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1.  Effects of decompressive cervical surgery on blood pressure in cervical spondylosis patients with hypertension: a time series cohort study 
BMC Surgery  2016;16:2.
Patients with cervical spondylosis myelopathy (CSM) and complicated with hypertension are often experiencing a blood pressure decrease after taking cervical decompressive surgery in clinical observations, but how this blood pressure reduction is associated with the surgery, which cut cervical sympathetic nervous, has never been rigorously assessed. Thus, the purpose of this study is to investigate the effect of cervical decompressive surgery on blood pressure among CSM patients with hypertension.
The study will be a time series cohort study. Fifty eligible patients will be selected consecutively from the Peking University First Hospital. Two 24-h ambulatory blood pressure measurement (ABPM) will be taken before the surgery, apart by at least 3 days. The patients will be followed up for another two ABPMs at 1 and 3 months after the surgery.
We will recruit subjects with cervical spondylosis myelopathy meeting operation indications and scheduled for receiving cervical decompressive surgery, aged 18–84 years, have a history of hypertension or office systolic blood pressure ≥140 mmHg on initial screening, and willing to participate in the study and provide informed consent. Exclusion criteria includes a history of known secondary hypertension, visual analogue scale (VAS) score ≥4, and unable to comply with study due to severe psychosis.
The change in systolic ABPs over the four times will be analyzed to observe the overall pattern of the blood pressure change in relation to the surgery, but the primary analysis will be the comparison of systolic ABP between the 2nd and 3rd , 4th measurements (before and after the surgery). We will also calculate the regression-to-the-mean adjusted changes in systolic ABP as sensitivity analysis. Secondary endpoints are the changes in 24 h ABPM diastolic blood pressure, blood pressure control status, the use and dose adjustment of antihypertensive medication, and the incidence of operative complications. Primary outcome analyses will be carried out using analysis of covariance, as well as the first secondary endpoint.
This study will inform us the important knowledge about cervical sympathetic nervous system (SNS) and blood pressure. Once confirmed, it may help to produce new method for control of hypertension, which is the leading cause of death in the world.
Trial registration
The study is registered to Clinical (NCT02016768).
PMCID: PMC4704254  PMID: 26738624
Cervical spondylosis myelopathy; Cervical decompressive surgery; Hypertension; 24 h ambulatory blood pressure measurement
2.  Enhancement of Cell Ingrowth, Proliferation, and Early Differentiation in a Three-Dimensional Silicon Carbide Scaffold Using Low-Intensity Pulsed Ultrasound 
Tissue Engineering. Part A  2014;21(1-2):53-61.
Concerns over the use of autografts or allografts have necessitated the development of biomaterials for bone regeneration. Various studies have been performed to optimize the cultivation of osteogenic cells using osteoconductive porous scaffolds. The aim of this study was to evaluate the osteogenic efficiency of bone cell ingrowth, proliferation, and early differentiation in a silicon carbide (SiC) porous ceramic scaffold promoted with low-intensity pulsed ultrasound. MC3T3-E1 mouse preosteoblasts were seeded onto scaffolds and cultured for 4 and 7 days with daily of 20-min ultrasound treatment. The cells were evaluated for cell attachment, morphology, viability, ingrowth depth, volumetric proliferation, and early differentiation. After 4 and 7 days of culture and ultrasound exposure, the cell density was higher in the ultrasound-treated group compared with the sham-treated group on SiC scaffolds. The cell ingrowth depths inside the SiC scaffolds were 149.2±27.3 μm at 1 day, 310.1±12.6 μm for the ultrasound-treated group and 248.0±19.7 μm for the sham control at 4 days, and 359.6±18.5 μm for the ultrasound-treated group and 280.0±17.7 μm for the sham control at 7 days. They were significantly increased, that is, 25% (p=0.0029) and 28% (p=0.0008) increase, respectively, with ultrasound radiation force as compared with those in sham control at 4 and 7 days postseeding. The dsDNA contents were 583.5±19.1 ng/scaffold at 1 day, 2749.9±99.9 ng/scaffold for the ultrasound-treated group and 2514.9±114.7 ng/scaffold for the sham control at 4 days, and 3582.3±325.3 ng/scaffold for the ultrasound-treated group and 2825.7±134.3 ng/scaffold for the sham control at 7 days. There was a significant difference in the dsDNA content between the ultrasound- and sham-treated groups at 4 and 7 days. The ultrasound-treated group with the SiC construct showed a 9% (p=0.00029) and 27% (p=0.00017) increase in the average dsDNA content at 4 and 7 days over the sham control group, respectively. Alkaline phosphatase activity was significantly increased by the treatment of ultrasound at 4 (p=0.012) and 7 days (p=0.035). These results suggested that ultrasound treatment with low-intensity acoustic energy facilitated the cellular ingrowth and enhanced the proliferation and early differentiation of osteoblasts in SiC scaffolds.
PMCID: PMC4293095  PMID: 24935158
3.  Vitamin D/VDR signaling attenuates lipopolysaccharide-induced acute lung injury by maintaining the integrity of the pulmonary epithelial barrier 
Molecular Medicine Reports  2015;13(2):1186-1194.
