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1.  Update on the Clinical Effect of Acupuncture Therapy in Patients with Gouty Arthritis: Systematic Review and Meta-Analysis 
Objective. The aim of this study is to evaluate the clinical efficacy and safety of acupuncture therapy in the treatment of acute gouty arthritis. Methods. A literature search of PubMed, EMBASE, ISI Web of Science, CENTRAL, and CNKI was conducted from the inception date of each database up to October 2015. Two investigators screened each article independently and were blinded to the findings of the other reviewer. Data was extracted according to the predetermined collection form. Meta-analysis was performed. Results. We analyzed data from 28 RCTs involving 2237 patients with gouty arthritis. Compared with conventional pharmacological treatments acupuncture was more effective in rendering patients free from symptoms after 24 hours, lowering serum urate, alleviating pain associated with gouty arthritis, and decreasing the ESR; regarding CRP, no statistically significant difference was found. In addition, the frequency of adverse events in acupuncture treatment was lower than that in control group. Conclusion. Based on the findings of our study, we cautiously suggest that acupuncture is an effective and safe therapy for patients with gouty arthritis. However, the potential beneficial effect of acupuncture might be overstated due to the methodological deficiency of included studies. High quality RCTs with larger scale are encouraged.
PMCID: PMC5099464  PMID: 27847529
2.  Prognostic significance of fibroblast growth factor receptor 4 polymorphisms on biochemical recurrence after radical prostatectomy in a Chinese population 
Scientific Reports  2016;6:33604.
Fibroblast growth factor receptor 4 (FGFR4) is a transmembrane receptor with ligand-induced tyrosine kinase activity and is involved in various biological and pathological processes. Several polymorphisms of FGFR4 are associated with the incidence and mortality of numerous cancers, including prostate cancer. In this study, we investigated whether the polymorphisms of FGFR4 influence the biochemical recurrence of prostate cancer in Chinese men after radical prostatectomy. Three common polymorphisms (rs1966265, rs2011077, and rs351855) of FGFR4 were genotyped from 346 patients with prostate cancer by using the Sequenom MassARRAY system. Kaplan–Meier curves and Cox proportional hazard models were used for survival analysis. Results showed biochemical recurrence (BCR) free survival was significantly affected by the genotypes of rs351855 but not influenced by rs1966265 and rs2011077. After adjusting for other variables in multivariable analysis, patients with rs351855 AA/AG genotypes showed significantly worse BCR-free survival than those with the GG genotype (HR = 1.873; 95% CI, 1.209–2.901; P = 0.005). Hence, FGFR4 rs351855 could be a novel independent prognostic factor of BCR after radical prostatectomy in the Chinese population. This functional polymorphism may also provide a basis for surveillance programs. Additional large-scale studies must be performed to validate the significance of this polymorphism in prostate cancer.
PMCID: PMC5027536  PMID: 27640814
3.  Sweroside ameliorates α-naphthylisothiocyanate-induced cholestatic liver injury in mice by regulating bile acids and suppressing pro-inflammatory responses 
Acta Pharmacologica Sinica  2016;37(9):1218-1228.
Sweroside is an iridoid glycoside with diverse biological activities. In the present study we investigated the effects of sweroside on α-naphthylisothiocyanate (ANIT)-induced cholestatic liver injury in mice.
Mice received sweroside (120 mg·kg−1·d−1, ig) or a positive control INT-747 (12 mg·kg−1·d−1, ig) for 5 d, and ANIT (75 mg/kg, ig) was administered on d 3. The mice were euthanized on d 5, and serum biochemical markers, hepatic bile acids and histological changes were analyzed. Hepatic expression of genes related to pro-inflammatory mediators and bile acid metabolism was also assessed. Primary mouse hepatocytes were exposed to a reconstituted mixture of hepatic bile acids, which were markedly elevated in the ANIT-treated mice, and the cell viability and expression of genes related to pro-inflammatory mediators were examined.
Administration of sweroside or INT-747 effectively ameliorated ANIT-induced cholestatic liver injury in mice, as evidenced by significantly reduced serum biochemical markers and attenuated pathological changes in liver tissues. Furthermore, administration of sweroside or INT-747 significantly decreased ANIT-induced elevation of individual hepatic bile acids, such as β-MCA, CA, and TCA, which were related to its effects on the expression of genes responsible for bile acid synthesis and transport as well as pro-inflammatory responses. Treatment of mouse hepatocytes with the reconstituted bile acid mixture induced significant pro-inflammatory responses without affecting the cell viability.
Sweroside attenuates ANIT-induced cholestatic liver injury in mice by restoring bile acid synthesis and transport to their normal levels, as well as suppressing pro-inflammatory responses.
PMCID: PMC5022106  PMID: 27498779
sweroside; INT-747; α-naphthylisothiocyanate; bile acids; cholestasis; hepatotoxicity; hepatocytes; inflammation
4.  Effect of Ulinastatin in the Treatment of Postperative Cognitive Dysfunction: Review of Current Literature 
BioMed Research International  2016;2016:2571080.
