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1.  Synaptic mutant huntingtin inhibits synapsin-1 phosphorylation and causes neurological symptoms 
The Journal of Cell Biology  2013;202(7):1123-1138.
Polyglutamine-expanded huntingtin specifically targeted to synapses binds to synapsin-1, inhibits its phosphorylation, and causes defects in neurotransmitter release and age-dependent defects in neurological function.
Many genetic mouse models of Huntington’s disease (HD) have established that mutant huntingtin (htt) accumulates in various subcellular regions to affect a variety of cellular functions, but whether and how synaptic mutant htt directly mediates HD neuropathology remains to be determined. We generated transgenic mice that selectively express mutant htt in the presynaptic terminals. Although it was not overexpressed, synaptic mutant htt caused age-dependent neurological symptoms and early death in mice as well as defects in synaptic neurotransmitter release. Mass spectrometry analysis of synaptic fractions and immunoprecipitation of synapsin-1 from HD CAG150 knockin mouse brains revealed that mutant htt binds to synapsin-1, a protein whose phosphorylation is critical for neurotransmitter release. We found that polyglutamine-expanded exon1 htt binds to the C-terminal region of synapsin-1 to reduce synapsin-1 phosphorylation. Our findings point to a critical role for synaptic htt in the neurological symptoms of HD, providing a new therapeutic target.
PMCID: PMC3787372  PMID: 24081492
2.  Screening plasma miRNAs as biomarkers for renal ischemia-reperfusion injury in rats 
Acute kidney injury is a common clinical comorbidity and early diagnosis is crucial for improving prognosis, but there is still no ideal biomarker for early diagnosis.
miRNA microarray was used for detecting miRNA in kidney subjected to renal ischemia-reperfusion injury 12 h after reperfusion. Real-time PCR was performed to validate the results of microarray. miRNAs in the ischemia group were twice as high as in the sham group. Kidney-enriched miR-10a, miR-192, and miR-194 were detected in rat plasma to screen potential biomarkers for renal ischemia-reperfusion injury. Aberrant expressed miRNA in plasma at 12 h were further detected at 1 h, 2 h, 6 h, 12 h, and 24 h to observe the changing trend of these miRNAs and were compared to blood urea nitrogen and serum creatinine.
Thirty-six miRNAs were aberrantly expressed in kidney of rats with renal ischemia-reperfusion injury, among which 15 miRNAs had a 2-fold greater change. Results of real-time PCR were generally in accordance with microarray results. Levels of the 15 miRNAs differentially expressed in injured kidney were not significantly different from those in sham kidney. However, miR-10a, miR-192, and miR-194 were significantly increased in plasma of rats with renal ischemia-reperfusion injury, among which miR-10a was elevated within 1 h after reperfusion, whereas miR-192 and miR-194 were elevated at 6 h after injury. Blood urea nitrogen was increased at 12 h and serum creatinine was increased at 6 h after injury.
Plasma miR-10a, miR-192, and miR-194 were potential biomarkers for renal ischemia reperfusion injury in rats, and miR-10a might be the most promising plasma biomarker for renal injury because of its elevation within 1 h after renal injury, as well as renal specificity.
PMCID: PMC3937038  PMID: 24553149
Reperfusion Injury; Acute Kidney Injury; Biological Markers; MicroRNAs
3.  Association between the PARP1 Val762Ala Polymorphism and Cancer Risk: Evidence from 43 Studies 
PLoS ONE  2014;9(1):e87057.
Poly (ADP-ribose) polymerase-1 (PARP-1) plays critical roles in the detection and repair of damaged DNA, as well as cell proliferation and death. Numerous studies have examined the associations between PARP1 Val762Ala (rs1136410 T>C) polymorphism and cancer susceptibility; nevertheless, the findings from different research groups remain controversial.
We searched literatures from MEDLINE, EMBASE and CBM pertaining to such associations, and then calculated pooled odds ratio (OR) and 95% confidence interval (CI) by using random-effects model. The false-positive report probability (FPRP) analysis was used to confirm the validity of significant findings. Moreover, potential effects of rs1136410 variants on PARP1 mRNA expression were analyzed for three ethnicities by combining data from HapMap (genotype) and SNPexp (mRNA expression).