Vitamin D and its receptor have a protective effect on epithelial barriers in various tissues. Low levels of vitamin D are associated with numerous pulmonary diseases, including acute lung injury (ALI) and acute respiratory distress syndrome. The present study investigated whether the vitamin D/vitamin D receptor (VDR) pathway may ameliorate lipopolysaccharide (LPS)-induced ALI through maintaining the integrity of the alveolar epithelial barrier. This was investigated by exposing wild-type (WT) and VDR knockout C57BL/6J mice to LPS, then comparing the healthy and LPS-treated mice lungs and bronchoalveolar lavage fluid (BALF). More specifically, lung histology, mRNA levels of proinflammatory cytokines and chemokines, and protein expression levels of tight junction proteins were determined. In addition, a vitamin D analog (paricalcitol) was administered to WT mice in order to investigate the effect of vitamin D on the alveolar epithelial barrier following exposure to LPS. VDR knockout mice exhibited severe lung injuries (P<0.001), increased alveolar permeability [demonstrated by a higher wet-dry ratio of lung weight (P<0.05), greater expression levels of BALF protein (P<0.001) and fluorescein isothiocyanate-conjugated 4 kDa dextran (P<0.001) leakage into the alveolar space], elevated proinflammatory cytokine and chemokine mRNA levels, as demonstrated by reverse transcription-quantitative polymerase chain reaction (P<0.05), and decreased protein and mRNA expression levels of occludin (P<0.01) and zonula occludens-1 (ZO-1; P<0.01) compared with WT mice. Paricalcitol treatment partially inhibited these pathological changes in WT mice by maintaining the mRNA and protein expression levels of occludin (P<0.01) and ZO-1 (P<0.05). A lack of VDRs in the pulmonary epithelial barrier appeared to compromise its defense, leading to more severe LPS-induced lung injury. Furthermore, vitamin D treatment alleviated LPS-induced lung injury and preserved alveolar barrier function. Therefore vitamin D treatment may present as a potential therapeutic strategy in ALI and acute respiratory distress syndrome.
PMCID: PMC4732862  PMID: 26675943
acute lung injury; permeability; vitamin D; tight junction; vitamin D receptor
4.  miR-96 induces cisplatin chemoresistance in non-small cell lung cancer cells by downregulating SAMD9 
Oncology Letters  2015;11(2):945-952.
Cisplatin is effective as a single agent or in combination with other drugs for the treatment of non-small cell lung cancer (NSCLC). A concerning clinical challenge with cisplatin-based NSCLC chemotherapy is the intrinsic and acquired chemoresistance to cisplatin. The sterile α motif domain-containing (SAMD9) gene has been reported as a potent tumor suppressor gene that inhibits tumorigenesis and progression of NSCLC. microRNAs (miRNA) have been revealed to play important roles in the regulation of cancer chemoresistance. To the best of our knowledge the present study explored the role of miRNA/SAMD9 signaling in regulating cisplatin chemoresistance in NSCLC for the first time. Out of the several candidate miRNAs predicted to bind the 3′-untranslated region (UTR) of the SAMD9 gene, miRNA-96 (miR-96) demonstrated significant target-sequence-specific inhibition of the SAMD9 3′-UTR luciferase reporter activity in NSCLC cells. In addition, while NSCLC tumor samples exhibited significantly higher expression levels of miR-96 compared with adjacent normal tissues, the expression levels of SAMD9 were significantly lower than those in adjacent normal tissues. miR-96 and SAMD9 were overexpressed and knocked down in the human NSCLC H358 and H23 cell lines and the half maximal inhibitory concentration (IC50) of cisplatin and cell apoptosis rate under cisplatin treatment were used as measures of cisplatin chemoresistance. The present results identified that overexpression of miR-96 in NSCLC cells markedly decreased SAMD9 expression and cisplatin-induced apoptosis, and increased the cisplatin IC50, which could be eliminated by overexpression of SAMD9. By contrast, knocking down miR-96 in NSCLC cells using antagomir-96 significantly increased SAMD9 expression and the cisplatin-induced apoptosis and decreased cisplatin IC50, which could be completely reversed by a knockdown of SAMD9. In conclusion, the current study demonstrates that miR-96 targets and downregulates SAMD9 in NSCLC, which decreases cisplatin-induced apoptosis and induces cisplatin chemoresistance in NSCLC cells. The findings of the present study add novel insights into the function of miR-96 and SAMD9 in cancer, as well as into the molecular mechanisms underlying NSCLC chemoresistance.
PMCID: PMC4734049  PMID: 26893673
miR-96; SAMD9; non-small cell lung cancer; cisplatin; chemoresistance; apoptosis
5.  Alpinetin inhibits lung cancer progression and elevates sensitization drug-resistant lung cancer cells to cis-diammined dichloridoplatium 
Alpinetin is a novel flavonoid that has demonstrated potent antitumor activity in previous studies. However, the efficacy and mechanism of alpinetin in treating lung cancer have not been determined.
We evaluated the impact of different doses and durations of alpinetin treatment on the cell proliferation, the apoptosis of lung cancer cells, as well as the drug-resistant lung cancer cells.
This study showed that the alpinetin inhibited the cell proliferation, enhanced the apoptosis, and inhibited the PI3K/Akt signaling in lung cancer cells. Moreover, alpinetin significantly increased the sensitivity of drug-resistant lung cancer cells to the chemotherapeutic effect of cis-diammined dichloridoplatium. Taken together, this study demonstrated that alpinetin significantly suppressed the development of human lung cancer possibly by influencing mitochondria and the PI3K/Akt signaling pathway and sensitized drug-resistant lung cancer cells.
