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1.  Identification of miRNAs during mouse postnatal ovarian development and superovulation 
MicroRNAs are small noncoding RNAs that play critical roles in regulation of gene expression in wide array of tissues including the ovary through sequence complementarity at post-transcriptional level. Tight regulation of multitude of genes involved in ovarian development and folliculogenesis could be regulated at transcription level by these miRNAs. Therefore, tissue specific miRNAs identification is considered a key step towards understanding the role of miRNAs in biological processes.
To investigate the role of microRNAs during ovarian development and folliculogenesis we sequenced eight different libraries using Illumina deep sequencing technology. Different developmental stages were selected to explore miRNAs expression pattern at different stages of gonadal maturation with/without treatment of PMSG/hCG for superovulation.
From massive sequencing reads, clean reads of 16–26 bp were selected for further analysis of differential expression analysis and novel microRNA annotation. Expression analysis of all miRNAs at different developmental stages showed that some miRNAs were present ubiquitously while others were differentially expressed at different stages. Among differentially expressed miRNAs we reported 61 miRNAs with a fold change of more than 2 at different developmental stages among all libraries. Among the up-regulated miRNAs, mmu-mir-1298 had the highest fold change with 4.025 while mmu-mir-150 was down-regulated more than 3 fold. Furthermore, we found 2659 target genes for 20 differentially expressed microRNAs using seven different target predictions programs (DIANA-mT, miRanda, miRDB, miRWalk, RNAhybrid, PICTAR5, TargetScan). Analysis of the predicted targets showed certain ovary specific genes targeted by single or multiple microRNAs. Furthermore, pathway annotation and Gene ontology showed involvement of these microRNAs in basic cellular process.
These results suggest the presence of different miRNAs at different stages of ovarian development and superovulation. Potential role of these microRNAs was elucidated using bioinformatics tools in regulation of different pathways, biological functions and cellular components underlying ovarian development and superovulation. These results provide a framework for extended analysis of miRNAs and their roles during ovarian development and superovulation. Furthermore, this study provides a base for characterization of individual miRNAs to discover their role in ovarian development and female fertility.
Electronic supplementary material
The online version of this article (doi:10.1186/s13048-015-0170-2) contains supplementary material, which is available to authorized users.
PMCID: PMC4499447  PMID: 26152307
Non-coding RNAs; Deep sequencing; Ovarian development; Mouse
2.  Staged Surgery with Total Excision and Lamellar Reconstructive for Medium-sized Divided Nevus of the Eyelids 
Supplemental Digital Content is available in the text.
To explore a prior treatment strategy for medium-sized (1.5–20 cm) divided nevus of the eyelids.
Six patients who suffered from divided nevus of eyelids were recruited to this prospective, case series study between July 2008 and January 2014 (4 male and 2 female patients). The patients’ ages ranged from 14 to 29 years, with an average age of 24.5 years. All lesions were medium-sized (1.5–20 cm in diameter) and invaded eyelid margins and the posterior lamella of eyelids. Staged surgery involved total excision of lesions and then repair of the defects with advanced skin flaps and tarsoconjunctival flaps. Two staged surgeries were completed at intervals of at least 3 months.
All of the patients were followed up at least 3 months after the second surgery. Malignant transformation and recurrence were not observed. All of the flaps survived well, and all of the donor sites were healed with inconspicuous scarring. The only complication was eyelash sacrifices, and 5 of 6 patients suffered from this complication. Excellent cosmetic results were gained in all patients, with the exception of 1 patient who thought his postoperative appearance was only good because of the impalpable disparity in color and thickness between the skin flaps and recipient sites.
A staged surgery approach with the total excision of lesions and lamellar reconstructive procedures to repair the defect is a reasonable treatment strategy and can achieve satisfactory cosmetic results for medium-sized (1.5–20 cm in diameter) divided nevus of eyelid.
PMCID: PMC4494508  PMID: 26180739
3.  Biofumigation on Post-Harvest Diseases of Fruits Using a New Volatile-Producing Fungus of Ceratocystis fimbriata 
PLoS ONE  2015;10(7):e0132009.
A variety of volatile organic compounds (VOCs) produced by Ceratocystis fimbriata have strong bioactivity against a wide range of fungi, bacteria and oomycetes. Mycelial growth, conidial production, and spore germination of fungi and oomycetes were significantly inhibited after exposure to cultures of C. fimbriata, and colony formation of bacteria was also inhibited. Two post-harvest diseases, peach brown rot caused by Monilinia fructicola and citrus green mold caused by Penicillium digitatum, were controlled during a 4-day storage by enclosing wound-inoculated fruits with 10 standard diameter Petri plate cultures of C. fimbriata in a 15 L box. The fruits were freshly inoculated at onset of storage and the cultures of C. fimbriata were 6 days old. Percentage of control was 92 and 97%, respectively. After exposure to C. fimbriata VOCs, severely misshapen hyphae and conidia of these two post-harvest pathogens were observed by scanning electron microscopy, and their pathogenicity was lost or greatly reduced.
PMCID: PMC4492557  PMID: 26147922
4.  Autophagy regulates the therapeutic potential of mesenchymal stem cells in experimental autoimmune encephalomyelitis 
Autophagy  2014;10(7):1301-1315.