The final meta-analysis incorporated 43 studies, consisting of 17,351 cases and 22,401 controls. Overall, our results did not suggest significant associations between Ala variant (Ala/Ala or Ala/Val genotype) and cancer risk. However, further stratification analysis showed significantly increased risk for gastric cancer (Ala/Ala vs. Val/Val: OR = 1.56, 95% CI = 1.01–2.42, Ala/Val vs. Val/Val: OR = 1.34, 95% CI = 1.14–1.58, dominant model: OR = 1.41, 95% CI = 1.21–1.65 and Ala vs. Val: OR = 1.29, 95% CI = 1.07–1.55). On the contrary, decreased risk for brain tumor (Ala/Val vs. Val/Val: OR = 0.77, 95% CI = 0.68–0.87, dominant model: OR = 0.77, 95% CI = 0.68–0.87 and Ala vs. Val: OR = 0.82, 95% CI = 0.74–0.91). Additionally, we found that the Ala carriers had a significantly increased risk in all models for Asians. Our mRNA expression data provided further biological evidence to consolidate this finding.
Despite some limitations, this meta-analysis found evidence for an association between the PAPR1 Val762Ala and cancer susceptibility within gastric cancer, brain tumor and Asian subgroups.
PMCID: PMC3904982  PMID: 24489833
4.  Bright/Arid3A Acts as a Barrier to Somatic Cell Reprogramming through Direct Regulation of Oct4, Sox2, and Nanog 
Stem Cell Reports  2014;2(1):26-35.
We show here that singular loss of the Bright/Arid3A transcription factor leads to reprograming of mouse embryonic fibroblasts (MEFs) and enhancement of standard four-factor (4F) reprogramming. Bright-deficient MEFs bypass senescence and, under standard embryonic stem cell (ESC) culture conditions, spontaneously form clones that in vitro express pluripotency markers, differentiate to all germ lineages, and in vivo form teratomas and chimeric mice. We demonstrate that BRIGHT binds directly to the promoter/enhancer regions of Oct4, Sox2, and Nanog to contribute to their repression in both MEFs and ESCs. Thus, elimination of the BRIGHT barrier may provide an approach for somatic cell reprogramming.
•Loss of Bright can alone reprogram or enhance conventional four-factor reprogramming•Bright directly represses Oct4, Sox2, and Nanog•Bright may function in somatic and embryonic stem cells to enforce differentiation
Popowski et al. show that loss of the transcription factor Bright/Arid3A induces reprogramming in mouse embryonic fibroblasts (MEFs) and enhancement of standard four-factor reprograming. Bright-deficient reprogrammed cells express all pluripotency markers and are capable of forming teratomas and chimeric mice. Bright binds directly to the promoter/enhancer regions of Oct4, Sox2, and Nanog and contributes to their repression in both MEFs and embryonic stem cells.
PMCID: PMC3916758  PMID: 24511468
5.  Doxycycline Prevents Matrix Remodeling and Contraction by Trichiasis-Derived Conjunctival Fibroblasts 
Trachoma is a conjunctival scarring disease, which is the leading infectious cause of blindness worldwide. Elimination of blinding trachoma is being held back by the high rate of trichiasis recurrence following surgery. There is currently no treatment available to suppress the profibrotic state and reduce recurrence. Although the mechanisms underlying trichiasis development are unknown, the profibrotic phenotype has been linked to matrix metalloproteinase (MMP) expression. Doxycycline, a well-known tetracycline antibiotic, can act as a broad MMP inhibitor and has showed some success in preventing fibrosis in various clinical contexts. The purpose of this work was to assess the antiscarring properties of doxycycline in an in vitro model of trichiasis fibroblast–mediated tissue contraction.
Primary cultures of fibroblasts were established from conjunctival samples obtained from normal donors or during surgery for trachomatous trichiasis. The effect of doxycycline on matrix contraction was investigated in our standard collagen gel contraction model. Cell morphology and matrix integrity were assessed using confocal reflection microscopy. Quantitative real time polymerase chain reaction and a FRET-based assay were used to measure MMP expression and activity, respectively.
Doxycycline treatment successfully suppressed the contractile phenotype of trichiasis fibroblasts, matrix degradation, and significantly altered the expression of MMP1, MMP9, and MMP12 associated with the profibrotic phenotype.
In view of the results presented here and the wider use of doxycycline in clinical settings, we propose that doxycycline might be useful as a treatment to prevent recurrence following trichiasis surgery.
Doxycycline suppressed trichiasis fibroblasts-mediated matrix contraction in vitro and altered the expression of matrix metalloproteinases associated with the pro-fibrotic phenotype. This suggests that doxycycline might be useful as a treatment to prevent recurrence following trichiasis surgery.