Alpinetin may be used as a potential compound for combinatorial therapy or as a complement to other chemotherapeutic agents when multiple lines of treatments have failed to reduce lung cancer.
PMCID: PMC4655908  PMID: 26604699
alpinetin; cell proliferation and apoptosis; drug resistance reversal; PI3K/Akt; lung cancer
6.  Factors Influencing Graft Outcomes Following Diagnosis of Polyomavirus –Associated Nephropathy after Renal Transplantation 
PLoS ONE  2015;10(11):e0142460.
Polyomavirus associated nephropathy (PVAN) is a significant cause of early allograft loss and the course is difficult to predict. The aim of this study is to identify factors influencing outcome for PVAN.
Between 2006 and 2014, we diagnosed PVAN in 48 (7.8%) of 615 patients monitored for BK virus every 1–4 weeks after modification of maintenance immunosuppression. Logistic or Cox regression analysis were performed to determine which risk factors independently affected clinical outcome and graft loss respectively.
After 32.1±26.4 months follow-up, the frequencies of any graft functional decline at 1 year post-diagnosis, graft loss and any graft functional decline at the last available follow-up were 27.1% (13/48), 25.0% (12/48), and 33.3% (16/48), respectively. The 1, 3, 5 year graft survival rates were 100%, 80.5% and 69.1%, respectively. The mean level of serum creatinine at 1 year post-diagnosis and long-term graft survival rates were the worst in class C (p<0.05). Thirty-eight of 46 (82.6%) BKV DNAuria patients reduced viral load by 90% with a median time of 2.75 months (range, 0.25–34.0 months) and showed better graft survival rates than the 8 patients (17.4%) without viral load reduction (p<0.001). Multivariate logistic regression analysis showed that extensive interstitial inflammation (OR 20.2, p = 0.042) and delayed fall in urinary viral load (>2.75 months for >90% decrease) in urine (OR 16.7, p = 0.055) correlated with worse creatinine at 1 year post-diagnosis. Multivariate Cox regression analysis showed that extensive interstitial inflammation (HR 46988, p = 0.032) at diagnosis, and high PVAN stage (HR 162.2, p = 0.021) were associated with worse long-term graft survival rates.
The extent of interstitial inflammation influences short and long-term graft outcomes in patients with PVAN. The degree of PVAN, rate of reduction in viral load, and viral clearance also can be used as prognostic markers in PVAN.
PMCID: PMC4636317  PMID: 26544696
7.  The Role and Mechanism of α-Klotho in the Calcification of Rat Aortic Vascular Smooth Muscle Cells 
BioMed Research International  2015;2015:194362.
Objective. To investigate the role and possible mechanism of α-Klotho in the calcification and the osteogenic transition of cultured VSMCs. Methods. VSMCs were cultured in vitro and divided into 5 groups, each using a different medium: (1) control; (2) β-GP; (3) β-GP + Klotho; (4) β-GP + LiCl; (5) β-GP + Klotho + LiCl. Calcium deposits were visualized using Alizarin Red S staining. The calcium concentrations were determined by the o-cresolphthalein complexone method. BMP2, Runx2 and β-catenin levels were estimated by western blotting, and the level of α-SMA was determined by using immunofluorescence at day 12. Results. β-GP induced an increase in the expression of BMP2, Runx2, and β-catenin. The calcium content increased, and the expression of α-SMA decreased. Alizarin Red S staining was positive under the high phosphorus conditions. BMP2, Runx2, and β-catenin levels and the calcium content decreased when the cells were cultured with rmKlotho; however, the levels of each were upregulated after treatment with the LiCl. Conclusions. Klotho can ameliorate the calcification and osteogenic transition of VSMCs induced by β-GP. The mechanism of Klotho in preventing calcification in VSMCs may be partially mediated by the inhibition of the Wnt/β-catenin signaling pathway.
PMCID: PMC4644825  PMID: 26609522
8.  Alteration of Regional Homogeneity within the Sensorimotor Network after Spinal Cord Decompression in Cervical Spondylotic Myelopathy: A Resting-State fMRI Study 
BioMed Research International  2015;2015:647958.
There is a lack of longitudinal research to evaluate the function of neurons' adaptive changes within the sensorimotor network (SMN) following recovery after cervical cord decompression. Regional homogeneity (ReHo) may provide information that is critical to fully understand CSM-related functional neural synchrony alterations. The purpose of this study was to assess the ReHo alterations of resting state-functional MRI (rs-fMRI) within pre- and postdecompression CSM and healthy controls (HC) and its correlations with clinical indices. Predecompression CSM demonstrated a significantly lower ReHo in the left primary sensory cortex and primary motor cortex (PostG/PreG) but enhanced ReHo in the right superior parietal lobule (SPL) compared with HC. In comparison with predecompression CSM, the postdecompression CSM showed increased ReHo in the left PostG/PreG but significantly lower ReHo in the right SPL compared with HC patients. Abnormal ReHo regions in pre- or postdecompression CSM showed no significant correlation with the Japanese Orthopaedic Association (JOA) scores, Neck Disability Index (NDI) scores, and disease duration (P > 0.05). This result demonstrated disrupted regional homogeneity within SMN in CSM. This adaptive change in the brain may favor the preservation of sensorimotor networks before and after cervical cord decompression and clinical symptoms independent of ReHo within SMN.