Background. Ulinastatin, identified as a urinary trypsin inhibitor, has been widely used in patients with inflammatory disorders. However, little is known about its effect on postoperative cognitive dysfunction (POCD). The aim of our current work is to review the current body of literature. Methods. A systematic literature search in PubMed and EMBASE was performed to identify randomized controlled trials. Incidence of POCD, MMSE score, and laboratory indicators (IL-6, TNF-α, CRP, and S100β) were selected as outcomes. Results. Five RCTs involving 461 elderly patients that underwent surgical operations were identified. The meta-analysis suggested no statistical difference of incidence of POCD between ulinastatin and control groups on postoperative day 1; but ulinastatin could significantly decrease the incidence of POCD on postoperative day 3 and day 7 when compared with control treatment. Ulinastatin was effective in improving the MMSE score on day 1, day 3, and day 7 after operation. IL-6 and S100β concentrations were lower up to postoperative day 2. The incidences of postoperative complications in ulinastatin groups were lower than control. Conclusion. Ulinastatin administration was effective in treating early POCD (postoperative day 3 and day 7) and reducing IL-6 and S100β concentrations within two days after operations. Studies with larger-scale and rigorous design are urgently needed.
PMCID: PMC5002304  PMID: 27597957
5.  Olig2 regulates Purkinje cell generation in the early developing mouse cerebellum 
Scientific Reports  2016;6:30711.
The oligodendrocyte transcription factor Olig2 plays a crucial role in the neurogenesis of both spinal cord and brain. In the cerebellum, deletion of both Olig2 and Olig1 results in impaired genesis of Purkinje cells (PCs) and Pax2+ interneurons. Here, we perform an independent study to show that Olig2 protein is transiently expressed in the cerebellar ventricular zone (VZ) during a period when PCs are specified. Further analyses demonstrate that Olig2 is expressed in both cerebellar VZ progenitors and early-born neurons. In addition, unlike in the ganglionic eminence of the embryonic forebrain where Olig2 is mostly expressed in proliferating progenitors, Olig2+ cells in the cerebellar VZ are in the process of leaving the cell cycle and differentiating into postmitotic neurons. Functionally, deletion of Olig2 alone results in a preferential reduction of PCs in the cerebellum, which is likely mediated by decreased neuronal generation from their cerebellar VZ progenitors. Furthermore, our long-term lineage tracing experiments show that cerebellar Olig gene-expressing progenitors produce PCs but rarely Pax2+ interneurons in the developing cerebellum, which opposes the “temporal identity transition” model of the cerebellar VZ progenitors stating that majority of Pax2+ interneuron progenitors are transitioned from Olig2+ PC progenitors.
PMCID: PMC4965836  PMID: 27469598
6.  Vaccination of Sheep with a Methanogen Protein Provides Insight into Levels of Antibody in Saliva Needed to Target Ruminal Methanogens 
PLoS ONE  2016;11(7):e0159861.
Methane is produced in the rumen of ruminant livestock by methanogens and is a major contributor to agricultural greenhouse gases. Vaccination against ruminal methanogens could reduce methane emissions by inducing antibodies in saliva which enter the rumen and impair ability of methanogens to produce methane. Presently, it is not known if vaccination can induce sufficient amounts of antibody in the saliva to target methanogen populations in the rumen and little is known about how long antibody in the rumen remains active. In the current study, sheep were vaccinated twice at a 3-week interval with a model methanogen antigen, recombinant glycosyl transferase protein (rGT2) formulated with one of four adjuvants: saponin, Montanide ISA61, a chitosan thermogel, or a lipid nanoparticle/cationic liposome adjuvant (n = 6/formulation). A control group of sheep (n = 6) was not vaccinated. The highest antigen-specific IgA and IgG responses in both saliva and serum were observed with Montanide ISA61, which promoted levels of salivary antibodies that were five-fold higher than the second most potent adjuvant, saponin. A rGT2-specific IgG standard was used to determine the level of rGT2-specific IgG in serum and saliva. Vaccination with GT2/Montanide ISA61 produced a peak antibody concentration of 7 × 1016 molecules of antigen-specific IgG per litre of saliva, and it was estimated that in the rumen there would be more than 104 molecules of antigen-specific IgG for each methanogen cell. Both IgG and IgA in saliva were shown to be relatively stable in the rumen. Salivary antibody exposed for 1–2 hours to an in vitro simulated rumen environment retained approximately 50% of antigen-binding activity. Collectively, the results from measuring antibody levels and stablility suggest a vaccination-based mitigation strategy for livestock generated methane is in theory feasible.
PMCID: PMC4966943  PMID: 27472482
7.  Salidroside ameliorates insulin resistance through activation of a mitochondria-associated AMPK/PI3K/Akt/GSK3β pathway 
British Journal of Pharmacology  2015;172(13):3284-3301.
Background and Purpose
Recent reports have suggested that salidroside could protect cardiomyocytes from oxidative injury and stimulate glucose uptake in skeletal muscle cells by activating AMP-activated protein kinase (AMPK). The aim of this study was to evaluate the therapeutic effects of salidroside on diabetic mice and to explore the underlying mechanisms.
Experimental Approach
The therapeutic effects of salidroside on type 2 diabetes were investigated. Increasing doses of salidroside (25, 50 and 100 mg·kg−1·day−1) were administered p.o. to db/db mice for 8 weeks. Biochemical analysis and histopathological examinations were conducted to evaluate the therapeutic effects of salidroside. Primary cultured mouse hepatocytes were used to further explore the underlying mechanisms in vitro.