PMCID: PMC3711612  PMID: 23766479
doxycycline; trichiasis; contraction; MMPs
6.  Comparison of the American-European Consensus Group Sjögren's syndrome classification criteria to newly proposed American College of Rheumatology criteria in a large, carefully characterized sicca cohort 
Annals of the rheumatic diseases  2013;73(1):10.1136/annrheumdis-2013-203845.
To compare the performance of the American-European Consensus Group (AECG) and the newly proposed American College of Rheumatology (ACR) classification criteria for Sjögren's syndrome in a well-characterized sicca cohort, given ongoing efforts to resolve discrepancies and weaknesses in the systems.
In a multidisciplinary clinic for the evaluation of sicca, we assessed features of salivary and lacrimal gland dysfunction and autoimmunity as defined by tests of both AECG and ACR criteria in 646 participants. Global gene expression profiles were compared in a subset of 180 participants.
Application of the AECG and ACR criteria resulted in classification of 279 and 268 participants with SS, respectively. Both criteria were met by 244 participants (81%). In 26 of the 35 AECG+/ACR- participants, the minor salivary gland biopsy focal score was ≥1 (74%), while 9 had positive anti-Ro/La (26%). There were 24 AECG-/ACR+ who met ACR criteria mainly due to differences in the scoring of corneal staining. All patients with SS, regardless of classification, had similar gene expression profiles, which were distinct from the healthy controls.
The two sets of classification criteria yield concordant results in the majority of cases and gene expression profiling suggests that patients meeting either set of criteria are more similar to other SS participants than to healthy controls. Thus, there is no clear evidence for increased value of the new ACR criteria over the old AECG criteria from the clinical or biological perspective. It is our contention, supported by this report, that improvements in diagnostic acumen will require a more fundamental understanding of the pathogenic mechanisms than is at present available.
PMCID: PMC3855629  PMID: 23968620
Sjögren's syndrome; Classification; Diagnosis
7.  Impact of Repeated Stress on Traumatic Brain Injury-Induced Mitochondrial Electron Transport Chain Expression and Behavioral Responses in Rats 
A significant proportion of the military personnel returning from Iraq and Afghanistan conflicts have suffered from both mild traumatic brain injury (mTBI) and post-traumatic stress disorder. The mechanisms are unknown. We used a rat model of repeated stress and mTBI to examine brain activity and behavioral function. Adult male Sprague-Dawley rats were divided into four groups: Naïve; 3 days repeated tail-shock stress; lateral fluid percussion mTBI; and repeated stress followed by mTBI (S-mTBI). Open field activity, sensorimotor responses, and acoustic startle responses (ASRs) were measured at various time points after mTBI. The protein expression of mitochondrial electron transport chain (ETC) complex subunits (CI-V) and pyruvate dehydrogenase (PDHE1α1) were determined in four brain regions at day 7-post mTBI. Compared to Naïves, repeated stress decreased horizontal activity; repeated stress and mTBI both decreased vertical activity; and the mTBI and S-mTBI groups were impaired in sensorimotor and ASRs. Repeated stress significantly increased CI, CII, and CIII protein levels in the prefrontal cortex (PFC), but decreased PDHE1α1 protein in the PFC and cerebellum, and decreased CIV protein in the hippocampus. The mTBI treatment decreased CV protein levels in the ipsilateral hippocampus. The S-mTBI treatment resulted in increased CII, CIII, CIV, and CV protein levels in the PFC, increased CI level in the cerebellum, and increased CIII and CV levels in the cerebral cortex, but decreased CI, CII, CIV, and PDHE1α1 protein levels in the hippocampus. Thus, repeated stress or mTBI alone differentially altered ETC expression in heterogeneous brain regions. Repeated stress followed by mTBI had synergistic effects on brain ETC expression, and resulted in more severe behavioral deficits. These results suggest that repeated stress could have contributed to the high incidence of long-term neurologic and neuropsychiatric morbidity in military personnel with or without mTBI.
PMCID: PMC3859919  PMID: 24376434
oxidative phosphorylation; mitochondria; electron transport chain; behavior change; TBI; PTSD
8.  Epigenetics-Based Therapeutics for Neurodegenerative Disorders 
Epigenetic regulation, such as DNA methylation and histone modification, is implicated in the aberrant changes in gene expression that occur during the progression of neurodegeneration. Many epigenetics-based drugs have been developed recently for the treatment of some neurodegenerative disorders, including Alzheimer’s, Parkinson’s, and Huntington’s diseases. Here we review recent studies that highlight the role of epigenetic modifications in neurodegeneration, among them DNA methylation and demethylation and histone acetylation and deacetylation; we also explore the possibility of using epigenetics-based therapeutics to treat neurodegenerative disorders.
