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1.  Quantitative Characterization of Functional Anatomical Contributions to Cognitive Control under Uncertainty 
Journal of cognitive neuroscience  2014;26(7):1490-1506.
While much evidence indicates that reaction time increases as a function of computational load in many cognitive tasks, quantification of changes in neural activity related to increasing demand of cognitive control has rarely been attempted. In this functional magnetic resonance imaging study, we used a majority function task to quantify the effect of computational load on brain activation, reflecting the mental processes instantiated by cognitive control under conditions of uncertainty. We found that the activation of the fronto-parieto-cingulate (FPC) system as well as the deactivation of the anticorrelated default mode network varied parametrically as a function of information entropy, estimated with an information theoretic model. The current findings suggest that activity changes in the dynamic networks of the brain (especially the FPC system) track with information entropy or uncertainty, rather than only conflict or other commonly proposed targets of cognitive control.
PMCID: PMC5070967  PMID: 24392900
Cognitive control; computational load; entropy; fMRI; information theory
2.  Preliminary in vitro and in vivo assessment of a new targeted inhibitor for choroidal neovascularization in age-related macular degeneration 
Choroidal neovascularization (CNV) in age-related macular degeneration usually causes blindness. We established a novel targeted inhibitor for CNV in age-related macular degeneration. The inhibitor CR2-sFlt 1 comprises a CR2-targeting fragment and an anti-vascular endothelial growth factor (VEGF) domain (sFlt 1). The targeting of CR2-sFlt 1 was studied using the transwell assay in vitro and frozen sections in vivo using green fluorescent labeling. Transwell assay results showed that CR2-sFlt 1 migrated to the interface of complement activation products and was present in the retinal tissue of the CR2-sFlt 1-treated CNV mice. Treatment effects were assessed by investigating the VEGF concentration in retinal pigmented epithelial cell medium and the thickness of the CNV complex in the mice treated with CR2-sFlt 1. CR2-sFlt 1 significantly reduced the VEGF secretion from retinal pigmented epithelial cells in vitro and retarded CNV progress in a mouse model. Expression analysis of VEGF and VEGFRs after CR2-sFlt 1 intervention indicated the existence of feedback mechanisms in exogenous CR2-sFlt 1, endogenous VEGF, and VEGFR interaction. In summary, we demonstrated for the first time that using CR2-sFlt 1 could inhibit CNV with clear targeting and high selectivity.
PMCID: PMC5076800  PMID: 27799741
choroidal neovascularization; macular degeneration; complement activation; vascular endothelial growth factor
3.  Therapeutic effects of mesenchymal stem cells administered at later phase of recurrent experimental autoimmune uveitis 
To test the therapeutic effects of delayed treatment of mesenchymal stem cells (MSCs) in recurrent experimental autoimmune uveitis (rEAU).
The efficacy of different regimens of MSC administration in rEAU were tested by evaluation of clinical and pathological intraocular inflammation, as well as retinal structural and functional integrity using optical coherence tomography (OCT) and electroretinogram (ERG). The retinal sections were also immunostained with antibodies to glial fibrillary acidic protein (GFAP) and rhodopsin (RHO).
Delayed treatment of MSCs effectively alleviated the severity of intraocular inflammation with relative intact of outer retinal structure and function. Moreover, double therapies with longer interval led to an even better clinical evaluation, as well as a trend of decrease in relapse and amelioration of retinal function. MSC therapies also effectively reduced GFAP expression and increased RHO expression in the retina.
MSC administration can effectively treat developed diseases of rEAU, and multiple therapies can provide additional therapeutic benefits.
PMCID: PMC5075650  PMID: 27803852
mesenchymal stem cells; recurrent experimental autoimmune uveitis; electroretinogram; optical coherence tomography
4.  Correlation between Serum Lipid Levels and Measured Glomerular Filtration Rate in Chinese Patients with Chronic Kidney Disease 
PLoS ONE  2016;11(10):e0163767.
Dyslipidemia is often detected in patients with chronic kidney disease (CKD). Previous studies of the relationship between lipid profiles and kidney function have yielded variable results. We aimed to investigate the correlation between serum lipid levels and kidney function evaluated by measured glomerular filtration rate (mGFR) in Chinese patients with CKD.
A cross-sectional study was conducted on 2036 Chinese CKD patients who had mGFR. Linear regression analysis was performed to evaluate the correlation between different serum lipid levels and mGFR, while logistic regression analysis was used to investigate the association between CKD stages and the risk of different types of dyslipidemia.
The mean age was 55 years and the mean mGFR was 63 mL/min/1.73m2. After adjusting for some confounders (age, gender, body mass index, a history of diabetes, fasting glucose, a history of hypertension, systolic blood pressure, diastolic blood pressure, smoking status, hemoglobin, serum potassium, serum albumin, and serum uric acid), serum triglyceride level showed a negative correlation with mGFR (β = -0.006, P = 0.006) in linear regression analysis, and CKD stages were positively related to the risk of hypertriglyceridemia (odds ratios were 1.329, 1.868, 2.514 and P were 0.046, < 0.001, < 0.001 for CKD stage 2, 3, 4/5, respectively) in logistic regression anlysis.