Key Results
Salidroside dramatically reduced blood glucose and serum insulin levels and alleviated insulin resistance. Hypolipidaemic effects and amelioration of liver steatosis were observed after salidroside administration. In vitro, salidroside dose-dependently induced an increase in the phosphorylations of AMPK and PI3K/Akt, as well as glycogen synthase kinase 3β (GSK3β) in hepatocytes. Furthermore, salidroside-stimulated AMPK activation was found to suppress the expression of PEPCK and glucose-6-phosphatase. Salidroside-induced AMPK activation also resulted in phosphorylation of acetyl CoA carboxylase, which can reduce lipid accumulation in peripheral tissues. In isolated mitochondria, salidroside inhibited respiratory chain complex I and disturbed oxidation/phosphorylation coupling and moderately depolarized the mitochondrial membrane potential, resulting in a transient increase in the AMP/ATP ratio.
Conclusions and Implications
Salidroside exerts an antidiabetic effect by improving the cellular metabolic flux through the activation of a mitochondria-related AMPK/PI3K/Akt/GSK3β pathway
PMCID: PMC4500366  PMID: 25754463
8.  Erectile Dysfunction in Chronic Prostatitis/Chronic Pelvic Pain Syndrome: Outcomes from a Multi-Center Study and Risk Factor Analysis in a Single Center 
PLoS ONE  2016;11(4):e0153054.
The aim of this study was to investigate the prevalence of erectile dysfunction (ED) in patients with chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) and explore the influence of UPOINT domains, National Institutes of Health-CP symptom index (NIH-CPSI) and other factors on ED prevalence. This was a prospective study of consecutive patients with CP/CPPS seen at 11 tertiary hospitals during January–July 2014. ED was diagnosed as a score of<21 on the International Index of Erectile Function (IIEF-5). Patients from one center were evaluated by the UPOINT system and NIH-CPSI. Each patient was assessed using clinical examination, asocio-demographic questionnaire, the Patient Health Questionnaire (PHQ), the Pain Catastrophizing Scale (PCS), NIH-CPSI and IIEF-5.1406 patients from 11 centers (mean age, 32.18 years; range 18–60 years) were enrolled. ED was found in 638/1406 patients (45.4%), and was categorized as mild in 291(45.6%), moderate in 297(46.6%) and severe in50(7.7%). 192 patients from one center(mean age,31.3 years; range 18–57 years) were further studied.IIEF-5 score correlated negatively with NIH-CPSI(r = 0.251), PHQ (r = 0.355) and PCS (r = 0.322)scores (P<0.001).PHQ score correlated positively with NIH-CPSI (r = 0.586) and PCS(r = 0.662) scores (P<0.001).NIH-CPSI, PHQ, PCS and IIEF-5 scores did not differ significantly between class IIIA and IIIB CP/CPPS. Multivariate logistic regression showed that UPOINT psychological (P) domain and NIH-CPSI symptom severity were independent risk factors for ED in CP/CPPS. It is concluded that psychological factors and symptom severity are independent risk factors for ED in CP/CPPS.
PMCID: PMC4847827  PMID: 27120096
9.  The Clinical Effect of Acupuncture in the Treatment of Obstructive Sleep Apnea: A Systematic Review and Meta-Analysis of Randomized Controlled Trials 
Purpose. This study aims to determine the clinical efficacy of acupuncture therapy in the treatment of obstructive sleep apnea. Methods. A systematic literature search was conducted in five databases including PubMed, EMBASE, CENTRAL, Wanfang, and CNKI to identify randomized controlled trials (RCTs) on the effect of acupuncture therapy for obstructive sleep apnea. Meta-analysis was conducted using the RevMan version 5.3 software. Results. Six RCTs involving 362 subjects were included in our study. Compared with control groups, manual acupuncture (MA) was more effective in the improvement of apnea/hypopnea index (AHI), apnea index, hypopnea index, and mean SaO2. Electroacupuncture (EA) was better in improving the AHI and apnea index when compared with control treatment, but no statistically significant differences in hypopnea index and mean SaO2 were found. In the comparison of MA and nasal continuous positive airway pressure, the results favored MA in the improvement of AHI; there was no statistical difference in the improvement in mean SaO2. No adverse events associated with acupuncture therapy were documented. Conclusion. Compared to control groups, both MA and EA were more effective in improving AHI and mean SaO2. In addition, MA could further improve apnea index and hypopnea index compared to control.
PMCID: PMC4834396  PMID: 27127530
10.  AB036. Effects and its potential mechanisms of Cox-2 inhibitors on ejaculation latency of rat with experimental autoimmune prostatitis 
Translational Andrology and Urology  2016;5(Suppl 1):AB036.
To investigate the effects and its potential mechanisms of Cox-2 inhibitors on ejaculation latency of rat with experimental autoimmune prostatitis (EAP).