Mesenchymal stem cell (MSC)-based therapy is a promising approach to treat various inflammatory disorders including multiple sclerosis. However, the fate of MSCs in the inflammatory microenvironment is largely unknown. Experimental autoimmune encephalomyelitis (EAE) is a well-studied animal model of multiple sclerosis. We demonstrated that autophagy occurred in MSCs during their application for EAE treatment. Inflammatory cytokines, e.g., interferon gamma and tumor necrosis factor, induced autophagy in MSCs synergistically by inducing expression of BECN1/Beclin 1. Inhibition of autophagy by knockdown of Becn1 significantly improved the therapeutic effects of MSCs on EAE, which was mainly attributable to enhanced suppression upon activation and expansion of CD4+ T cells. Mechanistically, inhibition of autophagy increased reactive oxygen species generation and mitogen-activated protein kinase 1/3 activation in MSCs, which were essential for PTGS2 (prostaglandin-endoperoxide synthase 2 [prostaglandin G/H synthase and cyclooxygenase]) and downstream prostaglandin E2 expression to exert immunoregulatory function. Furthermore, pharmacological treatment of MSCs to inhibit autophagy increased their immunosuppressive effects on T cell-mediated EAE. Our findings indicate that inflammatory microenvironment-induced autophagy downregulates the immunosuppressive function of MSCs. Therefore, modulation of autophagy in MSCs would provide a novel strategy to improve MSC-based immunotherapy.
PMCID: PMC4203554  PMID: 24905997
autophagy; experimental autoimmune encephalomyelitis; immunosuppression; mesenchymal stem cells; mitogen-activated protein kinase 1/3; prostaglandin-endoperoxide synthase 2; reactive oxygen species
5.  Chemoprevention of urothelial cell carcinoma growth and invasion by the dual COX-LOX inhibitor licofelone in UPII-SV40T transgenic mice 
Epidemiological and clinical data suggest that use of anti-inflammatory agents is associated with reduced risk for bladder cancer. We determined the chemopreventive efficacy of licofelone, a dual cyclooxygenase (COX)-lipoxygenase (LOX) inhibitor, in a transgenic UPII-SV40T mouse model of urothelial transitional cell carcinoma (TCC). After genotyping, six week-old UPII-SV40T mice (n=30/group) were fed control (AIN-76A) or experimental diets containing 150 or 300 ppm licofelone for 34 weeks. At 40 weeks of age, all mice were euthanized, and urinary bladders were collected to determine urothelial tumor weights and to evaluate histopathology. Results showed that bladders of the transgenic mice fed control diet weighed 3-5-fold more than did those of the wild type mice due to urothelial tumor growth. However, treatment of transgenic mice with licofelone led to a significant, dose-dependent inhibition of the urothelial tumor growth (by 68.6 - 80.2%, p<0.0001 in males; by 36.9 - 55.3%, p<0.0001 in females) compared with the control group. The licofelone diet led to the development of significantly fewer invasive tumors in these transgenic mice. Urothelial tumor progression to invasive TCC was inhibited in both male (up to 50%; p<0.01) and females mice (41-44%; p<0.003). Urothelial tumors of the licofelone-fed mice showed an increase in apoptosis (p53, p21, Bax, Caspase3) with a decrease in proliferation, inflammation and angiogenesis markers (proliferating cell nuclear antigen (PCNA), COX2, 5LOX, prostaglandin E synthase 1 (mPGES1), FLAP, and vascular endothelial growth factor (VEGF). These results suggest that licofelone can serve as potential chemopreventive for bladder TCC.
PMCID: PMC4310686  PMID: 24795386
Transitional Cell Carcinoma; Invasive Urothelial Cancer; UPII-SV40T; Licofelone; COX-2; 5-LOX; Chemoprevention
6.  Effects of chromium malate on glycometabolism, glycometabolism-related enzyme levels and lipid metabolism in type 2 diabetic rats: A dose–response and curative effects study 
The present study was designed to evaluate the effect of chromium malate on glycometabolism, glycometabolism-related enzyme levels and lipid metabolism in type 2 diabetic rats, and dose–response and curative effects.
Materials and Methods
The model of type 2 diabetes rats was developed, and daily treatment with chromium malate was given for 4 weeks. A rat enzyme-linked immunosorbent assay kit was used to assay glycometabolism, glycometabolism-related enzyme levels and lipid metabolism changes.
The results showed that the antihyperglycemic activity increased with administration of chromium malate in a dose–dependent manner. The serum insulin level, insulin resistance index and C-peptide level of the chromium malate groups at a dose of 17.5, 20.0 and 20.8 μg chromium/kg bodyweight were significantly lower than that of the model, chromium trichloride and chromium picolinate groups. The hepatic glycogen, glucose-6-phosphate dehydrogenase and glucokinase levels of the chromium malate groups at a dose of 17.5, 20.0 and 20.8 μg chromium/kg bodyweight were significantly higher than that of the model, chromium trichloride and chromium picolinate groups. Chromium malate at a dose of 20.0 and 20.8 μg chromium/kg bodyweight significantly changed the total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, and triglycerides levels compared with the chromium trichloride and chromium picolinate groups.