Serum triglyceride level is independently association with mGFR. Patients with reduced kidney function are more likely to have higher serum triglyceride levels. Further longitudinal, multicenter and well-conducted studies are needed to provide more evidence.
PMCID: PMC5047470  PMID: 27695128
5.  Interleukin-1β and tumour necrosis factor-α levels in conjunctiva of diabetic patients with symptomatic moderate dry eye: case–control study 
BMJ Open  2016;6(8):e010979.
To compare expression of interleukin (IL)-1β and tumour necrosis factor (TNF)-α in the conjunctiva of diabetic and non-diabetic patients with symptomatic moderate dry eye.
Setting and participants
Nineteen diabetic patients with dry eye, 15 non-diabetic patients with dry eye and 14 diabetic patients without dry eye were recruited. The relative expression of IL-1β and TNF-α in conjunctival impression cytology (CIC) specimens was evaluated using immunofluorescent staining and in conjunctival biopsy specimens using immunohistochemical staining.
The diabetic dry eye group showed significantly higher grades of metaplasia than the non-diabetic dry eye and diabetic without dry eye groups (both p<0.05). There was no significant difference in the concentration of IL-1β and TNF-α in CIC specimens between the three groups (p=0.504 and p=0.310, respectively). The mean levels of IL-1β and TNF-α in conjunctival biopsy specimens from the diabetic dry eye group was significantly increased compared with the non-diabetic dry eye and diabetic without dry eye groups (p=0.002, p<0.001; p=0.001, p<0.001, respectively). Interestingly, IL-1β- and TNF-α-positive cells were mainly located in the basal layer of the conjunctival epithelium, and rarely seen in the apical conjunctival epithelium in the three groups. The levels of both IL-1β and TNF-α did not correlate with conjunctival squamous metaplasia grades.
Levels of IL-1β and TNF-α in conjunctival biopsy specimens were increased in diabetic patients with dry eye, while levels of IL-1β and TNF-α in apical conjunctival epithelium were similar in the CIC specimens. These findings suggest that the inflammatory response is not limited to the surface of conjunctival epithelial cells, and is more serious in the basal layer of the epithelium, which may play an important role in the pathogenesis of dry eye in diabetic patients.
PMCID: PMC4985792  PMID: 27489152
dry eye; diabetes; conjunctiva; inflammatory cytokine; IL-1β; TNF-α
6.  Problematic Internet Users Show Impaired Inhibitory Control and Risk Taking with Losses: Evidence from Stop Signal and Mixed Gambles Tasks 
According to the balance model of self-regulation, dysfunction of the inhibitory control and reward processing might be a behavioral marker for addiction and problematic behaviors. Although several studies have separately examined the inhibitory control or reward processing of individuals exhibiting problematic Internet use (PIU), no study has explored these two functions simultaneously to examine the potential imbalance of these functions. This study aimed to investigate whether the self-regulatory failure of PIU individuals results from deficits in both inhibitory control [indexed with the stop signal reaction time (SSRT) in a stop signal task] and risk taking with losses (measured as the acceptance rates of risky gables or the ratio of win/loss in a mixed gambles task). The results revealed that PIU individuals, compared with controls, showed decreased SSRT and increased error rates as well as reduced risk taking with losses. Correlational analyses revealed a significant positive relationship between the SSRT and risk taking with losses. These findings suggest that both the inhibitory control and reward functions are impaired in PIU individuals and reveal an association between these two systems. These results strengthen the balance model of self-regulation theory’s argument that deficits in inhibitory control and risk taking with losses may assist in identifying risk markers for early diagnosis, progression, and prediction of PIU.
PMCID: PMC4794503  PMID: 27014170
problematic Internet use; inhibition response; risk taking with losses; cognitive control; reward processing
7.  The effect of immediate surgical bipolar plasmakinetic transurethral resection of the prostate on prostatic hyperplasia with acute urinary retention 
Asian Journal of Andrology  2015;18(1):134-139.