Thirty six male Wistar rats with normal sexual function were screened by using the copulatory test, and were randomly divided into 3 groups: the model group (n=16), the normal control group (n=10) and the celecoxib treatment group (n=10). EAP rat model was established in the model group and the celecoxib treatment group by subcutaneous multiple point’s injection of male prostate gland extract emulsified in an equal volume of Freund’s adjuvant at the 0 and 21th day. Control animals received equal volume of saline. From the 0th day, the celecoxib treatment group was given a gavage of celecoxib (18 mg·kg-1·d-1), the model group and the normal control group were given a gavage of saline (0.1 mL·kg-1·d-1). Eight weeks later, the sexual behavior was investigated by the copulatory test, the morphological change of prostatic tissue was observed by light microscopy after HE staining, cytokines (TNF-α, IL-1β) in serum were detected by ELISA, the levels of 5-HT, 5-HT1A receptor, 5-HT2C receptor and SERT in T13-L2 and L5-S2 spinal cord tissue were detected by immunohistochemical staining and Western Blot.
In model group, prostatic inflammation was found in 12 rats, and not in another 4 rats. The 4 rats were not included in the statistical analysis. In normal control group, prostatic inflammation was not found. In the celecoxib treatment group, there was a small amount of interstitial infiltration of inflammatory cells in rat’s prostate. In the copulatory test, compared with normal control group, mount latency (ML) and intromission latency (IL) in the model group were significantly prolonged (P<0.05); ejaculation latency (EL) in the model group was significantly shortened (P<0.05). There was no significant difference in these sexual behavior parameters between the normal control group and the celecoxib treatment group (P>0.05). Serum IL-1β and TNF-α levels in the model group were significantly higher than that in the control group (P<0.01). There was no significant difference in the levels of IL-1β and TNF-α between the normal control group and the celecoxib treatment group (P>0.05). In T13-L2 spinal cord tissue, compared with normal control group, 5-HT levels in the model group were significantly lower (P<0.05), 5-HT1A receptor levels in the model group were significantly increased (P<0.05), while the 5-HT2C receptor and SERT levels in the model group did not change significantly (P>0.05). In L5-S2 spinal cord tissues, compared with normal control group, 5-HT levels in the model group were significantly lower (P<0.05), while the 5-HT1A, 5-HT2C and SERT levels in the model group increased slightly, but the differences in 5-HT1A, 5-HT2C and SERT levels between the model group and the normal control group were statistically significant (P<0.05). There were not significant differences in 5-HT, 5-HT1A, 5-HT2C and SERT levels between the normal control group and the celecoxib treatment group (P>0.05).
EAP shorten rat’s EL by changing the levels of 5-HT and its receptors, SERT in spinal cord. Cox-2 inhibitors can prolong EL of EAP rat, the mechanisms might be that it can relieve inflammation of the prostate, reverse the effect of EAP on spinal cord 5-HT transmitter system. Cox-2 inhibitors can be used in the treatment of premature ejaculation caused by prostatitis.
PMCID: PMC4842501
Experimental autoimmune prostatitis (EAP); ejaculation latency (EL); premature ejaculation; Cox-2 inhibitors; serotonin
11.  Src homology 2 domain–containing inositol 5-phosphatase 1 deficiency leads to a spontaneous allergic inflammation in the murine lung 
Src homology 2 domain–containing inositol 5-phosphatase 1 (SHIP-1) controls the intracellular level of the phosphoinositide 3–kinase product phosphotidylinositol-3,4,5-trisphosphate and functions as a negative regulator of cytokine and immune receptor signaling. Emerging evidence suggests that the phosphoinositide 3-kinase pathway might be involved in allergic inflammation in the lung. However, the functional relevance of SHIP-1 in the TH2 activation pathway has not been established. SHIP-1−/− mice have spontaneous myeloproliferative inflammation in the lung, the nature of which has not been elucidated. We hypothesized that SHIP-1 plays an important role as a regulator in pulmonary allergic inflammation and in maintaining lung homeostasis.
To test our hypothesis, we characterized the pulmonary phenotype of SHIP-1−/− mice.
Analyses of lung histopathology and bronchoalveolar lavage cellularity revealed that the majority of SHIP-1−/− mice had progressive and severe pulmonary inflammation of macrophages, lymphocytes, neutrophils, and eosinophils; mucous hyperplasia; airway epithelial hypertrophy; and subepithelial fibrosis. These pathologic changes were accompanied by exaggerated production of TH2 cytokines and chemokines, including IL-4, IL-13, eotaxin, and monocyte chemoattractant protein 1, in the lung. Furthermore, the number of mast cells significantly increased, and many of these cells were undergoing degranulation, which was correlated with increased content and spontaneous release of histamine in the lung tissue of SHIP-1−/− mice.
These findings provide strong evidence that mice lacking SHIP-1 have an allergic inflammation in the lung, suggesting that SHIP-1 plays an important role in regulating the TH2 signaling pathway and in maintaining lung homeostasis.
Clinical implications
SHIP-1 as a regulator might be a potential therapeutic target for controlling allergic inflammation in diseases such as asthma.
PMCID: PMC4757810  PMID: 17208593
Phosphatase; phosphoinositide 3-kinase; signaling; TH2 inflammation; asthma; allergy
12.  Embryonal Control of Yellow Seed Coat Locus ECY1 Is Related to Alanine and Phenylalanine Metabolism in the Seed Embryo of Brassica napus 
G3: Genes|Genomes|Genetics  2016;6(4):1073-1081.