The results showed that chromium malate exhibits greater benefits in treating type 2 diabetes, and the curative effect of chromium malate is superior to chromium trichloride and chromium picolinate.
PMCID: PMC4511299  PMID: 26221518
Chromium malate; Glycometabolism; Lipid metabolism
7.  Diagnostic Accuracy of CT-Guided Transthoracic Needle Biopsy for Solitary Pulmonary Nodules 
PLoS ONE  2015;10(6):e0131373.
To evaluate the diagnostic accuracy of computed tomography (CT)-guided percutaneous lung biopsy for solitary pulmonary nodules. Three hundred and eleven patients (211 males and 100 females), with a mean age of 59.6 years (range, 19–87 years), who were diagnosed with solitary pulmonary nodules and underwent CT-guided percutaneous transthoracic needle biopsy between January 2008 and January 2014 were reviewed. All patients were confirmed by surgery or the clinical course. The overall diagnostic accuracy and incidence of complications were calculated, and the factors influencing these were statistically evaluated and compared. Specimens were successfully obtained from all 311 patients. A total of 217 and 94 cases were found to be malignant and benign lesions, respectively, by biopsy. Two hundred and twenty-five (72.3%) carcinomas, 78 (25.1%) benign lesions, and 8 (2.6%) inconclusive lesions were confirmed by surgery and the clinical course. The diagnostic accuracy, sensitivity, and specificity of CT-guided percutaneous transthoracic needle biopsy were 92.9%, 95.3%, and 95.7%, respectively. The incidences of pneumothorax and self-limiting bleeding were 17.7% and 11.6%, respectively. Taking account of all evidence, CT-guided percutaneous lung biopsy for solitary pulmonary nodules is an efficient, and safe diagnostic method associated with few complications.
PMCID: PMC4482532  PMID: 26110775
8.  High-Dose Polymerized Hemoglobin Fails to Alleviate Cardiac Ischemia/Reperfusion Injury due to Induction of Oxidative Damage in Coronary Artery 
Objective. Ischemia/reperfusion (I/R) injury is an unavoidable event for patients in cardiac surgery under cardiopulmonary bypass (CPB). This study was designed to investigate whether glutaraldehyde-polymerized human placenta hemoglobin (PolyPHb), a hemoglobin-based oxygen carrier (HBOC), can protect heart against CPB-induced I/R injury or not and to elucidate the underlying mechanism. Methods and Results. A standard dog CPB model with 2-hour cardiac arrest and 2-hour reperfusion was established. The results demonstrated that a low-dose PolyPHb (0.1%, w/v) provided a significant protection on the I/R heart, whereas the high-dose PolyPHb (3%, w/v) did not exhibit cardioprotective effect, as evidenced by the impaired cardiac function, decreased myocardial oxygen utilization, and elevated enzymes release and pathological changes. Further study indicated that exposure of isolated coronary arteries or human umbilical vein endothelial cells (HUVECs) to a high-dose PolyPHb caused impaired endothelium-dependent relaxation, which was companied with increased reactive oxygen species (ROS) production, reduced superoxide dismutase (SOD) activity, and elevated malonaldehyde (MDA) formation. Consistent with the increased oxidative stress, the NAD(P)H oxidase activity and subunits expression, including gp91phox, p47phox, p67phox, and Nox1, were greatly upregulated. Conclusion. The high-dose PolyPHb fails to protect heart from CPB-induced I/R injury, which was due to overproduction of NAD(P)H oxidase-induced ROS and resultant endothelial dysfunction.
PMCID: PMC4487275  PMID: 26161234
9.  Dual band dual focus optical coherence tomography for imaging the whole eye segment 
Biomedical Optics Express  2015;6(7):2481-2493.
We developed an improved dual band dual focus spectral domain optical coherence tomography (SD-OCT) for in vivo 2D/3D imaging of the whole eye segment, including the whole anterior segment and retina. The system featured two OCT channels with two different bands centered at 840 nm and 1050 nm, which were designed to image the retina and the anterior segments of the eye, respectively. By combing the two probe light beams for co-axial scanning and separating them for focusing at different segments of the eye with a combination of three dichroic mirrors, we not only minimized the loss of the backscattered light from the sample but also improved the imaging depth, scan range and resolution. The full resolved complex (FRC) method was applied to double the imaging depth for the whole anterior segment imaging, with which an imaging depth of 36.71 mm in air was achieved. We demonstrated that this system was capable of measuring the dynamic changes of ocular dimensions, including the asphericity of the cornea and lens, during accommodation.
PMCID: PMC4505703  PMID: 26203375
(110.4500) Optical coherence tomography; (330.7322) Visual optics, accommodation; (170.3880) Medical and biological imaging; (170.4460) Ophthalmic optics and devices; (170.4470) Ophthalmology; (170.4500) Optical coherence tomography
10.  Anaplasma infection of Bactrian camels (Camelus bactrianus) and ticks in Xinjiang, China 
Parasites & Vectors  2015;8:313.