PMCID: PMC4641924  PMID: 26605335
9.  A Drosophila genetic resource of mutants to study mechanisms underlying human genetic diseases 
Cell  2014;159(1):200-214.
Invertebrate model systems are powerful tools for studying human disease owing to their genetic tractability and ease of screening. We conducted a mosaic genetic screen of lethal mutations on the Drosophila X-chromosome to identify genes required for the development, function, and maintenance of the nervous system. We identified 165 genes, most of whose function has not been studied in vivo. In parallel, we investigated rare variant alleles in 1,929 human exomes from families with unsolved Mendelian disease. Genes that are essential in flies and have multiple human homologs were found to be likely to be associated with human diseases. Merging the human datasets with the fly genes allowed us to identify disease-associated mutations in six families and to provide insights into microcephaly associated with brain dysgenesis. This bidirectional synergism between fly genetics and human genomics facilitates the functional annotation of evolutionarily conserved genes involved in human health.
PMCID: PMC4298142  PMID: 25259927
EMS mutagenesis; Drosophila X-chromosome; whole-exome sequencing; CRX; bull’s eye maculopathy; DNM2; Charcot-Marie-Tooth disease; ANKLE2; microcephaly
10.  Stabilization of 4H hexagonal phase in gold nanoribbons 
Nature Communications  2015;6:7684.
Gold, silver, platinum and palladium typically crystallize with the face-centred cubic structure. Here we report the high-yield solution synthesis of gold nanoribbons in the 4H hexagonal polytype, a previously unreported metastable phase of gold. These gold nanoribbons undergo a phase transition from the original 4H hexagonal to face-centred cubic structure on ligand exchange under ambient conditions. Using monochromated electron energy-loss spectroscopy, the strong infrared plasmon absorption of single 4H gold nanoribbons is observed. Furthermore, the 4H hexagonal phases of silver, palladium and platinum can be readily stabilized through direct epitaxial growth of these metals on the 4H gold nanoribbon surface. Our findings may open up new strategies for the crystal phase-controlled synthesis of advanced noble metal nanomaterials.
Noble metals typically crystallize with the face-centered cubic structure. Here, the authors report the synthesis of gold nanoribbons in the 4H hexagonal polytype, a previously unreported, metastable phase of gold, and use it to stabilize 4H hexagonal phases of silver, palladium and platinum.
PMCID: PMC4525209  PMID: 26216712
11.  Shared Mechanisms between Drosophila Peripheral Nervous System Development and Human Neurodegenerative Diseases 
Signaling pathways and cellular processes that regulate neural development are used post-developmentally for proper function and maintenance of the nervous system. Genes that have been studied in the context of the development of Drosophila peripheral nervous system (PNS) and neuromuscular junction (NMJ) have been identified as players in the pathogenesis of human neurodegenerative diseases, including spinocerebellar ataxia, amyotrophic lateral sclerosis, and spinal muscular atrophy. Hence, by unraveling the molecular mechanisms that underlie proneural induction, cell fate determination, axonal targeting, dendritic branching, and synapse formation in Drosophila, novel features related to these disorders have been revealed. In this review, we summarize and discuss how studies of Drosophila PNS and NMJ development have provided guidance in experimental approaches for these diseases.
PMCID: PMC4122633  PMID: 24762652
spinocerebellar ataxia; SCA; amyotrophic lateral sclerosis; ALS; spinal muscular atrophy; SMA; neurodegenerative diseases; peripheral nervous system; PNS development; neuromuscular junction; NMJ
12.  Enhanced anti-ischemic stroke of ZL006 by T7-conjugated PEGylated liposomes drug delivery system 
Scientific Reports  2015;5:12651.
The treatment for ischemic stroke is one of the most challenging problems and the therapeutic effect remains unsatisfied due to the poor permeation of drugs across the blood brain barrier (BBB). In this study, HAIYPRH (T7), a peptide that targeted to transferrin receptor (TfR) can mediate the transport of nanocarriers across the BBB, was conjugated to liposomes for ischemic stroke targeting treatment of a novel neuroprotectant (ZL006). T7-conjugated PEGylated liposomes (T7-P-LPs) loaded with ZL006 (T7-P-LPs/ZL006) were showed satisfactory vesicle size and size distribution. Furthermore, the cellular uptake results showed that T7 modification increased liposomes uptake by the brain capillary endothelial cells (BCECs) and little cytotoxicity of liposomes with or without ZL006 was observed. The in vivo biodistribution and near-infrared fluorescence imaging evidenced that T7 modification rendered liposomes significantly enhanced the transport of liposomes across the BBB. The pharmacodynamic study suggested that, T7-P-LPs/ZL006 exhibited reduced infarct volume and ameliorated neurological deficit compared with unmodified liposomes or free ZL006. T7-P-LPs/ZL006 could be targeted to brain and displayed remarkable neuroprotective effects. They could be used as a potential targeted drug delivery system of ischemic stroke treatment.
