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1.  Sorting Nexin 27 Regulates Aβ Production through Modulating γ-secretase Activity 
Cell reports  2014;9(3):1023-1033.
Patients with Down syndrome (DS) invariably develop Alzheimer’s disease (AD) pathology in their 40s. We have recently found that overexpression of a chromosome 21-encoded microRNA-155 results in decreased levels of the membrane trafficking component, SNX27, diminishing glutamate receptor recycling and thereby impairing synaptic functions in DS. Here we report a function of SNX27 in regulating Aβ generation by modulating γ-secretase activity. Downregulation of SNX27 using RNA interference increased Aβ production, whereas overexpression of full-length SNX27 but not SNX27ΔPDZ reversed the RNAi-mediated Aβ elevation. Moreover, genetic deletion of Snx27 promoted Aβ production and neuronal loss, whereas overexpression of SNX27 using an AAV vector reduced hippocampal Aβ levels in a transgenic AD mouse model. SNX27 associates with the γ-secretase complex subunit presenilin 1; this interaction dissociates the γ-secretase complex, thus decreasing its proteolytic activity. Our study establishes a molecular mechanism for Aβ-dependent pathogenesis in both DS and AD.
PMCID: PMC4328673  PMID: 25437557
2.  IL-33/ST2 Correlates with Severity of Haemorrhagic Fever with Renal Syndrome and Regulates the Inflammatory Response in Hantaan Virus-Infected Endothelial Cells 
PLoS Neglected Tropical Diseases  2015;9(2):e0003514.
Hantaan virus (HTNV) causes a severe lethal haemorrhagic fever with renal syndrome (HFRS) in humans. Despite a limited understanding of the pathogenesis of HFRS, the importance of the abundant production of pro-inflammatory cytokines has been widely recognized. Interleukin 33 (IL-33) has been demonstrated to play an important role in physiological and pathological immune responses. After binding to its receptor ST2L, IL-33 stimulates the Th2-type immune response and promotes cytokine production. Depending on the disease model, IL-33 either protects against infection or exacerbates inflammatory disease, but it is unknown how the IL-33/ST2 axis regulates the immune response during HTNV infection.
Methodology/Principal Findings
Blood samples were collected from 23 hospitalized patients and 28 healthy controls. The levels of IL-33 and soluble ST2 (sST2) in plasma were quantified by ELISA, and the relationship between IL-33, sST2 and the disease severity was analyzed. The role of IL-33/sST2 axis in the production of pro-inflammatory cytokines was studied on HTNV-infected endothelial cells. The results showed that the plasma IL-33 and sST2 were significantly higher in patients than in healthy controls. Spearman analysis showed that elevated IL-33 and sST2 levels were positively correlated with white blood cell count and viral load, while negatively correlated with platelet count. Furthermore, we found that IL-33 enhanced the production of pro-inflammatory cytokines in HTNV-infected endothelial cells through NF-κB pathway and that this process was inhibited by the recombinant sST2.
Our results indicate that the IL-33 acts as an initiator of the “cytokine storm” during HTNV infection, while sST2 can inhibit this process. Our findings could provide a promising immunotherapeutic target for the disease control.
Author Summary
Hantaan virus (HTNV) causes human hemorrhagic fever with renal syndrome (HFRS) with a mortality rate of approximately 15% in Asia. At present, the primary treatment for HFRS is limited to critical care management and the use of anti-viral drugs, such as Ribavirin. However, the cytokine storm at the acute phase of HFRS, which is thought to contribute to the development of the disease, is still lacking an effective way to prevent. An alternative way to prevent the development of cytokine storm is of priority to overcome the problem. We found that IL-33 and sST2 levels were higher in the plasma of HFRS patients, especially in their acute phase. Although both of them were positively correlated with the severity of the diseases, they acted in different roles in the regulation of the immune response during HTNV infection. In vitro study showed that IL-33 acted as an initiator of the cytokine storm in HTNV-infected endothelial cells, while sST2 acted as an inhibitor of the process. For the first time, we defined the IL-33/ST2 axis as inflammatory regulators during HTNV infection. Our results may provide a novel therapeutic target of HTNV infections.
PMCID: PMC4319827  PMID: 25658420
3.  The Resveratrol Trimer Miyabenol C Inhibits β-Secretase Activity and β-Amyloid Generation 
PLoS ONE  2015;10(1):e0115973.
Accumulation and deposition of amyloid-β peptide (Aβ) in the brain is a primary cause of the pathogenesis of Alzheimer’s disease (AD). Aβ is generated from amyloid-β precursor protein (APP) through sequential cleavages first by β-secretase and then by γ-secretase. Inhibiting β-secretase activity is believed to be one of the most promising strategies for AD treatment. In the present study, we found that a resveratrol trimer, miyabenol C, isolated from stems and leaves of the small-leaf grape (Vitisthunbergii var. taiwaniana), can markedly reduce Aβ and sAPPβ levels in both cell cultures and the brain of AD model mice. Mechanistic studies revealed that miyabenol C affects neither protein levels of APP, the two major α-secretases ADAM10 and TACE, and the γ-secretase component Presenilin 1, nor γ-secretase-mediated Notch processing and TACE activity. In contrast, although miyabenol C has no effect on altering protein levels of the β-secretase BACE1, it can inhibit both in vitro and in vivo β-secretase activity. Together, our results indicate that miyabenol C is a prominent β-secretase inhibitor and lead compound for AD drug development.