In the present study, we evaluated the safety and efficacy of immediate surgical bipolar plasmakinetic transurethral resection of the prostate (PK-TURP) for patients with benign prostatic hyperplasia (BPH) with acute urinary retention (AUR). We conducted a retrospective analysis of clinical data of BPH patients who received PK-TURP. A total of 1126 BPH patients were divided into AUR (n = 348) and non-AUR groups (n = 778). After the urethral catheters were removed, the urine white blood cell (WBC) count in the AUR group significantly increased compared with the non-AUR group (P < 0.01). However, there was no significant difference in international prostate symptom score, painful urination, and maximal urinary flow rate. The duration of hospitalization of the AUR group was longer than that of the non-AUR group (P < 0.001). A total of 87.1% (303/348) patients in the AUR group and 84.1% (654/778) patients in the non-AUR group completed all of the postoperative follow-up visits. The incidence of urinary tract infection in the AUR group within 3 months after surgery was significantly higher than that in the non-AUR group (P < 0.01). The incidence of temporary urinary incontinence in the AUR group did not exhibit significant difference. During 3–12 months after surgery, there were no significant differences in major complications between the two groups. Multivariate regression analyses showed that age, postvoid residual, maximal urinary flow rate, diabetes, and hypertension, but not the presence of AUR, were independent predictors of IPSS post-PK-TURP. In conclusion, immediate PK-TURP surgery on patients accompanied by AUR was safe and effective.
PMCID: PMC4736342  PMID: 26178398
acute urinary retention; benign prostatic hyperplasia; lower urinary tract symptoms; plasmakinetic transurethral resection of the prostate
8.  Development and Identification of SSR Markers Associated with Starch Properties and β-Carotene Content in the Storage Root of Sweet Potato (Ipomoea batatas L.) 
Sweet potato (Ipomoea batatas L.) is a nutritious food crop and, based on the high starch content of its storage root, a potential bioethanol feedstock. Enhancing the nutritional value and starch quantity of storage roots are important goals of sweet potato breeding programs aimed at developing improved varieties for direct consumption, processing, and industrial uses. However, developing improved lines of sweet potato is challenging due to the genetic complexity of this plant and the lack of genome information. Short sequence repeat (SSR) markers are powerful molecular tools for tracking important loci in crops and for molecular-based breeding strategies; however, few SSR markers and marker-trait associations have hitherto been identified in sweet potato. In this study, we identified 1824 SSRs by using a de novo assembly of publicly available ESTs and mRNAs in sweet potato, and designed 1476 primer pairs based on SSR-containing sequences. We mapped 214 pairs of primers in a natural population comprised of 239 germplasms, and identified 1278 alleles with an average of 5.972 alleles per locus and a major allele frequency of 0.7702. Population structure analysis revealed two subpopulations in this panel of germplasms, and phenotypic characterization demonstrated that this panel is suitable for association mapping of starch-related traits. We identified 32, 16, and 17 SSR markers associated with starch content, β-carotene content, and starch composition in the storage root, respectively, using association analysis and further evaluation of a subset of sweet potato genotypes with various characteristics. The SSR markers identified here can be used to select varieties with desired traits and to investigate the genetic mechanism underlying starch and carotenoid formation in the starchy roots of sweet potato.
PMCID: PMC4773602  PMID: 26973669
amylose; β-carotene; marker development; marker-trait association; SSR; starch; sweet potato
9.  α-Melanocyte-stimulating hormone ameliorates ocular surface dysfunctions and lesions in a scopolamine-induced dry eye model via PKA-CREB and MEK-Erk pathways 
Scientific Reports  2015;5:18619.
Dry eye is a highly prevalent, chronic, and multifactorial disease that compromises quality of life and generates socioeconomic burdens. The pathogenic factors of dry eye disease (DED) include tear secretion abnormalities, tear film instability, and ocular surface inflammation. An effective intervention targeting the pathogenic factors is needed to control this disease. Here we applied α-Melanocyte-stimulating hormone (α-MSH) twice a day to the ocular surface of a scopolamine-induced dry eye rat model. The results showed that α-MSH at different doses ameliorated tear secretion, tear film stability, and corneal integrity, and corrected overexpression of proinflammatory factors, TNF-α, IL-1β, and IFN-γ, in ocular surface of the dry eye rats. Moreover, α-MSH, at 10−4 μg/μl, maintained corneal morphology, inhibited apoptosis, and restored the number and size of conjunctival goblet cells in the dry eye rats. Mechanistically, α-MSH activated both PKA-CREB and MEK-Erk pathways in the dry eye corneas and conjunctivas; pharmacological blockade of either pathway abolished α-MSH’s protective effects, suggesting that both pathways are necessary for α-MSH’s protection under dry eye condition. The peliotropic protective functions and explicit signaling mechanism of α-MSH warrant translation of the α-MSH-containing eye drop into a novel and effective intervention to DED.