PMCID: PMC3601938  PMID: 23526405
DNA methylation; DNA demethylation; Neurodegeneration; Therapeutics; DNMT inhibitors; HDAC inhibitors; Histone acetylation; Alzheimer’s disease; Parkinson’s disease; Huntington’s disease; Amyotrophic lateral sclerosis
9.  DB-02, a C-6-Cyclohexylmethyl Substituted Pyrimidinone HIV-1 Reverse Transcriptase Inhibitor with Nanomolar Activity, Displays an Improved Sensitivity against K103N or Y181C Than S-DABOs 
PLoS ONE  2013;8(11):e81489.
6-(cyclohexylmethyl)-5-ethyl-2-((2-oxo-2-phenylethyl)thio)pyrimidin-4(3H)-one (DB-02) is a member of the newly reported synthetic anti-HIV-1 compounds dihydro-aryl/alkylsulfanyl-cyclohexylmethyl-oxopyrimidines, S-DACOs. In vitro anti-HIV-1 activity and resistance profile studies have suggested that DB-02 has very low cytotoxicity (CC50>1mM) to cell lines and peripheral blood mononuclear cells (PBMCs). It displays potent anti-HIV-1 activity against laboratory adapted strains and primary isolated strains including different subtypes and tropism strains (EC50s range from 2.40 to 41.8 nM). Studies on site-directed mutagenesis, genotypic resistance profiles revealed that V106A was the major resistance contributor for the compound. Molecular docking analysis showed that DB-02 located in the hydrophobic pocket with interactions of Lys101, Val106, Leu234, His235. DB-02 also showed non-antagonistic effects to four approved antiretroviral drugs. All studies indicated that DB-02 would be a potential NNRTI with low cytotoxicity and improved activity.
PMCID: PMC3839930  PMID: 24282600
10.  Forsythiaside attenuates lipopolysaccharide-induced inflammatory responses in the bursa of Fabricius of chickens by downregulating the NF-κB signaling pathway 
Forsythiaside, a phenylethanoside product isolated from air-dried fruits of Forsythia suspensa, has been demonstrated to exhibit antioxidant, antibacterial and anti-inflammatory activities in vitro. However, its mechanism and the effects of lipopolysaccharide (LPS)-induced injury on the bursa of Fabricius (BF) of chickens are poorly understood. The present study aimed to investigate the anti-inflammatory effects of forsythiaside on LPS-induced acute inflammation. In addition, the potential molecular mechanisms of forsythiaside were analyzed in the BF, a special immune organ in chickens. Forty 15-day-old chickens were randomly divided into control, LPS and LPS plus forsythiaside (30 or 60 mg/kg) groups (n=10 for each group). In the LPS plus forsythiaside (30 or 60 mg/kg) groups, the chickens were orally administered with forsythiaside at doses of 30 and 60 mg/kg for seven days. At 21 days old, the chickens were intravenously injected with 200 μg/kg body weight LPS. Chickens in the control and LPS groups were only administered with vehicle or LPS, respectively, at day 21. At 3 h post-injection, the body temperature and nitric oxide (NO) levels were analyzed. In addition, the levels and mRNA expression of pro-inflammatory cytokines, including tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6) and IL-1β, and the mRNA expression of nuclear factor-κB (NF-κB), cyclooxygenase-2 (COX-2) and inducible NO synthase (iNOS), were examined in the BFs isolated from the chickens. The results revealed that forsythiaside was able to attenuate the LPS-induced inflammatory responses in the BFs of the chickens. The mechanisms by which forsythiaside exerted its anti-inflammatory effect were found to correlate with the inhibition of IL-6, IL-1β, TNF-α and COX-2 production, via the inactivation of NF-κB, indicating that the NF-κB-iNOS-NO signaling pathway may be important in this process.
PMCID: PMC3861409  PMID: 24348786
forsythiaside; bursa of Fabricius; lipopolysaccharide; inflammation; nuclear factor-κB
11.  Reprogramming of Round Spermatids by the Germinal Vesicle Cytoplasm in Mice 
PLoS ONE  2013;8(10):e78437.