PMCID: PMC4309453  PMID: 25629409
4.  A medical costs study of older patients with acute myocardial infarction and metabolic syndrome in hospital 
Older patients with acute myocardial infarction (AMI) usually have a poor prognosis, but whether this poor prognosis leads to high hospital costs remains unclear. This study investigated the clinical outcomes of and costs incurred by older patients with AMI and metabolic syndrome (MS) in hospital.
Methods and results
Patients with AMI seen at Qilu Hospital of Shandong University between January 2011 and May 2013 were separated into four groups: young non-MS patients (n=282), older non-MS patients (n=324), young MS patients (n=217), and older MS patients (n=174). We found that advanced age was significantly associated with worse clinical outcomes, and that the clinical outcomes in patients with AMI and MS are also worsened. At the same cost (RMB¥10,000), older patients with and without MS had a markedly increased number of cardiovascular incidences compared with younger patients without MS. In a comparison of the incremental cost-effectiveness ratio (ICER) of percutaneous coronary intervention, older patients without MS had a lower ICER for cardiovascular incidences and a higher ICER for cardiac event-free survival rate when compared with young patients without MS, but a lower ICER for cardiovascular incidences and a higher ICER for cardiac event-free survival rate when compared with older MS patients.
Older AMI patients have poor clinical outcomes and their treatment is not cost-effective; however, the results are worse in patients with AMI and MS. Percutaneous coronary intervention is a cost-effective therapy in older patients with AMI, but its cost-effectiveness decreases in patients with AMI and MS.
PMCID: PMC4315548
metabolic syndrome; aging; vascular; acute myocardial infarction; cost-effectiveness
5.  Dissecting the Signaling Mechanisms Underlying Recognition and Preference of Food Odors 
The Journal of Neuroscience  2014;34(28):9389-9403.
Food is critical for survival. Many animals, including the nematode Caenorhabditis elegans, use sensorimotor systems to detect and locate preferred food sources. However, the signaling mechanisms underlying food-choice behaviors are poorly understood. Here, we characterize the molecular signaling that regulates recognition and preference between different food odors in C. elegans. We show that the major olfactory sensory neurons, AWB and AWC, play essential roles in this behavior. A canonical Gα-protein, together with guanylate cyclases and cGMP-gated channels, is needed for the recognition of food odors. The food-odor-evoked signal is transmitted via glutamatergic neurotransmission from AWC and through AMPA and kainate-like glutamate receptor subunits. In contrast, peptidergic signaling is required to generate preference between different food odors while being dispensable for the recognition of the odors. We show that this regulation is achieved by the neuropeptide NLP-9 produced in AWB, which acts with its putative receptor NPR-18, and by the neuropeptide NLP-1 produced in AWC. In addition, another set of sensory neurons inhibits food-odor preference. These mechanistic logics, together with a previously mapped neural circuit underlying food-odor preference, provide a functional network linking sensory response, transduction, and downstream receptors to process complex olfactory information and generate the appropriate behavioral decision essential for survival.
PMCID: PMC4087214  PMID: 25009271
glutamatergic transmission; neuropeptide signaling; olfactory sensory neurons; olfactory sensory signaling; preference of food odors
6.  Benzoate Metabolism Intermediate Benzoyl Coenzyme A Affects Gentisate Pathway Regulation in Comamonas testosteroni 
Applied and Environmental Microbiology  2014;80(13):4051-4062.
A previous study showed that benzoate was catabolized via a coenzyme A (CoA)-dependent epoxide pathway in Azoarcus evansii (R. Niemetz, U. Altenschmidt, S. Brucker, and G. Fuchs, Eur. J. Biochem. 227:161-168, 1995), but gentisate 1,2-dioxygenase was induced. Similarly, we found that the Comamonas testosteroni strain CNB-1 degraded benzoate via a CoA-dependent epoxide pathway and that gentisate 1,2-dioxygenase (GenA) was also induced when benzoate or 3-hydroxybenzoate served as a carbon source for growth. Genes encoding the CoA-dependent epoxide (box genes) and gentisate (gen genes) pathways were identified. Genetic disruption revealed that the gen genes were not involved in benzoate and 3-hydroxybenzoate degradation. Hence, we investigated gen gene regulation in the CNB-1 strain. The PgenA promoter, a MarR-type regulator (GenR), and the GenR binding site were identified. We found that GenR took gentisate, 3-hydroxybenzoate, and benzoyl-CoA as effectors and that binding of GenR to its target DNA sequence was prohibited when these effectors were present. In vivo studies showed that the CNB-1 mutant that lost benzoyl-CoA synthesis was not able to activate PgenA promoter, while transcription of genA was upregulated in another CNB-1 mutant that lost the ability to degrade benzoyl-CoA. The finding that benzoyl-CoA (a metabolic intermediate of benzoate degradation) and 3-hydroxybenzoate function as GenR effectors explains why GenA was induced when CNB-1 grew on benzoate or 3-hydroxybenzoate. Regulation of gentisate pathways by MarR-, LysR-, and IclR-type regulators in diverse bacterial groups is discussed in detail.
PMCID: PMC4054210  PMID: 24771026
7.  Ambulatory surgery centers and outpatient urologic surgery among Medicare beneficiaries 
Urology  2014;84(1):57-61.