PMCID: PMC4518266  PMID: 26219474
13.  Disconnection of the hippocampus and amygdala associated with lesion load in relapsing–remitting multiple sclerosis: a structural and functional connectivity study 
Background and purpose
Little is known about the functional and structural connectivity (FC and SC) of the hippocampus and amygdala, which are two important structures involved in cognitive processes, or their involvement in relapsing–remitting multiple sclerosis (RRMS). In this study, we aimed to examine the connectivity of white-matter (WM) tracts and the synchrony of intrinsic neuronal activity in outer regions connected with the hippocampus or amygdala in RRMS patients.
Patients and methods
Twenty-three RRMS patients and 23 healthy subjects participated in this study. Diffusion tensor probabilistic tractography was used to examine the SC, the FC correlation coefficient (FC-CC) and combined FC strength (FCS), which was derived from the resting-state functional magnetic resonance imaging used to examine the FC, of the connection between the hippocampus or the amygdala and other regions, and the correlations of these connections with clinical markers.
Compared with healthy subjects, the RRMS patients showed significantly decreased SC and increased FCS of the bilateral hippocampus, and left amygdala. Their slightly increased FC-CC was positively correlated with WM tract damage in the right hippocampus (ρ=0.57, P=0.005); an increased FCS was also positively correlated with WM tract damage in the right amygdala. A relationship was observed between the WM lesion load and SC alterations, including the lg(N tracts) of the right hippocampus (ρ=−0.68, P<0.05), lg(N tracts) (ρ=−0.69, P<0.05), and fractional anisotropy (ρ=−0.68, P<0.05) and radial diffusivity of the left hippocampus (ρ=0.45, P<0.05). A relationship between WM lesion load and FCS of the left amygdale was also observed.
The concurrent increased functional connections and demyelination-related structural disconnectivity between the hippocampus or amygdala and other regions in RRMS suggest that the functional–structural relationships require further investigation.
PMCID: PMC4514382  PMID: 26229470
relapsing-remitting multiple sclerosis; hippocampus; limbic system; functional connectivity; structural connectivity; fiber tractography
14.  PKA turnover by the REGγ-proteasome modulates FoxO1 cellular activity and VEGF-induced angiogenesis 
The REGγ-proteasome serves as a short-cut for the destruction of certain intact mammalian proteins in the absence of ubiquitin-and ATP. The biological roles of the proteasome activator REGγ are not completely understood. Here we demonstrate that REGγ controls degradation of protein kinase A catalytic subunit-α (PKAca) both in primary human umbilical vein endothelial cells (HUVECs) and mouse embryonic fibroblast cells (MEFs). Accumulation of PKAca in REGγ-deficient HUVECs or MEFs results in phosphorylation and nuclear exclusion of the transcription factor FoxO1, indicating that REGγ is involved in preserving FoxO1 transcriptional activity. Consequently, VEGF-induced expression of the FoxO1 responsive genes, VCAM-1 and E-Selectin, was tightly controlled by REGγ in a PKA dependent manner. Functionally, REGγ is crucial for the migration of HUVECs. REGγ−/− mice display compromised VEGF-instigated neovascularization in cornea and aortic ring models. Implanted matrigel plugs containing VEGF in REGγ−/− mice induced fewer capillaries than in REGγ+/+ littermates. Taken together, our study identifies REGγ as a novel angiogenic factor that plays an important role in VEGF-induced expression of VCAM-1 and E-Selectin by antagonizing PKA signaling. Identification of the REGγ–PKA–FoxO1 pathway in endothelial cells (ECs) provides another potential target for therapeutic intervention in vascular diseases.
PMCID: PMC4237316  PMID: 24560667
Angiogenesis; E-Selectin; FoxO1; PKAca; REGγ; VCAM-1
15.  Yifei Xuanfei Jiangzhuo formula, a Chinese herbal decoction, improves memory impairment through inhibiting apoptosis and enhancing PKA/CREB signal transduction in rats with cerebral ischemia/reperfusion 
Molecular Medicine Reports  2015;12(3):4273-4283.
Apoptosis and the dysfunction of the cyclic adenosine monophosphate (cAMP)/protein kinase A (PKA)/cAMP-responsive element binding protein (CREB) signaling pathway have a key role in memory impairment in vascular dementia (VaD), a challenging clinical problem. Yifei Xuanfei Jiangzhuo formula (YXJF), a Chinese herbal decoction, has been used to treat VaD in clinical practice and has produced positive outcomes; however, convincing evidence is currently lacking. The present study aimed to investigate the effects of YXJF on memory impairment in rats with cerebral ischemia/reperfusion and to explore the underlying mechanism. YXJF ameliorated memory impairment in rats with cerebral ischemia/reperfusion, inhibited hippocampal apoptosis in a dose-dependent manner and attenuated increases in the protein expression of B-cell lymphoma 2 (Bcl-2)-associated X protein as well as c-Jun and a reduction in Bcl-2 protein expression in the hippocampal tissue of the rats. Furthermore, administration of YXJF significantly increased the protein expression of PKA C-α and CREB, and promoted CREB phosphorylation. The results indicated that YXJF improves memory impairment through inhibiting apoptosis and enhancing PKA/CREB signal transduction in rats with cerebral ischemia/reperfusion.
PMCID: PMC4526035  PMID: 26094797
Chinese medicine; vascular dementia; memory impairment; ischemia/reperfusion; apoptosis; signal transduction
16.  Characterizing Thalamocortical Disturbances in Cervical Spondylotic Myelopathy: Revealed by Functional Connectivity under Two Slow Frequency Bands 
PLoS ONE  2015;10(6):e0125913.