The birthrate following round spermatid injection (ROSI) remains low in current and evidence suggests that factors in the germinal vesicle (GV) cytoplasm and certain substances in the GV such as the nucleolus might be responsible for genomic reprogramming and embryonic development. However, little is known whether the reprogramming factors in GV oocyte cytoplasm and/or nucleolus in GV are beneficial to the reprogramming of round spermatids and development of ROSI embryos. Here, round spermatids were treated with GV cytolysates and injected this round spermatid alone or co-injected with GV oocyte nucleolus into mature metaphase II oocytes. Subsequent embryonic development was assessed morphologically and by Oct4 expression in blastocysts. There was no significant difference between experimental groups at the zygote to four-cell development stages. Blastocysts derived from oocytes which were injected with cytolysate treated-round spermatid alone or co-injected with nucleoli injection yielded 63.6% and 70.3% high quality embryos, respectively; comparable to blastocysts derived by intracytoplasmic sperm injection (ICSI), but higher than these oocytes which were co-injected with lysis buffer-treated round spermatids and nucleoli or injected with the lysis buffer-treated round spermatids alone. Furthermore, the proportion of live offspring resulting from oocytes which were co-injected with cytolysate treated-round spermatids and nucleoli or injected with cytolysate treated-round spermatids alone was higher than those were injected with lysis buffer treated-round spermaids, but comparable with the ICSI group. Our results demonstrate that factors from the GV cytoplasm improve round spermatid reprogramming, and while injection of the extra nucleolus does not obviously improve reprogramming its potential contribution, although which cannot be definitively excluded. Thus, some reprogramming factors are evidently present in GV oocyte cytoplasm and could significantly facilitate ROSI technology, while the nucleolus in GV seems also having a potential to improve reprogramming of round spermatids.
PMCID: PMC3805568  PMID: 24167624
12.  Decreased fructose-1,6-bisphosphatase-2 expression promotes glycolysis and growth in gastric cancer cells 
Molecular Cancer  2013;12:110.
Increasing evidence suggests that cancer is a metabolic disease. Here, we investigated the potential role of fructose-1,6-bisphosphatase-2 (FBP2), the enzyme that catalyses the hydrolysis of fructose-1,6-bisphosphate to fructose-6-phosphate and inorganic phosphate in glucose metabolism, in gastric cancer (GC) development.
Our data indicated that FBP2 was downregulated in GC tissues (86.2%, 100/116), and absent or low FBP2 expression in GC tissues was correlated with poor survival of GC patients (P = 0.019). Conversely, ectopic expression of FBP2 in GC cells activated AMP-activated protein kinase (AMPK) signalling, inhibited the Akt-mTOR pathway, suppressed glucose metabolism, enhanced apoptosis, and reduced cell proliferation. Bisulphite genomic sequencing (BGS) in gastric cancer cell lines revealed that the FBP2 promoter region was densely methylated, and treatment of GC cells with the demethylation reagent, 5-aza-2-deoxycytidine (5-Aza), led to an increase in FBP2 expression. Importantly, forced expression of FBP2 abrogated tumour formation of these GC cells in nude mice.
Our results indicate that FBP2 does negatively regulate cell growth, and reduced expression of FBP2 may contribute to carcinogenesis for GC. These findings suggest that restoration of FBP2 expression can be a promising strategy for the target therapy of GC.
PMCID: PMC3849177  PMID: 24063558
FBP2; Glycolysis; Gastric cancer; Cell growth; Prognosis
13.  Stable Isotope Labeling with Amino Acids in Drosophila for Quantifying Proteins and Modifications 
Journal of proteome research  2012;11(9):4403-4412.
Drosophila melanogaster is a common animal model for genetics studies, and quantitative proteomics studies of the fly are emerging. Here we present in detail the development of a procedure to incorporate stable isotope labeled amino acids into the fly proteome. In the method of Stable Isotope Labeling with Amino acids in Drosophila melanogaster (SILAC fly), flies were fed with SILAC labeled yeast grown with modified media, enabling near complete labeling in a single generation. Biological variation in proteome among individual flies was evaluated in a series of null experiments. We further applied the SILAC fly method to profile proteins from a model of fragile X syndrome, the most common cause of inherited mental retardation in human. The analysis identified a number of altered proteins in the disease model, including actin-binding protein profilin and microtubulin-associated protein futsch. The change of both proteins was validated by immunoblotting analysis. Moreover, we extended the SILAC fly strategy to study the dynamics of protein ubiquitination during the fly life span (from day 1 to day 30), by measuring the level of ubiquitin along with two major polyubiquitin chains (K48 and K63 linkages). The results show that the abundance of protein ubiquitination and the two major linkages do not change significantly within the measured age range. Together, the data demonstrate the application of the SILAC principle in Drosophila melanogaster, facilitating the integration of powerful fly genomics with emerging proteomics.