To determine the effect of an ambulatory surgery center (ASC) opening in a healthcare market on utilization and quality of outpatient urologic surgery.
Retrospective cohort study of Medicare beneficiaries undergoing outpatient urologic surgery from 2001 to 2010. Markets were classified into three groups based on ASC status (i.e., those with ASCs, those without ASCs, and those where ASCs were introduced). Multiple propensity score methods adjusted for differences between markets and general linear mixed models determined the effect of ASC opening on utilization and quality, defined by mortality and hospital admission within 30 days of the index procedure.
During the study period, 195 ASCs opened in markets previously without one. Rates of hospital based urologic surgery in markets where ASCs were introduced declined from 221 to 214 procedures per 10,000 beneficiaries in the 4 years after baseline. In contrast, rates in the other two market types increased over the same period (p < 0.001). Rates of outpatient urologic surgery overall (i.e., in the hospital and ASC) demonstrated similar growth across market types during same period (p = 0.56). The introduction of an ASC into a market was not associated with increases in hospital admission or mortality (p’s > 0.5).
The introduction of an ASC into a healthcare market lowered rates of outpatient urologic surgery performed in the more expensive hospital setting. This redistribution was not associated with declines in quality or with greater growth in overall outpatient surgery use.
PMCID: PMC4077194  PMID: 24976220
population; propensity score; administrative claims; healthcare market; hospital service area; mortality; hospital admission
8.  Genetic variants in antigen presentation-related genes influence susceptibility to hepatitis C virus and viral clearance: a case control study 
BMC Infectious Diseases  2014;14(1):3837.
Genes related to antigen presentation pathway, which are in the non-classical class-II region of human leukocyte antigen (HLA), play a vital role during the infection of hepatitis C virus (HCV).
The current study determined the genotypes of 34 tagging-SNPs (single nucleotide polymorphisms) from 9 candidate genes (HLA-DMA, HLA-DMB, HLA-DOA, HLA-DOB, TAP1, TAP2, LMP2, LMP7, and tapasin) in a Chinese population of paid blood donors with high risk of HCV infection. The distributions of those SNPs were compared among the 1207 former paid blood donors with different HCV infection outcomes.
HLA-DMA rs1063478 and HLA-DOA rs2284191 were independent factors of acquiring HCV infection. Carrying three favorable alleles of rs1063478-T and rs2284191-G offered the highest protective effect (odds ratio = 0.46, 95% confidence intervals = 0.27-0.78). HLA-DOB rs7383287 and LMP2 rs17587 were independent factors of infection chronicity. Subjects carrying two favorable alleles of rs7383287-G and rs17587-A had a decreased risk of HCV chronicity (odds ratio = 0.42, 95% confidence intervals = 0.26-0.66). The interaction analysis showed that experience of plasma donation interacted with the combined effects of rs1063478 and rs2284191 for HCV susceptibility, and the experience of whole blood donation interacted with the association of rs7383287 with HCV clearance.
Our results suggested that genetic variants in antigen presentation pathway had influence on susceptibility to HCV infection and viral clearance. HLA-DMA rs1063478, HLA-DOA rs2284191, and HLA-DOB rs7383287 were identified as novel loci in Chinese population that were involved in HCV infection.
Electronic supplementary material
The online version of this article (doi:10.1186/s12879-014-0716-8) contains supplementary material, which is available to authorized users.
PMCID: PMC4279674  PMID: 25528575
Hepatitis C; Genetic polymorphism; Human leukocyte antigen; Infection outcomes; Chinese population
9.  Effect of Urinary Protease Inhibitor (Ulinastatin) on Cardiopulmonary Bypass: A Meta-Analysis for China and Japan 
PLoS ONE  2014;9(12):e113973.
A meta-analysis was conducted to investigate the effects of ulinastatin treatment on adult patients undergoing cardiac surgery under cardiopulmonary bypass (CPB).
Seven electronic databases were searched for reports of randomized, controlled trials conducted up to February 2014 in which patients undergoing cardiac surgery with CPB were administered ulinastatin in the perioperative period.
Fifty-two studies with 2025 patients were retained for analysis. The results showed that the ulinastatin can attenuate the plasma levels of pro-inflammatory cytokines and enhance the anti-inflammatory cytokine levels in patients undergoing cardiac surgery with CPB. Meanwhile, the ulinastatin had a significant beneficial effect on myocardial injury. The mean differences (MD) and 95% confidence intervals (95% CI) of biochemical markers were −63.54 (−79.36, −47.72) for lactate dehydrogenase, −224.99 (−304.83, −145.14) for creatine kinase, −8.75 (−14.23, −3.28) for creatine kinase-MB, and −0.14 (−0.20, −0.09] for troponin I (all P<0.01). However, neither hemodynamics nor cardiac function improved significantly, except that the MD and 95% CI of mean arterial pressure were 2.50 (0.19, 4.80) (P = 0.03). There were no statistically significant differences in the use of inotropes, postoperative bleeding, postoperative complications, the intensive care unit (ICU) stay, and the hospital stay; however, the frequency of auto resuscitation increased significantly (OR 1.98, 95%CI 1.19 to 3.30, P<0.01), the duration of intubation (MD −1.58, 95%CI −2.84 to −0.32, P<0.01) and the duration of mechanical ventilation (MD −3.29, 95%CI −4.41 to −2.17, P<0.01) shortened significantly in patients who were treated with ulinastatin.