Background and Purpose
Recent advanced MRI studies on cervical spondylotic myelopathy (CSM) revealed alterations of sensorimotor cortex, but the disturbances of large-scale thalamocortical systems remains elusive. The purpose of this study was to characterizing the CSM-related thalamocortical disturbances, which were associated with spinal cord structural injury, and clinical measures.
A total of 17 patients with degenerative CSM and well-matched control subjects participated. Thalamocortical disturbances were quantified using thalamus seed-based functional connectivity in two distinct low frequencies bands (slow-5 and slow-4), with different neural manifestations. The clinical measures were evaluated by Japanese Orthopaedic Association (JOA) score system and Neck Disability Index (NDI) questionnaires.
Decreased functional connectivity was found in the thalamo-motor, -somatosensory, and -temporal circuits in the slow-5 band, indicating impairment of thalamo-cortical circuit degeneration or axon/synaptic impairment. By contrast, increased functional connectivity between thalami and the bilateral primary motor (M1), primary and secondary somatosensory (S1/S2), premotor cortex (PMC), and right temporal cortex was detected in the slow-4 band, and were associated with higher fractional anisotropy values in the cervical cord, corresponding to mild spinal cord structural injury.
These thalamocortical disturbances revealed by two slow frequency bands inform basic understanding and vital clues about the sensorimotor dysfunction in CSM. Further work is needed to evaluate its contribution in central functional reorganization during spinal cord degeneration.
PMCID: PMC4460123  PMID: 26053316
17.  Mefunidone Attenuates Tubulointerstitial Fibrosis in a Rat Model of Unilateral Ureteral Obstruction 
PLoS ONE  2015;10(6):e0129283.
Inflammation has a crucial role in renal interstitial fibrosis, which is the common pathway of chronic kidney diseases. Mefunidone (MFD) is a new compound which could effectively inhibit the proliferation of renal fibroblasts in vitro. However, the overall effect of Mefunidone in renal fibrosis remains unknown.
Sprague-Dawley rats were randomly divided intro 6 groups: sham operation, unilateral ureteral obstruction (UUO), UUO/Mefunidone (25, 50, 100mg/kg/day) and UUO/PFD (500mg/kg/day). The rats were sacrificed respectively on days 3, 7, and 14 after the operation. Tubulointerstitial injury index, interstitial collagen deposition, expression of fibronectin (FN), α-smooth muscle actin (α-SMA), type I and III collagen and the number of CD3+ and CD68+ cells were determined. The expressions of proinflammatory cytokines, p-ERK, p-IκB, and p-STAT3 were measured in human renal proximal tubular epithelial cells of HK-2 or macrophages.
Mefunidone treatment significantly attenuated tubulointerstitial injury, interstitial collagen deposition, expression of FN, α-SMA, type I and III collagen in the obstructive kidneys, which correlated with significantly reduced the number of T cells and macrophages in the obstructive kidneys. Mechanistically, Mefunidone significantly inhibited tumor necrosis factor-α (TNF-α-) or lipopolysaccharide (LPS)-induced production of proinflammatory cytokines. This effect is possibly due to the inhibition of phosphorylation of ERK, IκB, and STAT3.
Mefunidone treatment attenuated tubulointerstitial fibrosis in a rat model of UUO, at least in part, through inhibition of inflammation.
PMCID: PMC4456380  PMID: 26042668
18.  Relationship Between Cytomegalovirus Infection and Steroid Resistance in Inflammatory Bowel Disease: A Meta-Analysis 
Digestive Diseases and Sciences  2015;60(11):3203-3208.
Background and Aims
Steroid resistance presents an administration difficulty in inflammatory bowel disease (IBD). The reason of steroid resistance is still unclear, but cytomegalovirus (CMV) infection may be a potential cause in some IBD patients. We carried out a meta-analysis to investigate the relationship between CMV infection and steroid-resistant IBD.
The PubMed, EMBASE, and Cochrane Library databases were searched up to June 2014, with no language restrictions, for observational studies. Additional references were obtained from reviewed articles.
Eleven studies involving 867 IBD patients were included in the meta-analysis. Steroid resistance rate was 70.0 % in CMV-positive IBD patients, which was significantly higher than that in CMV-negative IBD patients (RR = 2.12, 95 % CI = 1.72–2.61). There was significant heterogeneity in the included eleven studies (I2 = 57.6 %). When the only one study with a few patients was excluded, sensitivity analysis suggested a similar outcome (RR = 2.07, 95 % CI = 1.80–2.39, 10 studies). Based on the funnel plot and Egger’s test, we considered that there was a probable publication bias.
Our meta-analysis suggests that CMV-positive IBD patients have a nearly double risk of steroid resistance compared with CMV-negative IBD patients, indicating that CMV infection is a probable cause of steroid-resistant IBD.
PMCID: PMC4621704  PMID: 26031424
Cytomegalovirus; Inflammatory bowel disease; Crohn’s disease; Ulcerative colitis; Meta-analysis
20.  Autoantibody Profiling on Human Proteome Microarray for Biomarker Discovery in Cerebrospinal Fluid and Sera of Neuropsychiatric Lupus 
PLoS ONE  2015;10(5):e0126643.