PMCID: PMC3443408  PMID: 22830426
SILAC; Drosophila melanogaster; proteomics; mass spectrometry; fragile X syndrome; ubiquitin
14.  Transcript Assembly and Quantification by RNA-Seq Reveals Differentially Expressed Genes between Soft-Endocarp and Hard-Endocarp Hawthorns 
PLoS ONE  2013;8(9):e72910.
Hawthorn (Crataegus spp.) is an important pome with a long history as a fruit, an ornamental, and a source of medicine. Fruits of hawthorn are marked by hard stony endocarps, but a hawthorn germplasm with soft and thin endocarp was found in Liaoning province of China. To elucidate the molecular mechanism underlying the soft endocarp of hawthorn, we conducted a de novo assembly of the fruit transcriptome of Crataegus pinnatifida and compared gene expression profiles between the soft-endocarp and the hard-endocarp hawthorn varieties. De novo assembly yielded 52,673 putative unigenes, 20.4% of which are longer than 1,000 bp. Among the high-quality unique sequences, 35,979 (68.3%) had at least one significant match to an existing gene model. A total of 1,218 genes, represented 2.31% total putative unigenes, were differentially expressed between the soft-endocarp hawthorn and the hard-endocarp hawthorn. Among these differentially expressed genes, a number of lignin biosynthetic pathway genes were down-regulated while almost all the flavonoid biosynthetic pathway genes were strongly up-regulated, concomitant with the formation of soft endocarp. In addition, we have identified some MYB and NAC transcription factors that could potentially control lignin and flavonoid biosynthesis. The altered expression levels of the genes encoding lignin biosynthetic enzymes, MYB and NAC transcription factors were confirmed by quantitative RT-PCR. This is the first transcriptome analysis of Crataegus genus. The high quality ESTs generated in this study will aid future gene cloning from hawthorn. Our study provides important insights into the molecular mechanisms underlying soft endocarp formation in hawthorn.
PMCID: PMC3764154  PMID: 24039819
15.  Associations of genetic polymorphisms of SAA1 with cerebral infarction 
Serum amyloid A protein (SAA) is both an inflammatory factor and an apolipoprotein. However, the relation between genetic polymorphisms of SAA and cerebral infarction (CI) remains unclear.
Methods and results
The previously reported 4 Single Nucleotide Polymorphisms (rs12218, rs4638289, rs7131332, and rs11603089) of SAA1 gene were genotyped by TaqMan method in a case–control study including 287 cerebral infarction patients and 376 control subjects. We found rs12218 CC genotype and rs7131332 AA genotype were more frequent among CI patients than among controls (9.76% versus 3.19%, P = 0.001; 32.75% versus 24.20%; p = 0.017; respectively). After adjustment of confounding factors such as sex, age, smoking, drinking, hypertension, diabetes, and lipids profile, the difference remained significant in rs12218 (P < 0.01, OR = 2.106, 95% CI: 1.811–7.121).
Genetic polymorphism of SAA1 may be a genetic maker of cerebral infarction in Chinese.
PMCID: PMC3765816  PMID: 23987125
Genetic polymorphisms; Serum amyloid A; Cerebral infarction
16.  Functional Val66Met polymorphism of Brain-derived neurotrophic factor in type 2 diabetes with depression in Han Chinese subjects 
Brain-derived neurotrophic factor (BDNF) has been implicated in the pathogenesis of major depression. Individuals with type 2 diabetes (T2DM) have a high prevalence of major depression and low levels of BDNF. We therefore explored whether the BDNF Val66Met polymorphism is associated with co-morbid depression and whether depression affects the serum levels of BDNF in a Han Chinese subjects with T2DM.
A Total of 296 T2DM patients and 70 healthy volunteers (Health control, HC group) were recruited in this study. T2DM patients were divided into two subgroups: depressive diabetes group (DDM group, n = 64) and non-depressive diabetes group (NDDM group, n = 232), according to the presence or the absence of depression assessed by Center for Epidemiologic Studies Depression Scale (CES-D) and Patient Health Questionnaire-9 (PHQ-9). Val66Met polymorphism was detected by polymerase chain reaction-restriction fragment length polymorphism analysis (PCR-RFLP). Serum BDNF levels were measured by ELISA kit.