Ulinastatin can reduce the plasma levels of pro-inflammatory cytokines and elevate anti-inflammatory cytokine in patients from China and Japan undergoing cardiac surgery with CPB. Ulinastatin treatment may have protective effects on myocardial injury, and can increase the frequency of auto resuscitation, shorten the duration of intubation and mechanical ventilation.
PMCID: PMC4263539  PMID: 25500819
10.  Excessive levels of nitric oxide in rat model of Parkinson’s disease induced by rotenone 
Systemic rotenone models of Parkinson’s disease (PD) are highly reproducible and may provide evidence on the pathogenesis of PD. In the present study, male Sprague-Dawley rats (1-year-old) were subcutaneously administered with rotenone (1.5 mg/kg/day) for six days and observed for the following three weeks. Compared with the control rats, a significant decrease was observed in the body weight and a marked increase was observed in the areas under the behavioral scoring curves in the rotenone-treated rats. Immunohistochemical staining revealed that the abundance of nigral tyrosine hydroxylase (TH)-positive neurons was markedly reduced following rotenone treatment. ELISA and neurochemical assays demonstrated a significant increase in the levels of nitric oxide (NO) and NO synthase, whereas a marked decrease was observed in the thiol levels in the brains of the rotenone-treated rats. Thus, subacute rotenone treatment was found to induce behavioral deficits and the loss of nigral TH-positive neurons which may be associated with the excessive levels of NO in the rat brains.
PMCID: PMC4280943  PMID: 25574233
nitric oxide; rotenone; Parkinson’s disease
11.  The impact of technology diffusion on treatment for prostate cancer 
Medical care  2013;51(12):1076-1084.
Use of local therapy for prostate cancer may increase because of the perceived advantages of new technologies such as intensity-modulated radiotherapy (IMRT) and robotic prostatectomy.
To examine the association of market-level technological capacity with receipt of local therapy.
Retrospective cohort.
Patients with localized prostate cancer who were diagnosed between 2003 and 2007 (n=59,043) from the Surveillance Epidemiology and End Results (SEER) – Medicare database.
We measured the capacity for delivering treatment with new technology as the number of providers offering robotic prostatectomy or IMRT per population in a market (hospital referral region). The association of this measure with receipt of prostatectomy, radiotherapy, or observation was examined with multinomial logistic regression.
For each 1,000 patients diagnosed with prostate cancer, 174 underwent prostatectomy, 490 radiotherapy, and 336 were observed. Markets with high robotic prostatectomy capacity had higher use of prostatectomy (146 vs. 118 per 1,000 men, p=0.008) but a trend towards decreased use of radiotherapy (574 vs. 601 per 1,000 men, p=0.068), resulting in a stable rate of local therapy. High versus low IMRT capacity did not significantly impact use of prostatectomy (129 vs. 129 per 1,000 men, p=0.947) and radiotherapy (594 vs. 585 per 1,000 men, p=0.579).
Although there was a small shift from radiotherapy to prostatectomy in markets with high robotic prostatectomy capacity, increased capacity for both robotic prostatectomy and IMRT did not change the overall rate of local therapy. Our findings temper concerns that new technology spurs additional therapy of prostate cancer.
PMCID: PMC3916901  PMID: 24226306
intensity-modulated radiotherapy; prostate cancer treatment; robotic prostatectomy; technology
12.  Therapeutic Potential of the Antimicrobial Peptide OH-CATH30 for Antibiotic-Resistant Pseudomonas aeruginosa Keratitis 
The therapeutic potential of antimicrobial peptides (AMPs) has been evaluated in many infectious diseases. However, the topical application of AMPs for ocular bacterial infection has not been well investigated. The AMP OH-CATH30, which was identified in the king cobra, exhibits potent antimicrobial activity. In this study, we investigated the therapeutic potential of OH-CATH30 for Pseudomonas aeruginosa keratitis. Ten isolates of P. aeruginosa from individuals with keratitis were susceptible to OH-CATH30 but not to cefoperazone, ciprofloxacin, gentamicin, and levofloxacin. The microdilution checkerboard assay showed that OH-CATH30 exhibited synergistic activity with ciprofloxacin and levofloxacin against antibiotic-resistant P. aeruginosa. Meanwhile, P. aeruginosa did not develop resistance to OH-CATH30, even after exposure at 0.5× the MIC for up to 25 subcultures. Furthermore, treatment with OH-CATH30, alone or in combination with levofloxacin, significantly improved the clinical outcomes of rabbit keratitis induced by antibiotic-resistant P. aeruginosa. Taken together, our data indicate that the topical application of OH-CATH30 is efficacious against drug-resistant P. aeruginosa keratitis. In addition, our study highlights the potential application of AMPs in treating ocular bacterial infections.
PMCID: PMC4068471  PMID: 24637683
13.  Isolation and epithelial co-culture of mouse renal peritubular endothelial cells 
BMC Cell Biology  2014;15(1):40.
