (MYOC) mutation.
METHODS
Fifteen members of a three-generation Chinese family with JOAG were recruited to this study. They all underwent ophthalmic common examinations. Patients suspected to have JOAG got an assessment of visual field and optical coherence tomography. Intraocular pressures (IOPs) of four patients were measured at 8, 10, 12, 14, 17 o'clock respectively after using anti-glaucoma drugs. Mutation screening of all MYOC gene coding exons of the participants was performed by using direct sequencing of PCR products.
RESULTS
Clinical examinations and pedigree analysis revealed eight family members were suffered from JOAG. Apparent genetics anticipation phenomenon was observed in this family. Their clinical features included elevated IOP of 35-55mmHg, loss of visual field, thinning of retinal nerve fiber layer, and glaucomatous optic disc damage. Noticeably, their intraocular pressure levels could be controlled within normal range at 8 and 10 o'clock by anti-glaucoma drugs, but their IOPs would elevate >21mmHg after 12 o'clock. Seven patients received trabeculectomy produced thin-walled, pale, and saccate filtering blebs maintaining lower intraocular pressure efficiently. Mutation screening indentified a heterozygous C→T missense mutation in the MYOC gene at position 1 109 in exon 3, corresponding to a substitution of a highly conserved proline to leucine at codon 370 in the olfactomedin domain of MYOC.
CONCLUSION
The clinical characteristics of JOAG in this family were 1) genetics anticipation; 2) high IOP; 3) temporay response to anti-glaucoma drugs; 4) filtering surgery produced thin-walled and saccate filtering blebs, helping maintain lower IOP.
doi:10.3980/j.issn.2222-3959.2014.01.08
PMCID: PMC3949457  PMID: 24634862
phenotype; anticipation; anti-glaucoma drugs; myocilin
13.  Ground Movement Analysis Based on Stochastic Medium Theory 
The Scientific World Journal  2014;2014:702561.
In order to calculate the ground movement induced by displacement piles driven into horizontal layered strata, an axisymmetric model was built and then the vertical and horizontal ground movement functions were deduced using stochastic medium theory. Results show that the vertical ground movement obeys normal distribution function, while the horizontal ground movement is an exponential function. Utilizing field measured data, parameters of these functions can be obtained by back analysis, and an example was employed to verify this model. Result shows that stochastic medium theory is suitable for calculating the ground movement in pile driving, and there is no need to consider the constitutive model of soil or contact between pile and soil. This method is applicable in practice.
doi:10.1155/2014/702561
PMCID: PMC3950366
14.  The Xin repeat-containing protein, mXinβ, initiates the maturation of the intercalated discs during postnatal heart development 
Developmental biology  2012;374(2):264-280.
The intercalated disc (ICD) is a unique structure to the heart and plays vital roles in communication and signaling among cardiomyocytes. ICDs are formed and matured during postnatal development through a profound redistribution of the intercellular junctions, as well as recruitment and assembly of more than 200 proteins at the termini of cardiomyocytes. The molecular mechanism underlying this process is not completely understood. The mouse orthologs (mXinα and mXinβ) of human cardiomyopathy-associated (CMYA)/Xin actin-binding repeat-containing protein (XIRP) genes (CMYA1/XIRP1 and CMYA3/XIRP2, respectively) encode proteins localized to ICDs. Ablation of mXinα results in adult late-onset cardiomyopathy with conduction defects and up-regulation of mXinβ. ICD structural defects are found in adult but not juvenile mXinα-null hearts. On the other hand, loss of mXinβ leads to ICD defects at postnatal day 16.5, a developmental stage when the heart is forming ICDs, suggesting mXinβ is required for ICD formation. Using quantitative Western blot, we showed in this study that mXinβ but not mXinα was uniquely up-regulated during the redistribution of intercellular junction from the lateral membrane of cardiomyocytes to their termini. In the absence of mXinβ, the intercellular junctions failed to be restricted to the termini of the cells, and the onset of such defect correlated with the peak expression of mXinβ. Immunofluorescence staining and subcellular fractionation showed that mXinβ preferentially associated with the forming ICDs, further suggesting that mXinβ functioned locally to promote ICD maturation. In contrast, the spatiotemporal expression profile of mXinα and the lack of more severe ICD defects in mXinα−/−;mXinβ−/− double knockout hearts than in mXinβ−/− hearts suggested that mXinα was not essential for the postnatal formation of ICDs. A two-step model for the development of ICD is proposed where mXinβ is essential for the redistribution of intercellular junction components from the lateral puncta to the cell termini.