Seed coat color is determined by the type of pigment deposited in the seed coat cells. It is related to important agronomic traits of seeds such as seed dormancy, longevity, oil content, protein content and fiber content. In Brassica napus, inheritance of seed coat color is related to maternal effects and pollen effects (xenia effects). In this research we isolated a mutation of yellow seeded B. napus controlled by a single Mendelian locus, which is named Embryonal Control of Yellow seed coat 1 (Ecy1). Microscopy of transverse sections of the mature seed show that pigment is deposited only in the outer layer of the seed coat. Using Illumina Hisequation 2000 sequencing technology, a total of 12 GB clean data, 116× coverage of coding sequences of B. napus, was achieved from seeds 26 d after pollination (DAP). It was assembled into 172,238 independent transcripts, and 55,637 unigenes. A total of 139 orthologous genes of Arabidopsis transparent testa (TT) genes were mapped in silico to 19 chromosomes of B. napus. Only 49 of the TT orthologous genes are transcribed in seeds. However transcription of all orthologs was independent of embryonal control of seed coat color. Only 55 genes were found to be differentially expressed between brown seeds and the yellow mutant. Of these 55, 50 were upregulated and five were downregulated in yellow seeds as compared to their brown counterparts. By KEGG classification, 14 metabolic pathways were significantly enriched. Of these, five pathways: phenylpropanoid biosynthesis, cyanoamino acid metabolism, plant hormone signal transduction, metabolic pathways, and biosynthesis of secondary metabolites, were related with seed coat pigmentation. Free amino acid quantification showed that Ala and Phe were present at higher levels in the embryos of yellow seeds as compared to those of brown seeds. This increase was not observed in the seed coat. Moreover, the excess amount of free Ala was exactly twice that of Phe in the embryo. The pigment substrate chalcone is synthesized from two molecules of Ala and one molecule of Phe. The correlation between accumulation of Ala and Phe, and disappearance of pigment in the yellow seeded mutant, suggests that embryonal control of seed coat color is related with Phe and Ala metabolism in the embryo of B. napus.
PMCID: PMC4825642  PMID: 26896439
Brassica napus; yellow seed coat; xenia effect; free amino acids; transcriptome sequencing
13.  SHP-1 Deficient Mast Cells Are Hyperresponsive to Stimulation and Critical in Initiating Allergic Inflammation in the Lung 
Phosphatase Src homology region 2 domain-containing phosphatase 1 (SHP-1)-deficient mice display an allergic asthma phenotype that is largely IL-13 and STAT6 dependent. The cell types responsible for the Th2 phenotype have not been identified. We hypothesized that SHP-1 deficiency leads to mast cell dysregulation and increased production and release of mediators and Th2 cytokines, leading to the allergic asthma phenotype. We examined SHP-1 regulation of mast cell differentiation, survival, and functional responses to stimulation using bone marrow-derived mast cells from viable motheaten (mev) mice. We assessed pulmonary phenotypical changes in mev mice on the mast cell-deficient KitW-Sh genetic background. The results showed that SHP-1 deficiency led to increased differentiation and survival, but reduced proliferation, of mast cells. SHP-1–deficient mast cells produced and released increased amounts of mediators and Th2 cytokines IL-4 and -13 spontaneously and in response to H2O2, LPS, and FcεI cross-linking, involving c-Kit–dependent and –independent processes. The FcεRI signaling led to binding of SHP-1 to linker for activation of T cells 2 and enhanced linker for activation of T cells 2 phosphorylation in mev bone marrow-derived mast cells. Furthermore, the number of mast cells in the lung tissue of mev mice was increased and mast cell production and release of Th2 cytokines were distinctly increased upon FcεRI stimulation. When backcrossed to the KitW-Sh background, mev mice had markedly reduced pulmonary inflammation and Th2 cytokine production. These findings demonstrate that SHP-1 is a critical regulator of mast cell development and function and that SHP-1–deficient mast cells are able to produce increased Th2 cytokines and initiate allergic inflammatory responses in the lung.
PMCID: PMC4755278  PMID: 20042576
14.  The RNA helicase, eIF4A‐1, is required for ovule development and cell size homeostasis in Arabidopsis 
The Plant Journal  2015;84(5):989-1004.
eIF4A is a highly conserved RNA‐stimulated ATPase and helicase involved in the initiation of mRNA translation. The Arabidopsis genome encodes two isoforms, one of which (eIF4A‐1) is required for the coordination between cell cycle progression and cell size. A T‐DNA mutant eif4a1 line, with reduced eIF4A protein levels, displays slow growth, reduced lateral root formation, delayed flowering and abnormal ovule development. Loss of eIF4A‐1 reduces the proportion of mitotic cells in the root meristem and perturbs the relationship between cell size and cell cycle progression. Several cell cycle reporter proteins, particularly those expressed at G2/M, have reduced expression in eif4a1 mutant meristems. Single eif4a1 mutants are semisterile and show aberrant ovule growth, whereas double eif4a1 eif4a2 homozygous mutants could not be recovered, indicating that eIF4A function is essential for plant growth and development.
Significance Statement
While transcriptional control mechanisms in cell cycle progression and development have been extensively dissected, less is known about the role of translation. Here we show that an Arabidopsis TDNA mutant with reduced levels of the translation initiation factor eIF4A exhibits several growth defects suggesting that eIF4A‐1 is required for normal cell cycle progression and coordination of cell division with cell growth.
PMCID: PMC4737287  PMID: 26493293
cell cycle; plant growth; translation factor; RNA helicase; DEAD‐box helicase; cell size homeostasis; Arabidopsis thaliana
15.  Astragaloside IV inhibits microglia activation via glucocorticoid receptor mediated signaling pathway 
Scientific Reports  2016;6:19137.