Endothelial-mesenchymal transition (EndoMT) has been shown to be a major source of myofibroblasts, contributing to kidney fibrosis. However, in vitro study of endothelial cells often relies on culture of isolated primary endothelial cells due to the unavailability of endothelial cell lines. Our recent study suggested that peritubular endothelial cells could contribute to kidney fibrosis through EndoMT. Therefore, successful isolation and culture of mouse peritubular endothelial cells could provide a new platform for studying kidney fibrosis. This study describes an immunomagnetic separation method for the isolation of mouse renal peritubular endothelial cells using anti-CD146 MicroBeads, followed by co-culture with mouse renal proximal tubular epithelial cells to maintain endothelial phenotype.
Flow cytometry showed that after isolation and two days of culture, about 95% of cells were positive for endothelial-specific marker CD146. The percentage of other cells, including dendritic cells (CD11c) and macrophages (F4/80), was less than 1%. Maintenance of endothelial cell phenotype required vascular endothelial growth factor (VEGF) and co-culture with mouse proximal tubular epithelial cells.
In this study, we established a method for the isolation of mouse renal peritubular endothelial cells by using immunomagnetic separation with anti-CD146 MicroBeads, followed by co-culture with mouse renal proximal tubular epithelial cells to maintain phenotype.
Electronic supplementary material
The online version of this article (doi:10.1186/s12860-014-0040-6) contains supplementary material, which is available to authorized users.
PMCID: PMC4260259  PMID: 25433516
Peritubular endothelial cells; Tubular epithelial cells; CD146; Co-culture; Vascular endothelial growth factor
14.  Gastrointestinal stromal tumor: 15-years’ experience in a single center 
BMC Surgery  2014;14(1):93.
Gastrointestinal stromal tumor (GIST) is known for its wide variability in biological behaviors and it is difficult to predict its malignant potential. The aim of this study is to explore the characteristics and prognostic factors of GIST.
Clinical and pathological data of 497 GIST patients in our center between 1997 and 2012 were reviewed.
Patients were categorized into very low-, low-, intermediate- and high-risk groups according to modified National Institutes of Health (NIH) consensus classification system. Among the 401 patients untreated with imatinib mesylate (IM), 5-year overall survival (OS) in very low-, low-, intermediate- and high-risk groups was 100%, 100%, 89.6% and 65.9%; and 5-year relapse-free survival (RFS) was 100%, 98.1%, 90.9% and 44.5%, respectively. Univariate analysis revealed that sex, tumor size, mitotic rate, risk grade, CD34 expression, and adjacent involvement were predictors of OS or RFS. COX hazard proportional model (Forward LR) showed that large tumor size, high mitotic rate, and high risk grade were independent risk factors to OS, whereas high mitotic rate, high risk grade and adjacent organ involvement were independent risk factors to RFS. The intermediate-high risk patients who received IM adjuvant therapy (n = 87) had better 5-year OS and RFS than those who did not (n = 188) (94.9% vs. 72.1; 82.3% vs. 56.3%, respectively). Similarly, advanced GIST patients underwent IM therapy (n = 45) had better 3-year OS and 1-year progression-free survival (PFS) than those who didn’t (n = 42) (75.6% vs. 6.8%; 87.6% vs. 12.4%, respectively).
Very low- and low-risk GISTs can be treated with surgery alone. Large tumor size, high mitotic rate, high risk grade, and adjacent organ involvement contribute to the poor outcome. IM therapy significantly improves the survival of intermediate-high risk or advanced GIST patients.
Electronic supplementary material
The online version of this article (doi:10.1186/1471-2482-14-93) contains supplementary material, which is available to authorized users.
PMCID: PMC4254179  PMID: 25403624
Gastrointestinal stromal tumor; Survival; Imatinib
15.  The Association of Homocysteine with Metabolic Syndrome in a Community-Dwelling Population: Homocysteine Might Be Concomitant with Metabolic Syndrome 
PLoS ONE  2014;9(11):e113148.
Elevated plasma total homocysteine (tHcy) and metabolic syndrome (MetS) are both associated with cardiovascular disease, but the association between tHcy and MetS is not well characterized. The aim of this study was to determine the relationship between tHcy and MetS.
To further estimate the time-dependent association of tHcy and MetS, we analyzed the tHcy level and MetS in 1499 subjects from a 4.8-year longitudinal study in Beijing, People’s Republic of China.
In multiple linear regression analysis, baseline tHcy levels associated with age, BMI, SBP, DBP, LDL-C and Cr independently over 4.8-years follow-up; age, BMI, SBP, DBP and Cr were found to be associated with tHcy levels independently at the end of follow-up. Logistic regression analysis showed that there was no association between the baseline tHcy level and MetS over the 4.8-year follow-up (odds ratio (OR), 1.32; 95% confidence interval (CI), 0.79–2.19; P = 0.282); rather, there was an association only with hypertension as a MetS component (OR, 1.53; 95% CI, 1.06–2.21; P = 0.024). tHcy levels were associated with MetS at both cross-sectional baseline (OR, 1.38; 95% CI, 1.02–1.88; P = 0.038) and cross-sectional follow-up (OR, 1.60; 95% CI, 1.02–2.50; P = 0.041). The tHcy levels of MetS subjects were higher than those of non-MetS subjects at both cross-sectional baseline (19.35±7.92 µmol/L vs. 17.45±6.70 µmol/L, respectively; P = 0.001) and cross-sectional follow-up (18.95±7.15 µmol/L vs. 17.11±5.98 µmol/L, respectively; P = 0.02).