doi:10.1016/j.ydbio.2012.12.007
PMCID: PMC3615896  PMID: 23261932
Xin repeat-containing family of proteins; Intercalated disc; Development; Maturation; N-cadherin; mXinα−/−;; mXinβ−/− double knockout
15.  Changes in liraglutide-induced body composition are related to modifications in plasma cardiac natriuretic peptides levels in obese type 2 diabetic patients 
Background and aims
Liraglutide treatment can improve glycemic control with a concomitant weight loss, but the underlying mechanism on weight loss is not completely understood. Cardiac natriuretic peptides (NPs) can resist body fat accumulation through increasing adipocytes lypolysis. In this study, we tested the hypothesis that liraglutide-induced weight loss was associated with increased plasma NPs concentrations.
Methods
Thirty-one outpatients with type 2 diabetes (T2D) treated with metformin and other oral antidiabetic drugs except for thiazolidinediones (TZDs) were subcutaneously administered with liraglutide for 12 weeks. Body composition, abdominal visceral adipose tissue areas (VAT) and subcutaneous adipose tissue areas (SAT) were assessed at pre- and post-treatment by dual-energy X-ray absorptiometry (DXA) scanning and abdominal computerized tomography (CT). Plasma atrial natriuretic peptides (ANP) and B-type ventricular natriuretic peptides (BNP) concentrations were tested by commercial ELISA Kit quantitatively.
Results
Following 12-week liraglutide treatment, body weight, waist circumference, total fat and lean mass, fat percentage, SAT and VAT areas were significantly reduced from baseline. Concurrently, plasma ANP and BNP levels were significantly increased following 12-week liraglutide treatment. There were significant correlations between the reductions in body compositions and the increases in both plasma ANP and BNP levels.
Conclusions
There were significant correlations between increases in both plasma ANP and BNP levels and changes in liraglutide-induced body composition. Our data implied that increases in plasma NPs may add a novel dimension to explain how liraglutide induces weight loss.
doi:10.1186/1475-2840-13-36
PMCID: PMC3923001  PMID: 24498905
Liraglutide; Body composition; Weight loss; Cardiac natriuretic peptides
16.  Prenylated Indolediketopiperazine Peroxides and Related Homologues from the Marine Sediment-Derived Fungus Penicillium brefeldianum SD-273 
Marine Drugs  2014;12(2):746-756.
Three new indolediketopiperazine peroxides, namely, 24-hydroxyverruculogen (1), 26-hydroxyverruculogen (2), and 13-O-prenyl-26-hydroxyverruculogen (3), along with four known homologues (4–7), were isolated and identified from the culture extract of the marine sediment-derived fungus Penicillium brefeldianum SD-273. Their structures were determined based on the extensive spectroscopic analysis and compound 1 was confirmed by X-ray crystallographic analysis. The absolute configuration of compounds 1–3 was determined using chiral HPLC analysis of their acidic hydrolysates. Each of the isolated compounds was evaluated for antibacterial and cytotoxic activity as well as brine shrimp (Artemia salina) lethality.
doi:10.3390/md12020746
PMCID: PMC3944513  PMID: 24473173
marine sediment; Penicillium brefeldianum SD-273; indolediketopiperazine; brine shrimp lethality
17.  Chronic Exposure to Rhodobacter Sphaeroides Extract Lycogen™ Prevents UVA-Induced Malondialdehyde Accumulation and Procollagen I Down-Regulation in Human Dermal Fibroblasts 
UVA contributes to the pathogenesis of skin aging by downregulation of procollagen I content and induction of matrix metalloproteinase (MMP)-associated responses. Application of antioxidants such as lycopene has been demonstrated as a convenient way to achieve protection against skin aging. Lycogen™, derived from the extracts of Rhodobacter sphaeroides, exerts several biological effects similar to that of lycopene whereas most of its anti-aging efficacy remains uncertain. In this study, we attempted to examine whether Lycogen™ could suppress malondialdehyde (MDA) accumulation and restore downregulated procollagen I expression induced by UVA exposure. In human dermal fibroblasts Hs68 cells, UVA repressed cell viability and decreased procollagen I protein content accompanied with the induction of MMP-1 and MDA accumulation. Remarkably, incubation with 50 μM Lycogen™ for 24 h ameliorated UVA-induced cell death and restored UVA-induced downregulation of procollagen in a dose-related manner. Lycogen™ treatment also prevented the UVA-induced MMP-1 upregulation and intracellular MDA generation in Hs68 cells. Activation of NFκB levels, one of the downstream events induced by UVA irradiation and MMP-1 induction, were also prevented by Lycogen™ administration. Taken together, our findings demonstrate that Lycogen™ may be an alternative agent that prevents UVA-induced skin aging and could be used in cosmetic and pharmaceutical applications.