PMCID: PMC4685655  PMID: 26685899
10.  Differential Tiam1/Rac1 activation in hippocampal and cortical neurons mediates differential spine shrinkage in response to oxygen/glucose deprivation 
Distinct neuronal populations show differential sensitivity to global ischemia, with hippocampal CA1 neurons showing greater vulnerability compared to cortical neurons. The mechanisms that underlie differential vulnerability are unclear, and we hypothesize that intrinsic differences in neuronal cell biology are involved. Dendritic spine morphology changes in response to ischemic insults in vivo, but cell type-specific differences and the molecular mechanisms leading to such morphologic changes are unexplored. To directly compare changes in spine size in response to oxygen/glucose deprivation (OGD) in cortical and hippocampal neurons, we used separate and equivalent cultures of each cell type. We show that cortical neurons exhibit significantly greater spine shrinkage compared to hippocampal neurons. Rac1 is a Rho-family GTPase that regulates the actin cytoskeleton and is involved in spine dynamics. We show that Rac1 and the Rac guanine nucleotide exchange factor (GEF) Tiam1 are differentially activated by OGD in hippocampal and cortical neurons. Hippocampal neurons express more Tiam1 than cortical neurons, and reducing Tiam1 expression in hippocampal neurons by shRNA enhances OGD-induced spine shrinkage. Tiam1 knockdown also reduces hippocampal neuronal vulnerability to OGD. This work defines fundamental differences in signalling pathways that regulate spine morphology in distinct neuronal populations that may have a role in the differential vulnerability to ischemia.
PMCID: PMC4269742  PMID: 25248834
cell death; cortex; dendritic spine; hippocampus; ischemia; OGD
11.  Insula–amygdala functional connectivity is correlated with habituation to repeated negative images 
Behavioral habituation during repeated exposure to aversive stimuli is an adaptive process. However, the way in which changes in self-reported emotional experience are related to the neural mechanisms supporting habituation remains unclear. We probed these mechanisms by repeatedly presenting negative images to healthy adult participants and recording behavioral and neural responses using functional magnetic resonance imaging. We were particularly interested in investigating patterns of activity in insula, given its significant role in affective integration, and in amygdala, given its association with appraisal of aversive stimuli and its frequent coactivation with insula. We found significant habituation behaviorally along with decreases in amygdala, occipital cortex and ventral prefrontal cortex (PFC) activity with repeated presentation, whereas bilateral posterior insula, dorsolateral PFC and precuneus showed increased activation. Posterior insula activation during image presentation was correlated with greater negative affect ratings for novel presentations of negative images. Further, repeated negative image presentation was associated with increased functional connectivity between left posterior insula and amygdala, and increasing insula–amygdala functional connectivity was correlated with increasing behavioral habituation. These results suggest that habituation is subserved in part by insula–amygdala connectivity and involves a change in the activity of bottom-up affective networks.
PMCID: PMC4221205  PMID: 24170933
habituation; emotion; functional connectivity; insula; amygdala
12.  α-Melanocyte-stimulating hormone prevents glutamate excitotoxicity in developing chicken retina via MC4R-mediated down-regulation of microRNA-194 
Scientific Reports  2015;5:15812.
Glutamate excitotoxicity is a common pathology to blinding ischemic retinopathies, such as diabetic retinopathy, glaucoma, and central retinal vein or artery occlusion. The development of an effective interventional modality to glutamate excitotoxicity is hence important to preventing blindness. Herein we showed that α-melanocyte-stimulating hormone (α-MSH) time-dependently protected against glutamate-induced cell death and tissue damage in an improved embryonic chicken retinal explant culture system. α-MSH down-regulated microRNA-194 (miR-194) expression during the glutamate excitotoxicity in the retinal explants. Furthermore, pharmacological antagonists to melanocortin 4 receptor (MC4R) and lentivirus-mediated overexpression of pre-miR-194 abrogated the suppressing effects of α-MSH on glutamate-induced activities of caspase 3 or 7, the ultimate enzymes for glutamate-induced cell death. These results suggest that the protective effects of α-MSH may be due to the MC4R mediated-down-regulation of miR-194 during the glutamate-induced excitotoxicity. Finally, α-MSH attenuated cell death and recovered visual functions in glutamate-stimulated post-hatch chick retinas. These results demonstrate the previously undescribed protective effects of α-MSH against glutamate-induced excitotoxic cell death in the cone-dominated retina both in vitro and in vivo, and indicate a novel molecular mechanism linking MC4R-mediated signaling to miR-194.
PMCID: PMC4623527  PMID: 26507936
13.  Development and validation of new glomerular filtration rate predicting models for Chinese patients with type 2 diabetes 
Previous researches has depicted that the performance of the recommended glomerular filtration rate (GFR)-estimating equations in the type 2 diabetic population is inferior to that in the non-diabetic population. We attempted to develop new GFR-predicting models for use in Chinese patients with type 2 diabetes in this study.
We enrolled 519 type 2 diabetic patients including a development data-set (n = 276), an internal validation data-set (n = 138) and an external validation data-set (n = 105) to establish new GFR-predicting models. 99mTc-DTPA-GFR revised by the dual sample method was referred to as the gold GFR standard.
Based on sex, age, serum creatinine and new predictor variables [body mass index (BMI), hemoglobinA1C, and urinary albumin creatinine ratio], eight new regression models and eight artificial neural network (ANN) models were developed. In the external validation group, only ANN3 was superior in both precision and accuracy over the original CKD-EPI equation (precision, 20.5 vs. 24.2 mL/min/1.73 m2, P < 0.001; 30 % accuracy, 88.6 vs. 80.6 %, P = 0.02).