The tHcy level was not predictive of the incidence of MetS; however, it may be a risk factor for hypertension as a MetS component. Furthermore, tHcy levels were associated with MetS at cross-sectional baseline and follow-up, which suggests that a higher level of tHcy might be concomitant with MetS.
PMCID: PMC4234666  PMID: 25401978
16.  Long-term impact of earthquake stress on fasting glucose control and diabetes prevalence among Chinese adults of Tangshan 
Objective: To investigate the long-term influence of stresses from the 1976 Tangshan earthquake on blood glucose control and the incidence of diabetes mellitus in Chinese people of Tangshan. Methods: 1,551 adults ≥ 37 years of age were recruited for this investigation in Tangshan city of China, where one of the deadliest earthquakes occurred in 1796. All subjects finished a questionnaire. 1,030 of them who experienced that earthquake were selected into the exposure group, while 521 were gathered as the control group who have not exposed to any earthquake. The numbers of subjects who were first identified with diabetes or had normal FBG but with diabetic history were added for the calculation of diabetes prevalence. Statistic-analysis was applied on the baseline data, and incidences of IFG as well as diabetes among all groups. Results: Statistic comparisons indicate there is no significant difference on average fasting glucose levels between the control group and the exposure group. However, the prevalence of IFG and diabetes among the exposure group displays significant variance with the control group. The prevalence of diabetes among exposure groups is significantly higher than the control group. Women are more likely to have diabetes after experiencing earthquake stresses compared to men. The earthquake stress was linked to higher diabetes incidence as an independent factor. Conclusions: The earthquake stress has long-term impacts on diabetes incidence as an independent risk factor. Emerging and long-term managements regarding the care of IFG and diabetes in populations exposed to earthquake stress should be concerned.
PMCID: PMC4276224  PMID: 25550966
Tangshan earthquake; stress; fasting blood glucose; impaired fasting glucose; diabetes mellitus
17.  Asymptotic Properties of Pearson's Rank-Variate Correlation Coefficient under Contaminated Gaussian Model 
PLoS ONE  2014;9(11):e112215.
This paper investigates the robustness properties of Pearson's rank-variate correlation coefficient (PRVCC) in scenarios where one channel is corrupted by impulsive noise and the other is impulsive noise-free. As shown in our previous work, these scenarios that frequently encountered in radar and/or sonar, can be well emulated by a particular bivariate contaminated Gaussian model (CGM). Under this CGM, we establish the asymptotic closed forms of the expectation and variance of PRVCC by means of the well known Delta method. To gain a deeper understanding, we also compare PRVCC with two other classical correlation coefficients, i.e., Spearman's rho (SR) and Kendall's tau (KT), in terms of the root mean squared error (RMSE). Monte Carlo simulations not only verify our theoretical findings, but also reveal the advantage of PRVCC by an example of estimating the time delay in the particular impulsive noise environment.
PMCID: PMC4230981  PMID: 25393286
18.  Adiponectin reduces carotid atherosclerotic plaque formation in ApoE−/− mice: Roles of oxidative and nitrosative stress and inducible nitric oxide synthase 
Molecular Medicine Reports  2014;11(3):1715-1721.
Adiponectin (APN) is an important anti-atherogenic adipocytokine. The aim of the present study was to investigate the role of adiponectin in atherosclerotic plaque formation and clarify its mechanisms. An atherosclerosis model was induced by in vivo perivascular constrictive silica collar placement on the left common carotid arteries in male apolipoprotein E-deficient (ApoE−/−) mice. All of the mice were fed a high-fat diet, and divided into phosphate-buffered saline, adenovirus (Ad)-β-galactosidase and Ad-APN treatment groups. Compared with treatment of Ad-β-gal or PBS, Ad-APN treatment markedly reduced inducible nitric oxide synthase (iNOS) protein expression, decreased in nitric oxide/superoxide production, blocked peroxynitrite formation and reversed the progression of atherosclerotic lesions. Adiponectin may be a natural molecule that reduces atherosclerosis by inhibiting iNOS and consequently diminishing oxidative/nitrative stress.
PMCID: PMC4270320  PMID: 25395016
adiponectin; atherosclerosis; oxidative stress; nitrite/nitrate; inducible nitric oxide synthase
19.  Homing and Restorative Effects of Bone Marrow-Derived Mesenchymal Stem Cells on Cisplatin Injured Ovaries in Rats 
Molecules and Cells  2014;37(12):865-872.
Premature ovarian failure (POF) is a long-term adverse effect of chemotherapy treatment. However, current available treatment regimens are not optimal. Emerging evidence suggests that bone marrow-derived mesenchymal stem cells (BMSCs) could restore the structure and function of injured tissues, but the homing and restorative effects of BMSCs on chemotherapy injured ovaries are still not clear. In this study, we found that granulosa cell (GC) apoptosis induced by cisplatin was reduced when BMSCs were migrated to granulosa cells (GCs) in vitro. Chemotherapy-induced POF was induced by intraperitoneal injection of cisplatin in rats. BMSCs labeled with enhanced green fluorescent protein (EGFP) were injected into the rats via the tail vein to investigate the homing and distribution of BMSCs in vivo. The number of BMSCs in the ovarian hilum and medulla was greater than in the cortex, but no BMSCs were found in the follicles and corpus lutea. In addition, the BMSCs treatment group’s antral follicle count and estradiol levels increased after 30 days, compared with the POF group. Hence, our study demonstrates that intravenously delivered BMSCs can home to the ovaries, and restore its structure and function in POF model rats.