Inhibition of microglia activation may provide therapeutic treatment for many neurodegenerative diseases. Astragaloside IV (ASI) with anti-inflammatory properties has been tested as a therapeutic drug in clinical trials of China. However, the mechanism of ASI inhibiting neuroinflammation is unknown. In this study, we showed that ASI inhibited microglia activation both in vivo and in vitro. It could enhance glucocorticoid receptor (GR)-luciferase activity and facilitate GR nuclear translocation in microglial cells. Molecular docking and TR-FRET GR competitive binding experiments demonstrated that ASI could bind to GR in spite of relative low affinity. Meanwhile, ASI modulated GR-mediated signaling pathway, including dephosphorylation of PI3K, Akt, I κB and NF κB, therefore, decreased downstream production of proinflammatory mediators. Suppression of microglial BV-2 activation by ASI was abrogated by GR inhibitor, RU486 or GR siRNA. Similarly, RU486 counteracted the alleviative effect of ASI on microgliosis and neuronal injury in vivo. Our findings demonstrated that ASI inhibited microglia activation at least partially by activating the glucocorticoid pathway, suggesting its possible therapeutic potential for neuroinflammation in neurological diseases.
PMCID: PMC4707476  PMID: 26750705
16.  Cep57 is a Mis12-interacting kinetochore protein involved in kinetochore targeting of Mad1–Mad2 
Nature Communications  2016;7:10151.
The spindle assembly checkpoint (SAC) arrests cells in mitosis by sensing unattached kinetochores, until all chromosomes are bi-oriented by spindle microtubules. Kinetochore accumulation of the SAC component Mad1–Mad2 is crucial for SAC activation. However, the mechanism by which Mad1–Mad2 accumulation at kinetochores is regulated is not clear. Here we find that Cep57 is localized to kinetochores in human cells, and binds to Mis12, a KMN (KNL1/Mis12 complex/Ndc80 complex) network component. Cep57 also interacts with Mad1, and depletion of Cep57 results in decreased kinetochore localization of Mad1–Mad2, reduced SAC signalling and increased chromosome segregation errors. We also show that the microtubule-binding activity of Cep57 is involved in the timely removal of Mad1 from kinetochores. Thus, these findings reveal that the KMN network-binding protein Cep57 is a mitotic kinetochore component, and demonstrate the functional connection between the KMN network and the SAC.
The spindle assembly checkpoint relies on the accumulation of Mad1-Mad2 at kinetochores, but the mechanism of regulation is not known. Here Zhou et al. show that the centrosomal protein Cep57 interacts with the kinetochore proteins Mis12 and Mad1, and regulates the recruitment of Mad1/Mad2 to kinetochores.
PMCID: PMC4729865  PMID: 26743940
17.  Neurotrophic Effect of Adipose Tissue-Derived Stem Cells on Erectile Function Recovery by Pigment Epithelium-Derived Factor Secretion in a Rat Model of Cavernous Nerve Injury 
Stem Cells International  2015;2016:5161248.
The paracrine effect is the major mechanism of stem cell therapy. However, the details of the effect's mechanism remain unknown. The aim of this study is to investigate whether adipose tissue-derived stem cells (ADSCs) can ameliorate cavernous nerve injury-induced erectile dysfunction (CNIED) rats and to determine its mechanism. Twenty-eight days after intracavernous injection of 5-ethynyl-2-deoxyuridine- (EdU-) labeled ADSCs, the erectile function of all the rats was evaluated by intracavernosal pressure (ICP). The ADSCs steadily secreted detectable pigment epithelium-derived factor (PEDF) in vitro. The expression of PEDF increased in the penis of the bilateral cavernous nerve injury (BCNI) group for 14 days and then gradually decreased. On day 28 after the intracavernous injection, the ADSCs group exhibited a significantly increased ICP compared with the phosphate buffered saline- (PBS-) treated group. Moreover, the neuronal nitric oxide synthase (nNOS) and S100 expression in penile dorsal nerves and the smooth muscle content to collagen ratio in penile tissues significantly increased. Furthermore, elevated PEDF, p-Akt, and p-eNOS were identified in the ADSCs group. This study demonstrated that intracavernous injection of ADSCs improved erectile function, repaired the nerve, and corrected penile fibrosis. One potential mechanism is the PEDF secretion of ADSCs and subsequent PI3K/Akt pathway activation.
PMCID: PMC4691496  PMID: 26783403
18.  All-trans retinoic acid regulates hepatic bile acid homeostasis 
Biochemical pharmacology  2014;91(4):483-489.