ANN3 based on sex, age, serum creatinine and BMI is the optimal model for GFR estimation in Chinese patients with type 2 diabetes.
Electronic supplementary material
The online version of this article (doi:10.1186/s12967-015-0674-y) contains supplementary material, which is available to authorized users.
PMCID: PMC4591744  PMID: 26412455
Glomerular filtration rate; Type 2 diabetes; Artificial neural network; Serum creatinine; Body mass index
14.  The effect and action mechanism of resveratrol on the vascular endothelial cell by high glucose treatment 
To investigate the effect and action mechanism of resveratrol on the vascular endothelial cell by high glucose treatment. Primarily cultured human umbilical vein endothelial cells (HUVECs) were pretreated by resveratrol (0.2 μmol/L) and holding for 6 h, and then cultured in Dulbecco Modified Eagle Medium (DMEM) within 0.45 mmol/L of palmimte acid and 32.8 mmol/L of glucose, which is holding for 12 h. The cells were collected to analyze the expression of E-selected element. Supernatant of cultured cells, induced by 100 nmol/L insulin for 30 min, was used to analyze the nitric oxide content. Compared with normal control cells, the secretion of nitric oxide is stimulated by insulin decrease, however, the expression of E-selected element increased in HUVEC. Resveratrol treatment increased the secretion of nitric oxide stimulated by insulin and decreased the expression of E-selected element and partly counteracts the impairment of high glucose and palmitate acid on the function of endothelial cells. Resveratrol can improve and protect the function of high glucose and fatty acid cultured endothelial cell, and therefore may be a promising medicine in the prevention or therapy of diabetic macrovascular diseases.
PMCID: PMC4705268  PMID: 26858561
Effect and action mechanism; Resveratrol; Vascular endothelial cell; High glucose
15.  New Conclusions Regarding Comparison of Sevelamer and Calcium-Based Phosphate Binders in Coronary-Artery Calcification for Dialysis Patients: A Meta-Analysis of Randomized Controlled Trials 
PLoS ONE  2015;10(7):e0133938.
Sevelamer hydrochloride is used widely, but its impact upon cardiovascular calcification, cardiovascular mortality, all-cause mortality and hospitalization is not known.
Primary outcome was cardiovascular calcification (coronary artery calcification scores (CACS) and aortic calcification scores (ACS)). Secondary outcomes were serum characteristics, hospitalization, cardiovascular mortality and all-cause mortality. Risk ratio (RR), mean differences and standard mean difference with 95% confidence intervals (CIs) were pooled using random- or fixed-effects models.
We identified 31 studies (on 23 randomized controlled trials with 4395 participants). An analysis pooling showed a significant decrease in serum levels of phosphate with calcium-based phosphate binders (CBPBs) by 0.17 mg/dL [mean difference (MD), 95% CI, 0.03, 0.31] than sevelamer. A significant difference in the change of CACS by –102.66 [MD: 95% CI, –159.51, –45.80] and ACS by –1008.73 [MD, 95% CI, –1664.75, –352.72] between sevelamer and CBPBs was observed. Prevalence of hypercalcemia (serum levels of calcium >10.2–10.5 mg/dL and >11.0 mg/dL) was significantly smaller for sevelamer (RR = 0.44, 95% CI, 0.33, 0.58; RR = 0.24, 95% CI, 0.14, 0.40). No significant difference was found in hospitalization, all-cause mortality or cardiovascular mortality.
This meta-analysis suggests that sevelamer benefits dialysis patients in terms of CACS, ACS and hypercalcemia.
PMCID: PMC4521824  PMID: 26230677
16.  Nighttime Systolic Blood-Pressure Load Is Correlated with Target-Organ Damage Independent of Ambulatory Blood-Pressure Level in Patients with Non-Diabetic Chronic Kidney Disease 
PLoS ONE  2015;10(7):e0131546.
The impacts of blood pressure (BP) load on target-organ damage in patients with chronic kidney disease (CKD) are largely unclear. We examined whether BP load is correlated with target-organ damage (TOD) in Chinese CKD patients independent of BP level.
We recruited 1219 CKD patients admitted to our hospital division in this cross-sectional study. The TOD were measured by estimated glomerular filtration rate (eGFR), proteinuria, left ventricular mass index (LVMI) and carotid intima-media thickness (cIMT) in this study. Univariate and multivariate linear analyses were used to evaluate the relationship between systolic blood pressure (SBP) load, diastolic blood pressure (DBP) load and these renal, cardiovascular parameters.