PMCID: PMC4275703  PMID: 25410907
bone marrow-derived mesenchymal stem cells; cisplatin; homing; intravenous injection; premature ovarian failure
20.  25-Hydroxyvitamin D3-Deficiency Enhances Oxidative Stress and Corticosteroid Resistance in Severe Asthma Exacerbation 
PLoS ONE  2014;9(11):e111599.
Oxidative stress plays a significant role in exacerbation of asthma. The role of vitamin D in oxidative stress and asthma exacerbation remains unclear. We aimed to determine the relationship between vitamin D status and oxidative stress in asthma exacerbation. Severe asthma exacerbation patients with 25-hydroxyvitamin D3-deficiency (V-D deficiency) or 25-hydroxyvitamin D-sufficiency (V-D sufficiency) were enrolled. Severe asthma exacerbation with V-D-deficiency showed lower forced expiratory volume in one second (FEV1) compared to that with V-D-sufficiency. V-D-deficiency intensified ROS release and DNA damage and increased TNF-α, OGG1 and NFκB expression and NFκB phosphorylation in severe asthma exacerbation. Supplemental vitamin D3 significantly increased the rates of FEV1 change and decreased ROS and DNA damage in V-D-deficiency. Vitamin D3 inhibited LPS-induced ROS and DNA damage and were associated with a decline in TNF-α and NFκB in epithelial cells. H2O2 reduces nuclear translocation of glucocorticoid receptors in airway epithelial cell lines. V-D pretreatment enhanced the dexamethasone-induced nuclear translocation of glucocorticoid receptors in airway epithelial cell lines and monocytes from 25-hydroxyvitamin D3-deficiency asthma patients. These findings indicate that V-D deficiency aggravates oxidative stress and DNA damage, suggesting a possible mechanism for corticosteroid resistance in severe asthma exacerbation.
PMCID: PMC4224414  PMID: 25380286
21.  HMGB1 mediates hyperglycaemia-induced cardiomyocyte apoptosis via ERK/Ets-1 signalling pathway 
Apoptosis is a key event involved in diabetic cardiomyopathy. The expression of high mobility group box 1 protein (HMGB1) is up-regulated in diabetic mice. However, the molecular mechanism of high glucose (HG)-induced cardiomyocyte apoptosis remains obscure. We aimed to determine the role of HMGB1 in HG-induced apoptosis of cardiomyocytes. Treating neonatal primary cardiomyocytes with HG increased cell apoptosis, which was accompanied by elevated levels of HMGB1. Inhibition of HMGB1 by short-hairpin RNA significantly decreased HG-induced cell apoptosis by reducing caspase-3 activation and ratio of Bcl2-associated X protein to B-cell lymphoma/leukemia-2 (bax/bcl-2). Furthermore, HG activated E26 transformation-specific sequence-1 (Ets-1), and HMGB1 inhibition attenuated HG-induced activation of Ets-1 via extracellular signal-regulated kinase 1/2 (ERK1/2) signalling. In addition, inhibition of Ets-1 significantly decreased HG-induced cardiomyocyte apoptosis. Similar results were observed in streptozotocin-treated diabetic mice. Inhibition of HMGB1 by short-hairpin RNA markedly decreased myocardial cell apoptosis and activation of ERK and Ets-1 in diabetic mice. In conclusion, inhibition of HMGB1 may protect against hyperglycaemia-induced cardiomyocyte apoptosis by down-regulating ERK-dependent activation of Ets-1.
PMCID: PMC4224563  PMID: 25210949
high glucose; cardiomyocyte; apoptosis; diabetes; HMGB1; Ets-1
22.  Associations of IFN-γ rs2430561 T/A, IL28B rs12979860 C/T and ERα rs2077647 T/C polymorphisms with outcomes of hepatitis B virus infection: a meta-analysis 
Journal of Biomedical Research  2014;28(6):484-493.
Several studies investigated associations of IFN-γ rs2430561 T/A, IL28B rs12979860 C/T and ERα rs2077647 T/C gene polymorphisms with outcomes of hepatitis B virus (HBV) infection, but the results were controversial. Therefore, we performed a meta-analysis of all published observational studies to address this inconsistency. Literature was searched in online database and a systematic review was conducted based on the search results. A total of 24 studies were included and dichotomous data were presented as odds ratio (OR) with a 95% confidence interval (CI). The rs2430561 T allele was associated with reduced persistent HBV infection risk (T vs. A: OR, 0.690; 95% CI, [0.490, 0.971]), while the rs2077647 T allele significantly increased the risk of persistent HBV infection (T vs. C: OR, 1.678; 95% CI, [1.212, 2.323]). Rs 2077647 CC might play a role in protecting individuals against HBV persistence (TT vs. CC: OR, 4.109; 95% CI, [2.609, 6.473]). Furthermore, carriers of the rs2430561 TT genotype were more likely to clear HBV spontaneously compared with those of the AA genotype (TT vs. AA: OR, 0.555; 95% CI, [0.359, 0.856]). For rs12979860 C/T polymorphism, no significant correlation with HBV infection outcomes was found. In subgroup analyses, the results were similar to those of overall analysis. However, for rs2077647 TT vs. TC+CC, significantly increased risks were observed in the Asian and hospital-based population, but not in the overall analysis. IFN-γ rs2430561 T/A and ERα rs2077647 T/C genetic polymorphisms were associated with outcomes of HBV infection, but no association was found between IL28B rs12979860 C/T and HBV infection.