To date, anaplasmosis has been reported to be a subclinical disease in Indian and Arabian one-humped camels (Camelus dromedarius) and llamas (Lama glama). However, no information on Anaplasma infection in two-humped Bactrian camels (Camelus bactrianus) in China has been published to date. The aim of this study was to investigate the prevalence of Anaplasma spp. in domestic Bactrian camels and ticks in Xinjiang, China.
A total of 382 ticks were collected from the Bactrian camels and from environmental sources. Of these, 84 were morphologically identified as belonging to the Rhipicephalus sanguineus group and genetically identified (12S rDNA, 16S rDNA and the cytochrome c oxidase 1 genes) as R. sanguineus group ticks (temporally designated as Rhipicephalus sp. Xinjiang). PCR testing showed that 7.2 % (20/279) of the camels harbored Anaplasma platys DNA. However, microscopic examination revealed no A. platys inclusions in blood smears from the camels. The PCR prevalence of A. platys DNA was 9.5 % (6/63) in Rhipicephalus sp. Xinjiang from the Bactrian camels and 14.3 % (3/21) in Rhipicephalus sp. Xinjiang from the vegetation. A. platys DNA was not detected by PCR in other tick species (Hyalomma asiaticum, Dermacentor niveus and Hyalomma dromedarii), and no other Anaplasma species were detected in these samples.
This is the first report of A. platys in Bactrian camels in Xinjiang, China. The moderate positivity observed indicates that these animals might be a natural host for this pathogen in China.
PMCID: PMC4464610  PMID: 26055661
Anaplasma platys; Detection; Bactrian camel; PCR; Xinjiang; China
11.  Ultrasound Current Source Density Imaging of the Cardiac Activation Wave Using a Clinical Cardiac Catheter 
Ultrasound current source density imaging (UCSDI), based on the acoustoelectric (AE) effect, is a noninvasive method for mapping electrical current in 4-D (space + time). This technique potentially overcomes limitations with conventional electrical mapping procedures typically used during treatment of sustained arrhythmias. However, the weak AE signal associated with the electrocardiogram is a major challenge for advancing this technology. In this study, we examined the effects of the electrode configuration and ultrasound frequency on the magnitude of the AE signal and quality of UCSDI using a rabbit Langendorff heart preparation. The AE signal was much stronger at 0.5 MHz (2.99 μV/MPa) than 1.0 MHz (0.42 μV/MPa). Also, a clinical lasso catheter placed on the epicardium exhibited excellent sensitivity without penetrating the tissue. We also present, for the first time, 3-D cardiac activation maps of the live rabbit heart using only one pair of recording electrodes. Activation maps were used to calculate the cardiac conduction velocity for atrial (1.31 m/s) and apical (0.67 m/s) pacing. This study demonstrated that UCSDI is potentially capable of real-time 3-D cardiac activation wave mapping, which would greatly facilitate ablation procedures for treatment of arrhythmias.
PMCID: PMC4406765  PMID: 25122512
Acoustoelectric; cardiac activation; cardiac arrhythmia; cardiac mapping; electrocardiogram (ECG/EKG)
12.  Homocysteine Triggers Inflammatory Responses in Macrophages through Inhibiting CSE-H2S Signaling via DNA Hypermethylation of CSE Promoter 
Hyperhomocysteinemia (HHcy) is an independent risk factor of atherosclerosis and other cardiovascular diseases. Unfortunately, Hcy-lowering strategies were found to have limited effects in reducing cardiovascular events. The underlying mechanisms remain unclear. Increasing evidence reveals a role of inflammation in the pathogenesis of HHcy. Homocysteine (Hcy) is a precursor of hydrogen sulfide (H2S), which is formed via the transsulfuration pathway catalyzed by cystathionine β-synthase and cystathionine γ-lyase (CSE) and serves as a novel modulator of inflammation. In the present study, we showed that methionine supplementation induced mild HHcy in mice, associated with the elevations of TNF-α and IL-1β in the plasma and reductions of plasma H2S level and CSE expression in the peritoneal macrophages. H2S-releasing compound GYY4137 attenuated the increases of TNF-α and IL-1β in the plasma of HHcy mice and Hcy-treated raw264.7 cells while CSE inhibitor PAG exacerbated it. Moreover, the in vitro study showed that Hcy inhibited CSE expression and H2S production in macrophages, accompanied by the increases of DNA methyltransferase (DNMT) expression and DNA hypermethylation in cse promoter region. DNMT inhibition or knockdown reversed the decrease of CSE transcription induced by Hcy in macrophages. In sum, our findings demonstrate that Hcy may trigger inflammation through inhibiting CSE-H2S signaling, associated with increased promoter DNA methylation and transcriptional repression of cse in macrophages.
PMCID: PMC4490461  PMID: 26047341
homocysteine; cystathionine γ-lyase; hydrogen sulfide; macrophage; DNA methylation
13.  Transmembrane-Bound IL-15–Promoted Epithelial-Mesenchymal Transition in Renal Cancer Cells Requires the Src-Dependent Akt/GSK-3β/β-Catenin Pathway12 
Neoplasia (New York, N.Y.)  2015;17(5):410-420.