In this study, 21.6% (64/296) patients with T2DM had depression. The BDNF Val66Met genotype distributions were statistically different among the three groups (χ2 = 7.39, p < 0.05). DDM group carried the highest frequencies of Met allele (53.9%) compared to HC group (39.3%) and NDDM group (38.8%). Subjects with Met/Met had lowest serum BDNF levels (76.59 ± 5.12 pg/ml, F = 7.39, p < 0.05) compared to subjects with Val/Met (79.04 ± 5.19 pg/ml) and Val/Val (83.83 ± 3.97 pg/ml). Within T2DM group, it was also observed that the serum BDNF levels in DDM group were significantly lower than those in NDDM group (76.67 ± 5.35 vs. 79.84 ± 3.97 pg/ml, p < 0.05). In type 2 diabetes subjects, BDNF serum levels were significant correlations with genotypes (r = −0.346, p < 0.01), depression scores (r = −0.486, p < 0.01) and HbA1c (r = −0.168, p < 0.05). After adjustment for gender, HbA1c, BMI and numbers of complications, BDNF Val/Met genotype distributions (OR = 2.105, p < 0.05) and decreased serum BDNF levels (OR = 0.835, p < 0.01) were independently associated with depression in T2DM.
The BDNF Val66Met polymorphism might be implicated in the pathogenesis of depression in T2DM by decreasing serum BDNF levels in Han Chinese Subjects.
PMCID: PMC3765870  PMID: 23968401
Type 2 diabetes (T2DM); Depression; Brain-derived neurotrophic factor (BDNF); Polymorphism
17.  Genetics of Sjögren’s syndrome in the genome-wide association era 
Journal of autoimmunity  2012;39(1-2):57-63.
While Sjögren’s syndrome (SS) is more common than related autoimmune disorders, such as systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA), scientific and medical research in SS has lagged behind significantly. This is especially true in the field of SS genetics, where efforts to date have relied heavily on candidate gene approaches. Within the last decade, the advent of the genome-wide association (GWA) scan has altered our understanding of disease pathogenesis in hundreds of disorders through the successful identification of novel risk loci. With strong evidence for a genetic component in SS as evidenced by familial aggregation of SS as well as similarities between SS and SLE and RA, the application of GWA approaches would likely yield numerous novel risk loci in SS. Here we review the fundamental scientific principles employed in GWA scans as well as the limitations of this tool, and we discuss the application of GWA scans in determining genetic variants at play in complex disease. We also examine the successful application of GWA scans in SLE, which now has more than 40 confirmed risk loci, and consider the possibility for a similar trajectory of SS genetic discovery in the era of GWA scans. Ultimately, the GWA studies that will be performed in SS have the potential to identify a myriad of novel genetic loci that will allow scientists to begin filling in the gaps in our understanding of the SS pathogenesis.
PMCID: PMC3518871  PMID: 22289719
genetics; Sjögren’s syndrome; genome-wide association
18.  Higenamine Combined with [6]-Gingerol Suppresses Doxorubicin-Triggered Oxidative Stress and Apoptosis in Cardiomyocytes via Upregulation of PI3K/Akt Pathway 
Sini decoction is a well-known formula of traditional Chinese medicine, which has been used to treat cardiovascular disease for many years. Previously, we demonstrated that Sini decoction prevented doxorubicin-induced heart failure in vivo. However, its active components are still unclear. Thus, we investigated the active components of Sini decoction and their cardioprotective mechanisms in the in vitro neonatal rat cardiomyocytes and H9c2 cell line models of doxorubicin-induced cytotoxicity. Our results demonstrated that treatment with higenamine or [6]-gingerol increased viability of doxorubicine-injured cardiomyocytes. Moreover, combined use of higenamine and [6]-gingerol exerted more profound protective effects than either drug as a single agent, with effects similar to those of dexrazoxane, a clinically approved cardiac protective agent. In addition, we found that treatment with doxorubicin reduced SOD activity, increased ROS generation, enhanced MDA formation, induced release of LDH, and triggered the intrinsic mitochondria-dependent apoptotic pathway in cardiomyocytes, which was inhibited by cotreatment of higenamine and [6]-gingerol. Most importantly, the cytoprotection of higenamine plus [6]-gingerol could be abrogated by LY294002, a PI3K inhibitor. In conclusion, combination of higenamine and [6]-gingerol exerts cardioprotective effect against doxorubicin-induced cardiotoxicity through activating the PI3K/Akt signaling pathway. Higenamine and [6]-gingerol may be the active components of Sini decoction.