Autoantibodies in cerebrospinal fluid (CSF) from patients with neuropsychiatric systemic lupus erythematosus (NPSLE) may be potential biomarkers for prediction, diagnosis, or prognosis of NPSLE. We used a human proteome microarray with~17,000 unique full-length human proteins to investigate autoantibodies associated with NPSLE. Twenty-nine CSF specimens from 12 NPSLE, 7 non-NPSLE, and 10 control (non-systemic lupus erythematosus)patients were screened for NPSLE-associated autoantibodies with proteome microarrays. A focused autoantigen microarray of candidate NPSLE autoantigens was applied to profile a larger cohort of CSF with patient-matched sera. We identified 137 autoantigens associated with NPSLE. Ingenuity Pathway Analysis revealed that these autoantigens were enriched for functions involved in neurological diseases (score = 43).Anti-proliferating cell nuclear antigen (PCNA) was found in the CSF of NPSLE and non-NPSLE patients. The positive rates of 4 autoantibodies in CSF specimens were significantly different between the SLE (i.e., NPSLE and non-NPSLE) and control groups: anti-ribosomal protein RPLP0, anti-RPLP1, anti-RPLP2, and anti-TROVE2 (also known as anti-Ro/SS-A). The positive rate for anti-SS-A associated with NPSLE was higher than that for non-NPSLE (31.11% cf. 10.71%; P = 0.045).Further analysis showed that anti-SS-A in CSF specimens was related to neuropsychiatric syndromes of the central nervous system in SLE (P = 0.009). Analysis with Spearman’s rank correlation coefficient indicated that the titers of anti-RPLP2 and anti-SS-A in paired CSF and serum specimens significantly correlated. Human proteome microarrays offer a powerful platform to discover novel autoantibodies in CSF samples. Anti-SS-A autoantibodies may be potential CSF markers for NPSLE.
PMCID: PMC4425696  PMID: 25954975
21.  Global transcriptional disturbances underlie Cornelia de Lange syndrome and related phenotypes 
Cornelia de Lange syndrome (CdLS) is a genetically heterogeneous disorder that presents with extensive phenotypic variability, including facial dysmorphism, developmental delay/intellectual disability (DD/ID), abnormal extremities, and hirsutism. About 65% of patients harbor mutations in genes that encode subunits or regulators of the cohesin complex, including NIPBL, SMC1A, SMC3, RAD21, and HDAC8. Wiedemann-Steiner syndrome (WDSTS), which shares CdLS phenotypic features, is caused by mutations in lysine-specific methyltransferase 2A (KMT2A). Here, we performed whole-exome sequencing (WES) of 2 male siblings clinically diagnosed with WDSTS; this revealed a hemizygous, missense mutation in SMC1A that was predicted to be deleterious. Extensive clinical evaluation and WES of 32 Turkish patients clinically diagnosed with CdLS revealed the presence of a de novo heterozygous nonsense KMT2A mutation in 1 patient without characteristic WDSTS features. We also identified de novo heterozygous mutations in SMC3 or SMC1A that affected RNA splicing in 2 independent patients with combined CdLS and WDSTS features. Furthermore, in families from 2 separate world populations segregating an autosomal-recessive disorder with CdLS-like features, we identified homozygous mutations in TAF6, which encodes a core transcriptional regulatory pathway component. Together, our data, along with recent transcriptome studies, suggest that CdLS and related phenotypes may be “transcriptomopathies” rather than cohesinopathies.
PMCID: PMC4319410  PMID: 25574841
22.  Targeted mouse complement inhibitor CR2-Crry protects against the development of atherosclerosis in mice 
Atherosclerosis  2014;234(1):237-243.
Atherosclerosis is a chronic inflammatory and immune vascular disease, and clinical and experimental evidence has indicated an important role of complement activation products, including the terminal membrane attack complex (MAC), in atherogenesis. Here, we investigated whether complement inhibition represents a potential therapeutic strategy to treat/prevent atherogenesis using CR2-Crry, a recently described complement inhibitor that specifically targets to sites of C3 activation.
Methods and Results
Previous studies demonstrated that loss of CD59 (a membrane inhibitor of MAC formation) accelerated atherogenesis in Apoe deficient (Apoe−/−) mice. Here, both CD59 sufficient and CD59 deficient mice in an Apoe deficient background (namely, mCd59ab+/+/Apoe−/− and mCd59ab−/−/Apoe−/−) were treated with CR2-Crry for 4 and 2 months respectively, while maintained on a high fat diet. Compared to control treatment, CR2-Crry treatment resulted in significantly fewer atherosclerotic lesions in the aorta and aortic root, and inhibited the accelerated atherogenesis seen in mCd59ab+/+/Apoe−/− and mCd59ab−/−/Apoe−/− mice. CR2-Crry treatment also resulted in significantly reduced C3 and MAC deposition in the vasculature of both mice, as well as a significant reduction in the number of infiltrating macrophages and T cells.
The data demonstrate the therapeutic potential of targeted complement inhibition.
PMCID: PMC4267679  PMID: 24685815
Complement; complement regulation; atherosclerosis; Crry; CD59 and therapeutics
23.  Helicobacter pylori infection and inflammatory bowel disease in Asians: A meta-analysis 
AIM: To investigate the relationship between Helicobacter pylori infection and inflammatory bowel disease (IBD) in an Asian population.
METHODS: The PubMed, EMBASE, and Cochrane Library databases were searched for observational studies published up until June 2014, without language restrictions. Additional references were obtained from reviewed articles.