doi:10.3390/ijms15021686
PMCID: PMC3958816  PMID: 24463291
Lycogen™; skin aging; UVA; procollagen I; matrix metalloproteinase
18.  In Silico Identification and Characterization of N-Terminal Acetyltransferase Genes of Poplar (Populus trichocarpa) 
N-terminal acetyltransferase (Nats) complex is responsible for protein N-terminal acetylation (Nα-acetylation), which is one of the most common covalent modifications of eukaryotic proteins. Although genome-wide investigation and characterization of Nat catalytic subunits (CS) and auxiliary subunits (AS) have been conducted in yeast and humans they remain unexplored in plants. Here we report on the identification of eleven genes encoding eleven putative Nat CS polypeptides, and five genes encoding five putative Nat AS polypeptides in Populus. We document that the expansion of Nat CS genes occurs as duplicated blocks distributed across 10 of the 19 poplar chromosomes, likely only as a result of segmental duplication events. Based on phylogenetic analysis, poplar Nat CS were assigned to six subgroups, which corresponded well to the Nat CS types (CS of Nat A–F), being consistent with previous reports in humans and yeast. In silico analysis of microarray data showed that in the process of normal development of the poplar, their Nat CS and AS genes are commonly expressed at one relatively low level but share distinct tissue-specific expression patterns. This exhaustive survey of Nat genes in poplar provides important information to assist future studies on their functional role in poplar.
doi:10.3390/ijms15021852
PMCID: PMC3958825  PMID: 24473137
acetyltransferase; Nα-acetylation; genome identification; woody plants; phylogenetic analysis
19.  Combination of chemotherapy and immunotherapy for colon cancer in China: A meta-analysis 
AIM: To investigate whether autologous dendritic cell (DC)-cytokine-induced killer (CIK) cell therapy is able to improve the therapeutic efficacy of chemotherapy in colon cancer.
METHODS: We conducted a systematic review of published papers from the sources of MEDLINE, the Cochrane Central Register of Controlled Trials, EMBASE, the Wanfang Database, the China Science and Technology Periodical Database and China Journal Net. Published data were extracted independently by two authors using predefined database templates. The quality of the data from individual papers was also assessed. The effects of chemotherapy were compared with those of chemotherapy in combination with DC-CIK immunotherapy. The pooled analysis was performed using the data from random or fixed-effect models.
RESULTS: Seven trials matched our inclusion criteria (n = 533). The overall analysis showed significant survival benefit [one-year overall survival (OS), P < 0.0001; two-year OS, P = 0.009; three-year OS, P = 0.002] in favor of DC-CIK immunotherapy combined with chemotherapy. Disease-free survival (DFS) rate was improved after the combination of DC-CIK immunotherapy and chemotherapy (one-year DFS, P < 0.0001; two-year DFS, P = 0.002; three-year DFS, P = 0.02). An improved overall response rate (P = 0.009) was also observed in patients who received DC-CIK therapy. Furthermore, the analysis of T-lymphocyte subsets in peripheral blood indicated that the number of CD4+ T cells significantly increased in the DC-CIK plus chemotherapy group (P < 0.05).
CONCLUSION: The combination of DC-CIK immunotherapy and chemotherapy was superior in prolonging the survival time and enhancing immunological responses.
doi:10.3748/wjg.v20.i4.1095
PMCID: PMC3921535  PMID: 24574784
Dendritic cells; Cytokine-induced killer cells; Meta-analysis; Colon cancer; Immunotherapy
20.  Fuzi Attenuates Diabetic Neuropathy in Rats and Protects Schwann Cells from Apoptosis Induced by High Glucose 
PLoS ONE  2014;9(1):e86539.