In multivariable-adjusted models, BP load and ambulatory BP levels both independently correlated with LVMI, eGFR and proteinuria in all groups of CKD patients (p<0.05), 24-h SBP correlated with cIMT only in non-diabetic CKD patients without hypertension (p<0.05), while nighttime SBP load was associated with cIMT only in non-diabetic CKD patients (p<0.05). Furthermore, nighttime SBP load additionally increased coefficient of determination (R2) and correlated with LVMI, proteinuria in non-diabetic CKD patients without hypertension (R2 = 0.034, P<0.001 and R2 = 0.012, P = 0.006 respectively) and LVMI, cIMT, eGFR in non-diabetic CKD patients with hypertension (R2>0.008, P<0.05) in multivariable-adjusted model which already including the 24-h BP. BP load did not refine this correlation based on the 24-h BP level in diabetic CKD patients.
Night-time SBP load was correlated with TOD in patients with non-diabetic chronic kidney disease independent of BP level.
PMCID: PMC4506060  PMID: 26186336
17.  Simple Access to Elusive α-Boryl Carbanions and Their Alkylation: An Umpolung Construction for Organic Synthesis 
Journal of the American Chemical Society  2014;136(30):10581-10584.
The reaction of 1,1-bis(pinacolboronate) esters with alkyl halides can be effected by metal alkoxides and provides a strategy for the construction of organoboronate compounds. The reaction is found to occur by alkoxide-induced deborylation and generation of a boron-stabilized carbanion.
PMCID: PMC4353009  PMID: 25019925
18.  Apocynin Attenuates Cardiac Injury in Type 4 Cardiorenal Syndrome via Suppressing Cardiac Fibroblast Growth Factor-2 With Oxidative Stress Inhibition 
Type 4 cardiorenal syndrome (CRS) refers to the cardiac injury induced by chronic kidney disease. We aimed to assess oxidative stress and cardiac injury in patients with type 4 CRS, determine whether the antioxidant apocynin attenuated cardiac injury in rats with type 4 CRS, and explore potential mechanisms.
Methods and Results
A cross-sectional study was conducted among patients with type 4 CRS (n=17) and controls (n=16). Compared with controls, patients with type 4 CRS showed elevated oxidative stress, which was significantly correlated with cardiac hypertrophy and decreased ejection fraction. In vivo study, male Sprague-Dawley rats underwent 5/6 subtotal nephrectomy and sham surgery, followed with apocynin or vehicle treatment for 8 weeks. Eight weeks after surgery, the 5/6 subtotal nephrectomy rats mimicked type 4 CRS, showing increased serum creatinine, cardiac hypertrophy and fibrosis, and decreased ejection fraction compared with sham-operated animals. Cardiac malondialdehyde, NADPH oxidase activity, fibroblast growth factor-2, and extracellular signal-regulated kinase 1/2 (ERK1/2) phosphorylation increased significantly in the 5/6 subtotal nephrectomy rats. These changes were significantly attenuated by apocynin. In vitro study showed that apocynin reduced angiotensin II–induced NADPH oxidase–dependent oxidative stress, upregulation of fibroblast growth factor-2 and fibrosis biomarkers, and ERK1/2 phosphorylation in cardiac fibroblasts. Importantly, the ERK1/2 inhibitor U0126 reduced the upregulation of fibroblast growth factor-2 and fibrosis biomarkers in angiotensin II–treated fibroblasts.
Oxidative stress is a candidate mediator for type 4 CRS. Apocynin attenuated cardiac injury in type 4 CRS rats via inhibiting NADPH oxidase–dependent oxidative stress-activated ERK1/2 pathway and subsequent fibroblast growth factor-2 upregulation. Our study added evidence to the beneficial effect of apocynin in type 4 CRS.
PMCID: PMC4608061  PMID: 26109504
cardiac remodeling; cardiorenal syndrome; extracellular signal-regulated kinase 1/2; fibroblast growth factor; pharmacology
19.  Multi-Stage Tuberculosis Subunit Vaccine Candidate LT69 Provides High Protection against Mycobacterium tuberculosis Infection in Mice 
PLoS ONE  2015;10(6):e0130641.
Effective tuberculosis (TB) vaccine should target tubercle bacilli with various metabolic states and confer long-term protective immunity. In this study, we constructed a novel multi-stage TB subunit vaccine based on fusion protein ESAT6-Ag85B-MPT64(190-198)-Mtb8.4-HspX (LT69 for short) which combined early expressed antigens and latency-associated antigen. The fusion protein was mixed with an adjuvant being composed of N, N’-dimethyl-N, N’-dioctadecylammonium bromide (DDA) and polyriboinosinic polyribocytidylic acid (PolyI:C) to construct subunit vaccine, whose immunogenicity and protective ability were evaluated in C57BL/6 mice. The results showed that LT69 had strong immunogenicity and high protective effect against Mycobacterium tuberculosis (M. tuberculosis) H37Rv aerosol challenge. Low-dose (2 μg) of LT69 generated long-term immune memory responses and provided effective protection, which was even higher than traditional vaccine BCG did at 30 weeks post the last vaccination. In conclusion, multistage subunit vaccine LT69 showed high and long-term protection against M. tuberculosis infection in mice, whose effect could be enhanced by using a relative low dosage of antigen.