PMCID: PMC4250527  PMID: 25469118
meta-analysis; single nucleotide polymorphism; IFN-γ rs2430561 T/A; IL28B rs12979860 C/T; ERα rs2077647 T/C; hepatitis B virus
23.  Field Dissipation and Storage Stability of Glufosinate Ammonium and Its Metabolites in Soil 
A simple analytical method was developed to measure concentrations of glufosinate ammonium and its metabolites, 3-methylphosphinico-propionic acid (MPP) and 2-methylphosphinico-acetic acid (MPA), in field soil samples. To determine the minimum quantification limit, samples were spiked at different levels (0.1, 0.5, and 1.0 mg/kg). Soil samples were extracted with ammonium hydroxide solution 5% (v/v), concentrated, and reacted with trimethyl orthoacetate (TMOA) in the presence of acetic acid for derivatization. The derivatives were quantified by gas chromatography (GC) using a flame photometric detector (FPD). The linear correlation coefficients of glufosinate ammonium, MPP, and MPA in soil were 0.991, 0.999, and 0.999, respectively. The recoveries of this method for glufosinate ammonium, MPP, and MPA in soil were 77.2–95.5%, 98.3–100.3%, and 99.3–99.6% with relative standard deviations (RSD) of 1.8–4.1%, 0.4–1.4%, and 1.3–2.0%, respectively. Glufosinate ammonium dissipated rapidly in soil to MPA in hours and gradually degraded to MPP. The half-life of glufosinate ammonium degradation in soil was 2.30–2.93 days in an open field. In soil samples stored at −20°C glufosinate ammonium was stable for two months. The results of this study should provide guidance for the safe application of the herbicide glufosinate ammonium to agricultural products and the environment.
PMCID: PMC4211169  PMID: 25374604
24.  Meta-Analysis of Associations of IL1 Receptor Antagonist and Estrogen Receptor Gene Polymorphisms with Systemic Lupus Erythematosus Susceptibility 
PLoS ONE  2014;9(10):e109712.
Systemic lupus erythematosus (SLE) is an autoimmune disease that affects a number of different organs and tissues. Interleukin-1 (IL1) and estrogen are considered potential elements in the pathology of SLE. Recently, the variable number of tandem repeats (VNTR) polymorphism in the IL1 receptor antagonist gene (IL1-RN) and PvuII (rs2234693) and XbaI (rs9340799) polymorphisms in the estrogen receptor 1 gene (ESR1) have been associated with a predisposition to SLE. However, the evidence for these associations is inconclusive. We therefore conducted a meta-analysis to validate the roles of these polymorphisms in SLE susceptibility. We searched four databases and identified a total of 17 eligible articles comprising 24 studies. The Newcastle-Ottawa quality assessment scale was used to assess the qualities of the selected studies. We assessed the strengths of the associations using odds ratios (ORs) with 95% confidence intervals (95% CIs). Regarding the IL-1RN VNTR, the 2 allele significantly increased SLE susceptibility (2 vs. L: OR = 1.34, 95% CI = 1.03–1.73, P = 0.03). The ESR1 PvuII CC/CT genotype was also associated with SLE susceptibility (CC/CT vs. TT: OR = 1.25, 95% CI = 1.06–1.47, P = 0.01), and the difference was especially pronounced among Asians (CC/CT vs. TT: OR = 1.33, 95% CI = 1.04–1.69, P = 0.02). No significant association between the ESR1 XbaI polymorphism and SLE susceptibility was observed in the overall analysis. However, a marginally significant association between the GG/GA genotype was found in individuals of Asian descent (GG/GA vs. AA: OR = 1.30, 95% CI = 1.01–1.67, P = 0.04). These results indicate that the IL1-RN VNTR 2 allele, ESR1 PvuII CC/CT genotype and ESR1 XbaI GG/GA genotype may increase SLE susceptibility, especially in Asian individuals.
PMCID: PMC4186846  PMID: 25286391
25.  Repositioning of Tyrosine Kinase Inhibitors as Antagonists of ATP-Binding Cassette Transporters in Anticancer Drug Resistance 
Cancers  2014;6(4):1925-1952.
The phenomenon of multidrug resistance (MDR) has attenuated the efficacy of anticancer drugs and the possibility of successful cancer chemotherapy. ATP-binding cassette (ABC) transporters play an essential role in mediating MDR in cancer cells by increasing efflux of drugs from cancer cells, hence reducing the intracellular accumulation of chemotherapeutic drugs. Interestingly, small-molecule tyrosine kinase inhibitors (TKIs), such as AST1306, lapatinib, linsitinib, masitinib, motesanib, nilotinib, telatinib and WHI-P154, have been found to have the capability to overcome anticancer drug resistance by inhibiting ABC transporters in recent years. This review will focus on some of the latest and clinical developments with ABC transporters, TKIs and anticancer drug resistance.
PMCID: PMC4276951  PMID: 25268163
multidrug resistance; ABC transporters; tyrosine kinase inhibitor; clinical relevance; pharmacogenomics

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