Retinoic acid (RA) and bile acids share common roles in regulating lipid homeostasis and insulin sensitivity. In addition, the receptor for RA (retinoid x receptor) is a permissive partner of the receptor for bile acids, farnesoid x receptor (FXR/NR1H4). Thus, RA can activate the FXR-mediated pathway as well. The current study was designed to understand the effect of all-trans RA on bile acid homeostasis. Mice were fed an all-trans RA-supplemented diet and the expression of 46 genes that participate in regulating bile acid homeostasis was studied. The data showed that all-trans RA has a profound effect in regulating genes involved in synthesis and transport of bile acids. All-trans RA treatment reduced the gene expression levels of Cyp7a1, Cyp8b1, and Akr1d1, which are involved in bile acid synthesis. All-trans RA also decreased the hepatic mRNA levels of Lrh-1 (Nr5a2) and Hnf4α (Nr2a1), which positively regulate the gene expression of Cyp7a1 and Cyp8b1. Moreover, all-trans RA induced the gene expression levels of negative regulators of bile acid synthesis including hepatic Fgfr4, Fxr, and Shp (Nr0b2) as well as ileal Fgf15. All-trans RA also decreased the expression of Abcb11 and Slc51b, which have a role in bile acid transport. Consistently, all-trans RA reduced hepatic bile acid levels and the ratio of CA/CDCA, as demonstrated by liquid chromatography-mass spectrometry. The data suggest that all-trans RA-induced SHP may contribute to the inhibition of CYP7A1 and CYP8B1, which in turn reduces bile acid synthesis and affects lipid absorption in the gastrointestinal tract.
PMCID: PMC4236914  PMID: 25175738
liver; nuclear receptor; FXR; SHP; CYP7A1; CYP8B1
19.  The implantation of a Nickel-Titanium shape memory alloy ameliorates vertebral body compression fractures: a cadaveric study 
Objective: To evaluate the effect of a Nickel-Titanium (Ni-Ti) shape memory alloy in the treatment of vertebral body compression fractures. Methods: The experimental thoracic-lumbar fracture units were made with adult human fresh-frozen vertebral specimens. A total of 30 fresh-frozen vertebral units were randomly assigned to 3 experimental groups: control group, percutaneous kyphoplasty group (PKP group), and percutaneous Ni-Ti shape memory alloys implant group (Ni-Ti implant group). Vertebral height and ultimate compression load of the vertebral body before and after procedures were measured to determine the restoration of vertebral heights and compressive strength, respectively. Results: The Ni-Ti implant group achieved a vertebrae endplate reduction effect comparable to the PKP group. The vertebral height of the PKP group was restored from 2.01±0.21 cm to 2.27±0.18 cm after procedure, whereas that of the Ni-Ti implant group was restored from 2.00±0.18 cm to 2.31±0.17 cm. The ultimate loads of the vertebrae body of the PKP and the Ni-Ti implant groups were 2880.75±126.17 N and 2888.00±144.69 N, respectively, both of which were statistically significantly higher than that of the control group (2017.17±163.71 N). There was no significant difference in ultimate compression load of vertebrae body between the Ni-Ti implant and PKP groups. Conclusions: The implantation of Ni-Ti shape memory alloys of vertebral body induced effective endplate reduction, restored vertebral height, and provided immediate biomechanical spinal stability.
PMCID: PMC4659129  PMID: 26629241
Osteoporosis; Ni-Ti shape memory alloys; ultimate load; endplate reduction
20.  PNPLA3 I148M variant affects non-alcoholic fatty liver disease in liver transplant recipients 
World Journal of Gastroenterology : WJG  2015;21(34):10054-10056.
De novo non-alcoholic fatty liver disease (NAFLD) is a common late complication for long-term survivors after liver transplantation. Genomic studies confirmed that PNPLA3 I148M and TM6SF2 E167K polymorphisms affected NAFLD susceptibility in the general population. However, this association was not validated in survivors after liver transplantation (LT). We performed a cross-sectional survey to investigate this relationship. A comprehensive survey, including anthropometric measurements, fasting venous blood sampling, ultrasound, and questionnaires was performed in the short-term. The clinical indications and patient’s steatosis status before LT were collected from inpatient medical records. Sixty-five long-term recipients with a survival exceeding 10 years were enrolled in the final analysis. De novo NAFLD was more frequent in PNPLA3 GG carriers (0.33 vs 0.10 for GG vs CC + CG carriers, P = 0.018), while the genetic impact on NAFLD susceptibility was insignificant when categorized by the TM6SF2 polymorphism (0.19 in CC vs 0.14 in CT + TT carriers, P = 0.883). Multi-covariate analysis revealed that PNPLA3 exerted a significant genetic effect on de novo NAFLD following a recessive model (GG vs CC + CG, OR = 14.2, 95%CI: 1.78-113, P = 0.012). Compared to recipients with only the PNPLA3 GG allele or obesity (defined as body mass index > 25 kg/m2), steatosis was highly prevalent (71.4%) in PNPLA3 GG carriers with obesity. In conclusion, PNPLA3 I148M, but not TM6SF2 E167K, affects de novo NAFLD occurrence with a prominent interaction with obesity. Weight control might be a meaningful method to reduce the genetic susceptibility to NAFLD exerted by PNPLA3 variants.
PMCID: PMC4566377  PMID: 26379412
PNPLA3; TM6SF2; Non-alcoholic fatty liver disease; Liver transplantation; Recipient
22.  Numerical Methods for the Analysis of Power Transformer Tank Deformation and Rupture Due to Internal Arcing Faults 
PLoS ONE  2015;10(7):e0133851.