PMCID: PMC4476732  PMID: 26098302
20.  Differential signaling mechanism for HIV-1 Nef-mediated production of IL-6 and IL-8 in human astrocytes 
Scientific Reports  2015;5:9867.
Variety of HIV-1 viral proteins including HIV-1 Nef are known to activate astrocytes and microglia in the brain and cause the release of pro-inflammatory cytokines, which is thought to be one of the mechanisms leading to HIV-1- mediated neurotoxicity. IL-6 and IL-8 have been found in the CSF of patients with HIV-1 associated dementia (HAD), suggesting that they might play important roles in HIV-1 neuropathology. In the present study we examined the effects of HIV-1 Nef on IL-6 and IL-8 induction in astrocytes. The results demonstrate that both IL-6 and IL-8 are significantly induced in HIV-1 Nef-transfected SVGA astrocytes and HIV-1 Nef-treated primary fetal astrocytes. We also determined the molecular mechanisms responsible for the HIV-1 Nef-induced increased IL-6 and IL-8 by using chemical inhibitors and siRNAs against PI3K/Akt/PKC, p38 MAPK, NF-κB, CEBP and AP-1. Our results clearly demonstrate that the PI3K/PKC, p38 MAPK, NF-κB and AP-1 pathways are involved in HIV-1 Nef-induced IL-6 production in astrocytes, while PI3K/PKC and NF-κB pathways are involved in HIV-1 Nef-induced IL-8 production. These results offer new potential targets to develop therapeutic strategy for treatment of HIV-1 associated neurological disorders, prevalent in > 40% of individuals infected with HIV-1.
PMCID: PMC4467202  PMID: 26075907
21.  Polysaccharide Hydrogel Combined with Mesenchymal Stem Cells Promotes the Healing of Corneal Alkali Burn in Rats 
PLoS ONE  2015;10(3):e0119725.
Corneal chemical burns are common ophthalmic injuries that may result in permanent visual impairment. Although significant advances have been achieved on the treatment of such cases, the structural and functional restoration of a chemical burn-injured cornea remains challenging. The applications of polysaccharide hydrogel and subconjunctival injection of mesenchymal stem cells (MSCs) have been reported to promote the healing of corneal wounds. In this study, polysaccharide was extracted from Hardy Orchid and mesenchymal stem cells (MSCs) were derived from Sprague-Dawley rats. Supplementation of the polysaccharide significantly enhanced the migration rate of primarily cultured rat corneal epithelial cells. We examined the therapeutic effects of polysaccharide in conjunction with MSCs application on the healing of corneal alkali burns in rats. Compared with either treatment alone, the combination strategy resulted in significantly better recovery of corneal epithelium and reduction in inflammation, neovascularization and opacity of healed cornea. Polysaccharide and MSCs acted additively to increase the expression of anti-inflammatory cytokine (TGF-β), antiangiogenic cytokine (TSP-1) and decrease those promoting inflammation (TNF-α), chemotaxis (MIP-1α and MCP-1) and angiogenesis (VEGF and MMP-2). This study provided evidence that Hardy Orchid derived polysaccharide and MSCs are safe and effective treatments for corneal alkali burns and that their benefits are additive when used in combination. We concluded that combination therapy with polysaccharide and MSCs is a promising clinical treatment for corneal alkali burns and may be applicable for other types of corneal disorder.
PMCID: PMC4366244  PMID: 25789487
22.  Long-Term Therapeutic Effects of Mesenchymal Stem Cells Compared to Dexamethasone on Recurrent Experimental Autoimmune Uveitis of Rats 
We tested the long-term effects of different regimens of mesenchymal stem cell (MSC) administration in a recurrent experimental autoimmune uveitis (rEAU) model in rats, and compared the efficacy of MSC to that of dexamethasone (DEX).
One or two courses of MSC treatments were applied to R16-specific T cell–induced rEAU rats before or after disease onsets. The DEX injections were given for 7 or 50 days continuously after disease onsets. Clinical appearances were observed until the 50th day after transfer. On the 10th day, T cells from control and MSC groups were analyzed by flow cytometry. Supernatants from the proliferation assay and aqueous humor were collected for cytokine detection. Functions of T cells and APCs in spleens also were studied by lymphocyte proliferation assays.
One course of MSC therapy, administered after disease onset, led to a lasting therapeutic effect, with a decreased incidence, reduced mean clinical score, and reduced retinal impairment after 50 days of observation, while multiple courses of treatment did not improve the therapeutic benefit. Although DEX and MSCs equally reduced the severity of the first episode of rEAU, the effect of DEX was shorter lasting, and DEX therapy failed to control the disease even with long periods of treatment. The MSCs significantly decreased T helper 1 (Th1) and Th17 responses, suppressed the function of antigen-presenting cells, and upregulated T regulatory cells.
These results suggested that MSCs might be new corticosteroid spring agents, while providing fewer side effects and longer lasting suppressive effects for recurrent uveitis.