Radix aconite lateralis preparata (Fuzi), a folk medicine, has long been used for the treatment of diabetes and paralysis in China. We examined the effect of Fuzi alone on diabetic rats and Schwann cells in high glucose and the components responsible for its activity. The major constituents of FZE were identified by HPLC-MS/MS data. Male Sprague Dawley rats (n = 36) were randomly divided into control, diabetic, FZE 1.75 g/kg, FZE 3.50 g/kg, FZE 7.00 g/kg, and methylcobalamin groups. After two weeks treatment, nerve conduction velocity and paw withdrawal latency were measured. In vitro, the Schwann cells were grouped according to exposure: normal glucose (NG), normal glucose plus mannitol (NG+M), high glucose (HG), and HG plus different concentrations of FZE (0.1 µg/ml, 1.0 µg/ml, and 10.0 µg/ml). Oxygen free radicals and apoptosis were evaluated through DCFH2DA, DHE and annexin-PE/7-AAD assay, respectively. Apoptosis factors (Bax, Bcl-2, CytoC, caspase-3, and caspase-9) were analyzed using immunofluorescence. Nine alkaloids were identified. The results from animal model showed that FZE was effective in accelerating nerve conduction velocity and shortening paw withdrawal latency in diabetic rats. And in vitro, FZE was also found to protect Schwann cells against high glucose injury. FZE could significantly decrease the apoptotic ratio, superoxide anion and peroxide level. Furthermore, the apoptosis factors, including Bax, Bcl-2, CytoC, caspase-3, and caspase-9 were ameliorated in FZE treated groups. The HPLC-MSn method is simple and suitable for the identification of alkaloids in Fuzi. FZE has a protective effect in diabetic neuropathic rats, which is probably achieved by the antiapoptotic effect of FZE on Schwann cells. Apoptosis factor data imply that FZE protected Schwann cells through the mitochondria pathway. Alkaloids are major components contributing to the protective effect.
doi:10.1371/journal.pone.0086539
PMCID: PMC3900563  PMID: 24466139
21.  Genetic Determinants of Response to Warfarin during Initial Anticoagulation 
The New England journal of medicine  2008;358(10):999-1008.
BACKGROUND
Genetic variants of the enzyme that metabolizes warfarin, cytochrome P-450 2C9 (CYP2C9), and of a key pharmacologic target of warfarin, vitamin K epoxide reductase (VKORC1), contribute to differences in patients’ responses to various warfarin doses, but the role of these variants during initial anticoagulation is not clear.
METHODS
In 297 patients starting warfarin therapy, we assessed CYP2C9 genotypes (CYP2C9 *1, *2, and *3), VKORC1 haplotypes (designated A and non-A), clinical characteristics, response to therapy (as determined by the international normalized ratio [INR]), and bleeding events. The study outcomes were the time to the first INR within the therapeutic range, the time to the first INR of more than 4, the time above the therapeutic INR range, the INR response over time, and the warfarin dose requirement.
RESULTS
As compared with patients with the non-A/non-A haplotype, patients with the A/A haplotype of VKORC1 had a decreased time to the first INR within the therapeutic range (P = 0.02) and to the first INR of more than 4 (P = 0.003). In contrast, the CYP2C9 genotype was not a significant predictor of the time to the first INR within the therapeutic range (P = 0.57) but was a significant predictor of the time to the first INR of more than 4 (P = 0.03). Both the CYP2C9 genotype and VKORC1 haplotype had a significant influence on the required warfarin dose after the first 2 weeks of therapy.
CONCLUSIONS
Initial variability in the INR response to warfarin was more strongly associated with genetic variability in the pharmacologic target of warfarin, VKORC1, than with CYP2C9.
doi:10.1056/NEJMoa0708078
PMCID: PMC3894627  PMID: 18322281
22.  Integrated interventions for improving negative emotions and stress reactions of young women receiving total hysterectomy 
50% of women had obvious abnormal emotions before hysterectomy and hysterectomy can cause strong mental stress reaction. This study was to investigate the impact of psychological health education based integrated interventions on the preoperative negative emotions and stress of patients younger than 45 years receiving total hysterectomy. Forty patients undergoing total hysterectomy were randomly divided into psychological intervention (PI) group and control group (n=20 per group). Patients in PI received peri-operative psychological intervention (supportive psychotherapy, health education, individual depth psychotherapy, family and society supportive care, education on anesthesia and surgery etc.); Interventions were not used in control group. Hamilton Anxiety Scale and Hamilton Depression Rating Scale were used to evaluate patients in two groups on admission (T1) and before surgery (T2; after interventions in PI group). Serum levels of cortisol and IL-6 were detected at T1, T2 and the second day after surgery (T3). Results showed that 1) Patients had obvious anxiety and depression symptoms before and after total hysterectomy. For patients in PI group, the Hamilton Anxiety Scale (HAMA) score decreased from 14.4±5.9 to 9.1±4.2 and the Hamilton Depressing Scale (HAMD) score from 17.8±3.5 to 9.4±6.8 after interventions; 2) In PI group, the serum cortisol was 13.4±3.9 μg/dl at T2 and 14.2±4.8 μg/dl at T3 which were significantly lower than that at T1 (16.6±4.0 μg/dl) and that in the control group at T2 (13.4±3.9/15.5±4.3 μg/dl, t=2.10, P<0.05). Thus, preoperative integrated intervention based on psychological health education can improve peri-operative negative emotions and psychological stress in young patients undergoing hysterectomy.