Power transformer rupture and fire resulting from an arcing fault inside the tank usually leads to significant security risks and serious economic loss. In order to reveal the essence of tank deformation or explosion, this paper presents a 3-D numerical computational tool to simulate the structural dynamic behavior due to overpressure inside transformer tank. To illustrate the effectiveness of the proposed method, a 17.3MJ and a 6.3MJ arcing fault were simulated on a real full-scale 360MVA/220kV oil-immersed transformer model, respectively. By employing the finite element method, the transformer internal overpressure distribution, wave propagation and von-Mises stress were solved. The numerical results indicate that the increase of pressure and mechanical stress distribution are non-uniform and the stress tends to concentrate on connecting parts of the tank as the fault time evolves. Given this feature, it becomes possible to reduce the risk of transformer tank rupture through limiting the fault energy and enhancing the mechanical strength of the local stress concentrative areas. The theoretical model and numerical simulation method proposed in this paper can be used as a substitute for risky and costly field tests in fault overpressure analysis and tank mitigation design of transformers.
PMCID: PMC4521797  PMID: 26230392
23.  In vitro analysis of phosphorothioate modification of DNA reveals substrate recognition by a multiprotein complex 
Scientific Reports  2015;5:12513.
A wide variety of prokaryotes possess DNA modifications consisting of sequence-specific phosphorothioates (PT) inserted by members of a five-gene cluster. Recent genome mapping studies revealed two unusual features of PT modifications: short consensus sequences and partial modification of a specific genomic site in a population of bacteria. To better understand the mechanism of target selection of PT modifications that underlies these features, we characterized the substrate recognition of the PT-modifying enzymes termed DptC, D and E in a cell extract system from Salmonella. The results revealed that double-stranded oligodeoxynucleotides underwent de novo PT modification in vitro, with the same modification pattern as in vivo, i. e., GpsAAC/GpsTTC motif. Unexpectedly, in these in vitro analyses we observed no significant effect on PT modification by sequences flanking GAAC/GTTC motif, while PT also occurred in the GAAC/GTTC motif that could not be modified in vivo. Hemi-PT DNA also served as substrate of the PT-modifying enzymes, but not single-stranded DNA. The PT-modifying enzymes were then found to function as a large protein complex, with all of three subunits in tetrameric conformations. This study provided the first demonstration of in vitro DNA PT modification by PT-modifying enzymes that function as a large protein complex.
PMCID: PMC4515589  PMID: 26213215
24.  MiR-1188 at the imprinted Dlk1-Dio3 domain acts as a tumor suppressor in hepatoma cells 
Molecular Biology of the Cell  2015;26(8):1416-1427.
MiR-1188 at the imprinted Dlk1-Dio3 domain is a novel player in hepatocellular carcinoma. MiR-1188 expression was found to be decreased in hepatoma cells, and, when overexpressed, miR-1188 inhibited Bcl2 and Sp1 expression, suppressed cell proliferation and migration, promoted apoptosis in vitro, and inhibited tumor growth in vivo.
The aberrant expression of microRNAs (miRNAs) has frequently been reported in cancer studies; miRNAs play roles in development, progression, metastasis, and prognosis. Recent studies indicate that the miRNAs within the Dlk1-Dio3 genomic region are involved in the development of liver cancer, but the role of miR-1188 in hepatocellular carcinoma (HCC) and the pathway by which it exerts its function remain largely unknown. Here we demonstrate that miR-1188 is significantly down-regulated in mouse hepatoma cells compared with normal liver tissues. Enhanced miR-1188 suppresses cell proliferation, migration, and invasion in vitro and inhibits the tumor growth of HCC cells in vivo. Moreover, overexpressed miR-1188 promotes apoptosis, enhances caspase-3 activity, and also up-regulates the expression of Bax and p53. MiR-1188 directly targets and negatively regulates Bcl-2 and Sp1. Silencing of Bcl-2 and Sp1 exactly copies the proapoptotic and anti-invasive effects of miR-1188, respectively. The expression of apoptosis- and invasion-related genes, such as Vegfa, Fgfr1, and Rprd1b, decreases after enhancement of miR-1188, as determined by gene expression profiling analysis. Taken together, our results highlight an important role for miR-1188 as a tumor suppressor in hepatoma cells and imply its potential role in cancer therapy.
PMCID: PMC4395123  PMID: 25694452
25.  Efficacy of Acupuncture in Children with Nocturnal Enuresis: A Systematic Review and Meta-Analysis of Randomized Controlled Trials 
Background. Nocturnal enuresis (NE) is recognized as a widespread health problem in young children and adolescents. Clinical researches about acupuncture therapy for nocturnal enuresis are increasing, while systematic reviews assessing the efficacy of acupuncture therapy are still lacking. Objective. This study aims to assess the effectiveness of acupuncture therapy for nocturnal enuresis. Materials and Methods. A comprehensive literature search of 8 databases was performed up to June 2014; randomized controlled trials which compared acupuncture therapy and placebo treatment or pharmacological therapy were identified. A meta-analysis was conducted. Results. This review included 21 RCTs and a total of 1590 subjects. The overall methodological qualities were low. The results of meta-analysis showed that acupuncture therapy was more effective for clinical efficacy when compared with placebo or pharmacological treatment. Adverse events associated with acupuncture therapy were not documented. Conclusion. Based on the findings of this study, we cautiously suggest that acupuncture therapy could improve the clinical efficacy. However, the beneficial effect of acupuncture might be overstated due to low methodological qualities. Rigorous high quality RCTs are urgently needed.
PMCID: PMC4488007  PMID: 26167190

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