In this paper, we report for the first time to our knowledge that one course of MSC therapy, administered after disease is established, can provide a better alternative than corticosteroid with fewer side effects and longer lasting suppressive effects for chronic and recurrent autoimmune uveitis.
PMCID: PMC4580152  PMID: 25125599
mesenchymal stem cells; recurrent experimental autoimmune uveitis; dexamethasone; T cells; antigen-presenting cells
23.  Pyrosequencing Reveals Fungal Communities in the Rhizosphere of Xinjiang Jujube 
BioMed Research International  2015;2015:972481.
Fungi are important soil components as both decomposers and plant symbionts and play a major role in ecological and biogeochemical processes. However, little is known about the richness and structure of fungal communities. DNA sequencing technologies allow for the direct estimation of microbial community diversity, avoiding culture-based biases. We therefore used 454 pyrosequencing to investigate the fungal communities in the rhizosphere of Xinjiang jujube. We obtained no less than 40,488 internal transcribed spacer (ITS) rDNA reads, the number of each sample was 6943, 6647, 6584, 6550, 6860, and 6904, and we used bioinformatics and multivariate statistics to analyze the results. The index of diversity showed greater richness in the rhizosphere fungal community of a 3-year-old jujube than in that of an 8-year-old jujube. Most operational taxonomic units belonged to Ascomycota, and taxonomic analyses identified Hypocreales as the dominant fungal order. Our results demonstrated that the fungal orders are present in different proportions in different sampling areas. Redundancy analysis (RDA) revealed a significant correlation between soil properties and the abundance of fungal phyla. Our results indicated lower fungal diversity in the rhizosphere of Xinjiang jujube than that reported in other studies, and we hope our findings provide a reference for future research.
PMCID: PMC4313056  PMID: 25685820
24.  The Neural Correlates of Anomalous Habituation to Negative Emotional Pictures in Borderline and Avoidant Personality Disorder Patients 
Extreme emotional reactivity is a defining feature of borderline personality disorder, yet the neural-behavioral mechanisms underlying this affective instability are poorly understood. One possible contributor would be diminished ability to engage the mechanism of emotional habituation. We tested this hypothesis by examining behavioral and neural correlates of habituation in borderline patients, healthy controls, and a psychopathological control group of avoidant personality disorder patients.
During fMRI scan acquisition, borderline patients, healthy controls and avoidant personality disorder patients viewed novel and repeated pictures, providing valence ratings at each presentation. Statistical parametric maps of the contrasts of activation during repeat versus novel negative picture viewing were compared between groups. Psychophysiological interaction analysis was employed to examine functional connectivity differences between groups.
Unlike healthy controls, neither borderline nor avoidant personality disorder participants showed increased activity in dorsal anterior cingulate cortex when viewing repeat versus novel pictures. This failure to increase dorsal anterior cingulate activity was associated with greater affective instability in borderline participants. In addition, borderline and avoidant participants showed smaller insula-amygdala connectivity increases than healthy participants and did not show habituation in ratings of the emotional intensity of the images as did healthy participants. Borderline patients differed from avoidant patients in insula-ventral anterior cingulate connectivity during habituation.
Borderline patients fail to habituate to negative pictures as do healthy participants and differ from both healthy controls and avoidant patients in neural activity during habituation. A failure to effectively engage emotional habituation processes may contribute to affective instability in borderline patients.
PMCID: PMC3947284  PMID: 24275960
borderline personality disorder; avoidant personality disorder; affective instability; fMRI; functional connectivity
25.  Comparative Physiological and Transcriptional Analyses of Two Contrasting Drought Tolerant Alfalfa Varieties 
Drought is one of major environmental determinants of plant growth and productivity. Alfalfa (Medicago sativa) is a legume perennial forage crop native to the arid and semi-arid environment, which is an ideal candidate to study the biochemical and molecular mechanisms conferring drought resistance in plants. In this study, drought stress responses of two alfalfa varieties, Longdong and Algonquin, were comparatively assayed at the physiological, morphological, and transcriptional levels. Under control condition, the drought-tolerant Longdong with smaller leaf size and lower stomata density showed less water loss than the drought-sensitive Algonquin. After exposing to drought stress, Longdong showed less severe cell membrane damage, more proline, and ascorbate (ASC) contents and less accumulation of H2O2 than Algonquin. Moreover, significantly higher antioxidant enzymes activities after drought treatment were found in Longdong when compared with Algonquin. In addition, transcriptional expression analysis showed that Longdong exhibited significantly higher transcripts of drought-responsive genes in leaf and root under drought stress condition. Taken together, these results indicated that Longdong variety was more drought-tolerant than Algonquin variety as evidenced by less leaf firing, more lateral root number, higher relative aboveground/underground biomass per plant and survival rate.
PMCID: PMC4709457  PMID: 26793226
alfalfa; drought stress; stomata density; lateral root; physiological changes; transcriptional expression

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