Intrarenal interleukin-15 (IL-15) plays a major role controlling epithelial survival and polarization both in physiological and pathologic conditions. Herein, we confirmed that human renal cell carcinomas (RCCs) express a membrane-bound IL-15 isoform displaying an unusual molecular weight of 27 kDa. Its stimulation with soluble IL-15 receptor α chain (s-IL-15Rα) triggers epithelial-mesenchymal transition (EMT) process as shown by the down-regulation of E-cadherin and zona occludens 1 and the up-regulation of vimentin and N-cadherin and promotes the migratory and invasive properties of RCC. S-IL-15Rα treatment triggered the Src/PI3K/Akt/GSK-3β pathway and promoted β-catenin nuclei translocation. Deactivation of this pathway by using Src-specific inhibitor PP2, PI3K inhibitor LY294002, and AKT inhibitor MK2206 hampered β-catenin nuclei translocation and suppressed EMT, migration, and invasion of RCC. S-IL-15Rα treatment also enhanced Src-dependent phosphorylation of focal adhesion kinase (FAK) and extracellular signal–regulated kinase (Erk1/2). FAK knockdown significantly decreased the migration and invasion of RCC, which suggest that Src-FAK signaling was involved in s-IL-15Rα–favored migration and invasion of RCC. At the same time, inhibitors of Erk1/2 also significantly decreased the migration and invasion of RCC but could not reverse s-IL-15Rα–induced EMT. Taken together, our results reveal that Src-dependent PI3K/Akt/GSK3b/β-catenin pathway is required for s-IL-15Ra–dependent induction of EMT in RCC, while Src-FAK and Src-Erk1/2 signaling were involved in s-IL-15Rα–promoted migration and invasion properties of RCC. Our study provides a better understanding of IL-15 signaling in RCC tumor progression, which may lead to novel targeted therapies and provide some suggestions when using IL-15 in clinic.
PMCID: PMC4468369  PMID: 26025664
tmb-IL-15, transmembrane-bound interleukin-15; RCC, renal cell carcinoma; EMT, epithelial-mesenchymal transition; s-IL-15Rα, soluble IL-15 receptor α chain; siRNA, small interfering RNA; TGF-β, transforming growth factor–β; PI3K, phosphatidylinositol 3-kinase; GSK-3β, glycogen synthase kinase-3β; FAK, focal adhesion kinase; Erk, extracellular signal–regulated kinase; ZO-1, zona occludens 1; Akt, protein kinase B
14.  Gene expression changes in Porphyromonas gingivalis W83 after inoculation in rat oral cavity 
BMC Microbiology  2015;15:111.
The development of chronic periodontitis was due to not only periodontal pathogens, but also the interaction between periodontal pathogens and host. The aim of this study is to investigate the alterations in gene expression in Porphyromonas gingivalis (P.gingivalis) W83 after inoculation in rat oral cavity.
P.gingivalis W83 inoculation in rat oral cavity caused inflammatory responses in gingival tissues and destroyed host alveolar bone. Microarray analysis revealed that 42 genes were upregulated, and 22 genes were downregulated in the detected 1786 genes in the inoculated P.gingivalis W83. Real-time quantitative PCR detection confirmed the expression alterations in some selected genes. Products of these upregulated and downregulated genes are mainly related to transposon functions, cell transmembrane transportation, protein and nucleic acid metabolism, energy metabolism, cell division and bacterial pathogenicity.
P.gingivalis W83 has a pathogenic effect on host oral cavity. Meanwhile, inflammatory oral environment alters P.gingivalis W83 gene expression profile. These changes in gene expression may limit the proliferation and weaken the pathogenicity of P.gingivalis W83, and favor themselves to adapt local environment for survival.
PMCID: PMC4493947  PMID: 26001932
Porphyromonas gingivalis; Periodontitis; Microarray; Gene expression
15.  G-quadruplex induced chirality of methylazacalix[6]pyridine via unprecedented binding stoichiometry: en route to multiplex controlled molecular switch 
Scientific Reports  2015;5:10479.
Nucleic acid based molecular device is a developing research field which attracts great interests in material for building machinelike nanodevices. G-quadruplex, as a new type of DNA secondary structures, can be harnessed to construct molecular device owing to its rich structural polymorphism. Herein, we developed a switching system based on G-quadruplexes and methylazacalix[6]pyridine (MACP6). The induced circular dichroism (CD) signal of MACP6 was used to monitor the switch controlled by temperature or pH value. Furthermore, the CD titration, Job-plot, variable temperature CD and 1H-NMR experiments not only confirmed the binding mode between MACP6 and G-quadruplex, but also explained the difference switching effect of MACP6 and various G-quadruplexes. The established strategy has the potential to be used as the chiral probe for specific G-quadruplex recognition.
PMCID: PMC4438431  PMID: 25990684
16.  Hemodynamic characteristics of high-altitude headache following acute high altitude exposure at 3700 m in young Chinese men 
This study aimed to identify the systemic and cerebral hemodynamic characteristics and their roles in high-altitude headache (HAH) among young Chinese men following acute exposure.