RESULTS: Ten studies involving 1299 IBD patients and 1817 controls were included in the meta-analysis (24.9% of IBD patients had H. pylori infection vs 48.3% of the controls). The pooled risk ratio for H. pylori infection in IBD patients compared with controls was 0.48 (95%CI: 0.43-0.54; P < 0.001). There was no significant heterogeneity in the included studies (I2 = 21%). Egger’s linear regression indicated that there was no significant publication bias (P = 0.203).
CONCLUSION: The H. pylori infection rate in Asian IBD patients is significantly lower than in non-IBD patients, indicating that infection protects against the development of IBD.
PMCID: PMC4402325  PMID: 25914487
Asian population; Crohn’s disease; Helicobacter pylori; Inflammatory bowel disease; Meta-analysis; Ulcerative colitis
24.  Autophagy-mediated HMGB1 release promotes gastric cancer cell survival via RAGE activation of extracellular signal-regulated kinases 1/2 
Oncology Reports  2015;33(4):1630-1638.
High mobility group box-B1 (HMGB1), an autophagy activator, is crucial in tumorigenesis. However, its extracellular role and signaling in gastric cancer remain unclear. Samples were collected from gastric cancer patients and healthy controls. Immunohistochemistry and immunocytochemistry were used to determine the localization of HMGB1 in gastric cancer tissues, four gastric carcinoma cell lines (BGC-823, SGC-7901, MKN-28 and MKN-45) and a gastric epithelial cell line GES-1. Western blot analysis and ELISA were used to assess the effects of gefitinib, an epidermal growth factor receptor inhibitor, on autophagy and HMGB1 release in BGC-823 cells. MTT assay and western blot analysis assessed the effects of extracellular HMGB1 on cell proliferation and signaling transduction. Released HMGB1 promoted proliferation through activation of ERK1/2 MAPK. HMGB1 expression in gastric cancer tissues and serum was significantly increased compared to the controls and healthy serum. Gastric carcinoma cells showed an increased HMGB1 in the nuclei and cytoplasm, whereas GES-1 cells exhibited a lower HMGB1 with nuclear localization. Gefitinib increased autophagy and cytoplasmic HMGB1 release from the BGC-823 cells. Extracellular HMGB1 in autophagic cell supernatant promoted proliferation that was abolished by glycyrrhizic acid, an HMGB1 inhibitor. BGC-823 cells incubated with HMGB1 had increased ERK1/2 phosphorylation, while levels of JNK, p38 or AKT were not affected. Blocking RAGE-HMGB1 interaction with antibody or siRNA suppressed the ERK1/2 activation and gastric cancer cell growth, indicating that RAGE-mediated ERK1/2 signaling was necessary for tumor progression.
PMCID: PMC4358082  PMID: 25652880
gastric cancer; HMGB1; autophagy; RAGE; ERK; MAPK
25.  UBE2D3 is a positive prognostic factor and is negatively correlated with hTERT expression in esophageal cancer 
Oncology Letters  2015;9(4):1567-1574.
Human telomerase reverse transcriptase (hTERT) is a critical factor in unlimited cell proliferation and immortalization, with numerous studies demonstrating that high expression of hTERT is a poor prognostic factor in various types of cancer. Ubiquitin-conjugating enzyme E2D 3 (UBE2D3) is a member of the E2 family, and participates in the ubiquitin proteasome pathway to regulate basic cellular activities, such as cell cycle control, the DNA damage response, apoptosis, and tumorigenesis. Our previous study initially determined that downregulation of UBE2D3 expression increases hTERT expression and cell proliferation, however, the association between the expression of these two proteins and their functions in cancer tissues remains unknown. Therefore, the protein expression levels of hTERT and UBE2D3 were evaluated in 150 esophageal cancer and 30 adjacent healthy tissue samples by performing immunohistochemical analysis. Concurrently, the clinicopathological data of the enrolled patients were obtained to allow correlation analysis. It was identified that the expression of hTERT in the esophageal cancer tissues was significantly higher compared with that of the adjacent tissues (P=0.015), however, the expression of UBE2D3 was significantly lower in esophageal cancer tissues than the adjacent tissues (P=0.001). Additionally, the study demonstrated that hTERT was significantly upregulated in poorly-differentiated, advanced tumor-node-metastasis (TNM) stage cancer tissues (P<0.05 for all), however, UBE2D3 expression was downregulated in poorly-differentiated, lymph node invaded cancer tissues and recurrent cases. It was also identified that traditional factors, including tumor location, T stage, lymph node status, TNM stage, and molecular factors of hTERT and UBE2D3, were significantly associated with overall survival time (P<0.05 for all). Furthermore, UBE2D3, lymph node status and tumor location were independent prognostic factors for esophageal cancer in multivariate analysis. Most notably, hTERT and UBE2D3 expression were negatively correlated with each other. In conclusion, the findings of the present study indicated that hTERT and UBE2D3 proteins appear to be involved in the development of esophageal cancer, that UBE2D3 may a positive prognostic factor for esophageal cancer, and that UBE2D3 and hTERT expression levels are inversely correlated.
PMCID: PMC4356423  PMID: 25789002
ubiquitin-conjugating enzyme E2D 3; human telomerase reverse transcriptase; esophageal cancer; prognosis

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