PMCID: PMC3902281  PMID: 24482729
Hysterectomy; interventions; negative emotion; randomized controlled trial; stress
23.  Overexpression of RNF146 in Non-Small Cell Lung Cancer Enhances Proliferation and Invasion of Tumors through the Wnt/β-catenin Signaling Pathway 
PLoS ONE  2014;9(1):e85377.
Studies have suggested a possible correlation between the newly identified E3 ubiquitin ligase ring finger protein 146 (RNF146) and tumor development. However, until now, studies on RNF146 have been restricted to poly(ADP-ribosyl)ation and ubiquitin ligation, whereas the role of RNF146 in tumor biology has rarely been reported. In the present study, the role of RNF146 in non-small cell lung cancer (NSCLC) was investigated. The results showed that the expression of RNF146 was increased in clinical lung cancer samples and cell lines. RNF146 expression correlated with tumor size, differentiation level, lymphatic metastasis, pTNM staging, and prognosis of patients in stage I. RNF146 expression was negatively correlated with Axin expression but positively correlated with the nuclear expression of β-catenin in NSCLC tissues. RNF146 downregulated the expression of Axin in lung cancer cell lines and induced the expression and nuclear distribution of β-catenin. Overexpression of RNF146 in NSCLC cell lines increased the levels of cyclinD1, cyclinE, and CDK4, promoted cell cycle G0/G1-S transitions, and regulated cell proliferation. Overexpression of RNF146 led to upregulated levels of matrix metalloproteinases 2 and 7 and enhanced lung cancer cell invasiveness, events that were mediated by the classical Wnt/β-catenin signaling pathway. In summary, the data in the present study indicate that RNF146 regulated the development and progression of NSCLC by enhancing cell growth, invasion, and survival, suggesting that RNF146 may be a potential treatment target in NSCLC.
doi:10.1371/journal.pone.0085377
PMCID: PMC3891871  PMID: 24454854
24.  Evaluation of the Antitumor Effects of BPR1J-340, a Potent and Selective FLT3 Inhibitor, Alone or in Combination with an HDAC Inhibitor, Vorinostat, in AML Cancer 
PLoS ONE  2014;9(1):e83160.
Overexpression or/and activating mutation of FLT3 kinase play a major driving role in the pathogenesis of acute myeloid leukemia (AML). Hence, pharmacologic inhibitors of FLT3 are of therapeutic potential for AML treatment. In this study, BPR1J-340 was identified as a novel potent FLT3 inhibitor by biochemical kinase activity (IC50 approximately 25 nM) and cellular proliferation (GC50 approximately 5 nM) assays. BPR1J-340 inhibited the phosphorylation of FLT3 and STAT5 and triggered apoptosis in FLT3-ITD+ AML cells. The pharmacokinetic parameters of BPR1J-340 in rats were determined. BPR1J-340 also demonstrated pronounced tumor growth inhibition and regression in FLT3-ITD+ AML murine xenograft models. The combination treatment of the HDAC inhibitor vorinostat (SAHA) with BPR1J-340 synergistically induced apoptosis via Mcl-1 down-regulation in MOLM-13 AML cells, indicating that the combination of selective FLT3 kinase inhibitors and HDAC inhibitors could exhibit clinical benefit in AML therapy. Our results suggest that BPR1J-340 may be further developed in the preclinical and clinical studies as therapeutics in AML treatments.
doi:10.1371/journal.pone.0083160
PMCID: PMC3885398  PMID: 24416160
25.  Haemolytic uremic syndrome following fire ant bites 
BMC Nephrology  2014;15:5.
Background
Haemolytic-uremic syndrome (HUS) is a severe, life-threatening disease with symptoms such as haemolytic anaemia, renal failure, and a low platelet count. Possible aetiology includes bacterial infections, medication, post-hematopoietic cell transplantation, pregnancy, autoimmune disease, and acquired immunodeficiency syndrome.
Case presentation
We report the case of a 21-year-old healthy man who developed acute renal failure caused by HUS. Typical symptoms of HUS combined with severe uraemia developed following a large local reaction after suspected Solenopsis invicta (fire ant) bites. He was successfully treated with plasma exchange and achieved complete recovery of renal function.
Conclusion
This is the first case illustrating a serious systemic reaction of HUS to fire ant bites, and highlights this severe complication in patients who sustain fire ant bites.
doi:10.1186/1471-2369-15-5
PMCID: PMC3890644  PMID: 24400942
Fire ant; Haemolytic-uremic syndrome; Plasma exchange; Renal failure; Venomous insects

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