The subjects (n = 385) were recruited in June and July of 2012. They completed case report form questionnaires, as well as heart rate (HR), blood pressure, echocardiogram and transcranial Doppler examinations at 3700 m following a two-hour plane flight. A subgroup of 129 participants was examined at two altitudes (500 and 3700 m).
HAH was characterized by increased HR and cardiac output (CO) and lower saturation pulse oxygen (SpO2) (all p < 0.05). The change in tricuspid regurgitation was also different between the HAH positive (HAH+) and HAH negative (HAH-) subjects. Furthermore, the HAH+ subjects exhibited faster mean (Vm), systolic (Vs) and diastolic (Vd) velocities in the basilar artery (BA; all p < 0.05) and a faster Vd ( 25.96 ± 4.97 cm/s vs. 24.76 ± 4.76 cm/s, p = 0.045) in the left vertebral artery (VA). The bilateral VA asymmetry was also significantly different between the two groups. The pulsatility index (PI) and resistance index (RI) of left VA were lower in the HAH subjects (p < 0.05) and were negatively correlated with HAH (p < 0.05). Baseline CO and Vm in left VA (or right MCA in different regressions) were independent predictors for HAH, whereas CO/HR and ΔVd (Vd difference between bilateral VAs) were independent risk factors for HAH at 3700 m.
HAH was characterized, in part, by increased systemic hemodynamics and posterior cerebral circulation, which was reflected by the BA and left VA velocities, and lower arterial resistance and compliance. Furthermore, baseline CO and Vm in left VA or right MCA at sea level were independent predictors for HAH, whilst bilateral VA asymmetry may contribute to the development of HAH at high altitude.
Electronic supplementary material
The online version of this article (doi:10.1186/s10194-015-0527-3) contains supplementary material, which is available to authorized users.
PMCID: PMC4431987  PMID: 25968101
Systemic circulation; Cerebral circulation; Hemodynamic characteristics; High-altitude headache; Acute exposure
17.  Hydrogen Sulfide: A Therapeutic Candidate for Fibrotic Disease? 
Fibrotic diseases including chronic kidney disease, liver cirrhosis, idiopathic pulmonary fibrosis, and chronic disease account for 45% mortality in the developed countries and pose a great threat to the global health. Many great targets and molecules have been reported to be involved in the initiation and/or progression of fibrosis, among which inflammation and oxidative stress are well-recognized modulation targets. Hydrogen sulfide (H2S) is the third gasotransmitter with potent properties in inhibiting inflammation and oxidative stress in various organs. Recent evidence suggests that plasma H2S level is decreased in various animal models of fibrotic diseases and supplement of exogenous H2S is able to ameliorate fibrosis in the kidney, lung, liver, and heart. This leads us to propose that modulation of H2S production may represent a promising therapeutic venue for the treatment of a variety of fibrotic diseases. Here, we summarize and discuss the current data on the role and underlying mechanisms of H2S in fibrosis diseases related to heart, liver, kidney, and other organs.
PMCID: PMC4442291  PMID: 26078807
18.  PacCYP707A2 negatively regulates cherry fruit ripening while PacCYP707A1 mediates drought tolerance 
Journal of Experimental Botany  2015;66(13):3765-3774.
PacCYP707A2 plays a primary role in regulating ABA levels during the onset of cherry fruit ripening, while PacCYP707A1 regulates the ABA content in response to dehydration.
Sweet cherry is a non-climacteric fruit and its ripening is regulated by abscisic acid (ABA) during fruit development. In this study, four cDNAs (PacCYP707A1–4) encoding 8′-hydroxylase, a key enzyme in the oxidative catabolism of ABA, were identified in sweet cherry fruits using tobacco rattle virus-induced gene silencing (VIGS) and particle bombardment approaches. Quantitative real-time PCR confirmed significant down-regulation of target gene transcripts in VIGS-treated cherry fruits. In PacCYP707A2-RNAi-treated fruits, ripening and fruit colouring were promoted relative to control fruits, and both ABA accumulation and PacNCED1 transcript levels were up-regulated by 140%. Silencing of PacCYP707A2 by VIGS significantly altered the transcripts of both ABA-responsive and ripening-related genes, including the ABA metabolism-associated genes NCED and CYP707A, the anthocyanin synthesis genes PacCHS, PacCHI, PacF3H, PacDFR, PacANS, and PacUFGT, the ethylene biosynthesis gene PacACO1, and the transcription factor PacMYBA. The promoter of PacMYBA responded more strongly to PacCYP707A2-RNAi-treated fruits than to PacCYP707A1-RNAi-treated fruits. By contrast, silencing of PacCYP707A1 stimulated a slight increase in fruit colouring and enhanced resistance to dehydration stress compared with control fruits. These results suggest that PacCYP707A2 is a key regulator of ABA catabolism that functions as a negative regulator of fruit ripening, while PacCYP707A1 regulates ABA content in response to dehydration during fruit development.
PMCID: PMC4473978  PMID: 25956880
ABA; CYP707A; cherry ripening; colouring; dehydration stress; particle bombardment; VIGS.
19.  Why Do Mothers of Young Infants Choose to Formula Feed in China? Perceptions of Mothers and Hospital Staff 
In China the exclusive breastfeeding rate remains low and infant formula is widely used. This study aimed to elicit and compare mothers’ and hospital staff perceptions of the reasons that shaped mothers’ decision to formula feed. In-depth interviews with 50 mothers, and four focus group discussions with 33 hospital staff, were conducted in Hangzhou and Shenzhen in November 2014. Responses given by the mothers and hospital staff showed a number of commonalities. The perception of “insufficient breast milk” was cited by the majority of women (n = 37, 74%) as the reason for formula feeding. Mothers’ confidence in breastfeeding appears to be further reduced by maternal mothers or mothers-in-law’s and “confinement ladies” misconceptions about infant feeding. Inadequate breastfeeding facilities and limited flexibility at their workplace was another common reason given for switching to formula feeding. A substantial proportion of mothers (n = 27, 54%) lacked an understanding of the health benefits of breastfeeding. Antenatal education on breastfeeding benefits for expectant mothers and their families is recommended. Moreover, mothers should be provided with breastfeeding support while in hospital and be encouraged to seek professional assistance to deal with breastfeeding problems after discharge. Employers should also make work environments more breastfeeding-friendly.
PMCID: PMC4454923  PMID: 25918908
breastfeeding; infant formula; qualitative research; China
20.  Mesenchymal Stem Cells from Human Fat Engineered to Secrete BMP4 are Non-Oncogenic, Suppress Brain Cancer, and Prolong Survival 
Glioblastoma (GBM) is the most common adult primary malignant intracranial cancer. It is associated with poor outcomes due to its invasiveness and resistance to multimodal therapies. Human adipose-derived mesenchymal stem cells (hAMSCs) are a potential treatment because of their tumor tropism, ease of isolation, and ability to be engineered. In addition, bone morphogenetic protein 4 (BMP4) has tumor-suppressive effects on GBM and GBM brain tumor initiating cells (BTICs), but is difficult to deliver to brain tumors. We sought to engineer BMP4-secreting hAMSCs (hAMSCs-BMP4) and evaluate their therapeutic potential on GBM.
Experimental Design
The reciprocal effects of hAMSCs on primary human BTIC proliferation, differentiation, and migration were evaluated in vitro. The safety of hAMSC use was evaluated in vivo by intracranial co-injections of hAMSCs and BTICs in nude mice. The therapeutic effects of hAMSCs and hAMSCs-BMP4 on the proliferation and migration of GBM cells as well as the differentiation of BTICs, and survival of GBM-bearing mice were evaluated by intracardiac injection of these cells into an in vivo intracranial GBM murine model.
hAMSCs-BMP4 targeted both the GBM tumor bulk and migratory GBM cells, as well as induced differentiation of BTICs, decreased proliferation, and reduced the migratory capacity of GBMs in vitro and in vivo. In addition, hAMSCs-BMP4 significantly prolonged survival in a murine model of GBM. We also demonstrate that the use of hAMSCs in vivo is safe.
Both unmodified and engineered hAMSCs are non-oncogenic and effective against GBM, and hAMSCs-BMP4 are a promising cell-based treatment option for GBM.
PMCID: PMC4050066  PMID: 24789034
glioblastoma; human adipose-derived mesenchymal stem cells; brain tumor initiating cells; BMP4
21.  Downregulation of Spinal G Protein-Coupled Kinase 2 Abolished the Antiallodynic Effect of Electroacupuncture 
Acupuncture or electroacupuncture (EA) has been demonstrated to have a powerful antihypernociceptive effect on inflammatory pain. The attenuation of G protein-coupled receptor kinase 2 (GRK2) in spinal cord and peripheral nociceptor has been widely acknowledged to promote the transition from acute to chronic pain and to facilitate the nociceptive progress. This study was designed to investigate the possible role of spinal GRK2 in EA antiallodynic in a rat model with complete Freund's adjuvant (CFA) induced inflammatory pain. EA was applied to ST36 (“Zusanli”) and BL60 (“Kunlun”) one day after CFA injection. Single EA treatment at day 1 after CFA injection remarkably alleviated CFA induced mechanical allodynia two hours after EA. Repeated EA displayed significant antiallodynic effect from 2nd EA treatment and a persistent effect was observed during the rest of treatments. However, downregulation of spinal GRK2 by intrathecal exposure of GRK2 antisense 30 mins after EA treatment completely eliminated both the transient and persistent antiallodynic effect by EA treatment. These pieces of data demonstrated that the spinal GRK2 played an important role in EA antiallodynia on inflammatory pain.
PMCID: PMC4429192  PMID: 26064176
22.  Safety of Intracoronary Infusion of 20 Million C-Kit Positive Human Cardiac Stem Cells in Pigs 
PLoS ONE  2015;10(4):e0124227.
There is mounting interest in using c-kit positive human cardiac stem cells (c-kitpos hCSCs) to repair infarcted myocardium in patients with ischemic cardiomyopathy. A recent phase I clinical trial (SCIPIO) has shown that intracoronary infusion of 1 million hCSCs is safe. Higher doses of CSCs may provide superior reparative ability; however, it is unknown if doses >1 million cells are safe. To address this issue, we examined the effects of 20 million hCSCs in pigs.
Right atrial appendage samples were obtained from patients undergoing cardiac surgery. The tissue was processed by an established protocol with eventual immunomagnetic sorting to obtain in vitro expanded hCSCs. A cumulative dose of 20 million cells was given intracoronarily to pigs without stop flow. Safety was assessed by measurement of serial biomarkers (cardiac: troponin I and CK-MB, renal: creatinine and BUN, and hepatic: AST, ALT, and alkaline phosphatase) and echocardiography pre- and post-infusion. hCSC retention 30 days after infusion was quantified by PCR for human genomic DNA. All personnel were blinded as to group assignment.
Compared with vehicle-treated controls (n=5), pigs that received 20 million hCSCs (n=9) showed no significant change in cardiac function or end organ damage (assessed by organ specific biomarkers) that could be attributed to hCSCs (P>0.05 in all cases). No hCSCs could be detected in left ventricular samples 30 days after infusion.
Intracoronary infusion of 20 million c-kit positive hCSCs in pigs (equivalent to ~40 million hCSCs in humans) does not cause acute cardiac injury, impairment of cardiac function, or liver and renal injury. These results have immediate translational value and lay the groundwork for using doses of CSCs >1 million in future clinical trials. Further studies are needed to ascertain whether administration of >1 million hCSCs is associated with greater efficacy in patients with ischemic cardiomyopathy.
PMCID: PMC4408046  PMID: 25905721
23.  Assessment of Regional Human Health Risks from Lead Contamination in Yunnan Province, Southwestern China 
PLoS ONE  2015;10(4):e0119562.
Identification and management the 'critical risk areas' where hotspot lead exposures are a potential risk to human health, become a major focus of public health efforts in China. But the knowledge of health risk assessment of lead pollution at regional and national scales is still limited in China. In this paper, under the guidance of 'sources-pathways-receptors' framework, regional human health risk assessment model for lead contamination was developed to calculate the population health risk in Yunnan province. And the cluster and AHP (analytic hierarchy process) analysis was taken to classify and calculate regional health risk and the decomposition of the regional health risk in the greatest health risk region, respectively. The results showed that Yunnan province can be divided into three areas. The highest health risk levels, located in northeastern Yunnan, including Kunming, Qujing, Zhaotong region. In those regions, lead is present at high levels in air, food, water and soil, and high population density which pose a high potential population risk to the public. The current study also reveals that most regional health risk was derived from the child receptors (age above 3 years) 4.3 times than the child receptors (age under 3years), and ingestion of lead-contaminated rice was found to be the most significant contributor to the health risk (accounting for more than 49 % health risk of total). This study can provide a framework for regional risk assessment in China and highlighted some indicators and uncertainties.
PMCID: PMC4404351  PMID: 25893826
24.  Vascular Neural Network: the Importance of Vein Drainage in Stroke 
Translational stroke research  2014;5(2):163-166.
This perspective commentary summarized the stroke pathophysiology evolution, especially the focus in the past on neuroprotection and neurovascular protection and highlighted the newer term for stroke pathophysiology: vascular neural network. Emphasize is on the role of venules and veins after an acute stroke and as potential treatment targets. Vein drainage may contribute to the acute phase of brain edema and the outcomes of stroke patients.
PMCID: PMC3985555  PMID: 24563018
stroke; apoplex; vein drainage; vascular neural network
25.  Xyloketal B Attenuates Atherosclerotic Plaque Formation and Endothelial Dysfunction in Apolipoprotein E Deficient Mice 
Marine Drugs  2015;13(4):2306-2326.
Our previous studies demonstrated that xyloketal B, a novel marine compound with a unique chemical structure, has strong antioxidant actions and can protect against endothelial injury in different cell types cultured in vitro and model organisms in vivo. The oxidative endothelial dysfunction and decrease in nitric oxide (NO) bioavailability are critical for the development of atherosclerotic lesion. We thus examined whether xyloketal B had an influence on the atherosclerotic plaque area in apolipoprotein E-deficient (apoE−/−) mice fed a high-fat diet and investigated the underlying mechanisms. We found in our present study that the administration of xyloketal B dose-dependently decreased the atherosclerotic plaque area both in the aortic sinus and throughout the aorta in apoE−/− mice fed a high-fat diet. In addition, xyloketal B markedly reduced the levels of vascular oxidative stress, as well as improving the impaired endothelium integrity and NO-dependent aortic vasorelaxation in atherosclerotic mice. Moreover, xyloketal B significantly changed the phosphorylation levels of endothelial nitric oxide synthase (eNOS) and Akt without altering the expression of total eNOS and Akt in cultured human umbilical vein endothelial cells (HUVECs). Here, it increased eNOS phosphorylation at the positive regulatory site of Ser-1177, while inhibiting phosphorylation at the negative regulatory site of Thr-495. Taken together, these findings indicate that xyloketal B has dramatic anti-atherosclerotic effects in vivo, which is partly due to its antioxidant features and/or improvement of endothelial function.
PMCID: PMC4413213  PMID: 25874925
xyloketals; atherosclerosis; endothelium; eNOS; apoE-deficient mice

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