PMCID: PMC3687593  PMID: 23861719
19.  Effects of shielding on the induction of 53BP1 foci and micronuclei after Fe ion exposures 
Journal of Radiation Research  2013;55(1):10-16.
High atomic number and high-energy (HZE) particles in deep space are of low abundance but substantially contribute to the biological effects of space radiation. Shielding is so far the most effective way to partially protect astronauts from these highly penetrating particles. However, simulated calculations and measurements have predicted that secondary particles resulting from the shielding of cosmic rays produce a significant fraction of the total dose and dose equivalent. In this study, we investigated the biological effects of secondary radiation with two cell types, and with cells exposed in different phases of the cell cycle, by comparing the biological effects of a 200 MeV/u iron beam with a shielded beam in which the energy of the iron ion beam was decreased from 500 MeV/u to 200 MeV/u with PMMA, polyethylene (PE), or aluminum. We found that beam shielding resulted in increased induction of 53BP1 foci and micronuclei in a cell-type-dependent manner compared with the unshielded 200 MeV/u Fe ion beam. These findings provide experimental proof that the biological effects of secondary particles resulting from the interaction between HZE particles and shielding materials should be considered in shielding design.
PMCID: PMC3885111  PMID: 23728321
space radiation; shielding; secondary particles; survival; DNA damage
20.  Docetaxel, Cisplatin and Fluorouracil (DCF) Regimen Compared with Non-Taxane-Containing Palliative Chemotherapy for Gastric Carcinoma: A Systematic Review and Meta-Analysis 
PLoS ONE  2013;8(4):e60320.
Gastric carcinoma (GC) is one of the highest cancer-mortality diseases with a high incidence rate in Asia. For surgically unfit but medically fit patients, palliative chemotherapy is the main treatment. The chemotherapy regimen of docetaxel, cisplatin and 5-fluorouracil (DCF) has been used to treat the advanced stage or metastatic GC. It is necessary to compare effectiveness and toxicities of DCF regimen with non-taxane-containing palliative chemotherapy for GC.
PubMed, EmBase, Cochrane Central Register of Controlled Trials and China National Knowledge Infrastructure databases were searched to select relative randomized controlled trials (RCTs) comparing DCF to non-taxane-containing chemotherapy for patients with palliatively resected, unresectable, recurrent or metastatic GC. Primary outcome measures were 1-year and 2-year overall survival (OS) rates. Secondary outcome measures were median survival time (MST), median time to progression (TTP), response rate and toxicities.
Twelve RCTs were eligible and 1089 patients were analyzed totally (549 in DCF and 540 in control). DCF regimen increased partial response rate (38.8% vs 27.9%, p = 0.0003) and reduced progressive disease rate (18.9% vs 33.3%, p = 0.0005) compared to control regimen. Significant improvement of 2-year OS rate was found in DCF regimen (RR = 2.03, p = 0.006), but not of 1-year OS rate (RR = 1.22, p = 0.08). MST was significantly prolonged by DCF regimen (p = 0.039), but not median TTP (p = 0.054). Both 1-year OS rate and median TTP had a trend of prolongation by DCF regimen. Chemotherapy-related mortality was comparable (RR = 1.23, p = 0.49) in both regimens. In grade I-IV toxicities, DCF regimen showed a major raise of febrile neutropenia (RR = 2.33, p<0.0001) and minor raises of leucopenia (RR = 1.25, p<0.00001), neutropenia (RR = 1.19, p<0.00001), and diarrhea (RR = 1.59, p<0.00001), while in other toxicities there were no significant differences.
DCF regimen has better response than non-taxane containing regimen and could potentially improve the survival outcomes. The chemotherapy-related toxicity of DCF regimen is acceptable to some extent.
PMCID: PMC3617226  PMID: 23593191
21.  Haplotype Polymorphism in the Alpha-2B-Adrenergic Receptor Gene Influences Response Inhibition in a Large Chinese Sample 
Neuropsychopharmacology  2012;37(5):1115-1121.
Response inhibition refers to the suppression of inappropriate or irrelevant responses. It has a central role in executive functions, and has been linked to a wide spectrum of prevalent neuropsychiatric disorders. Increasing evidence from neuropharmacological studies has suggested that gene variants in the norepinephrine neurotransmission system make specific contributions to response inhibition. This study genotyped five tag single-nucleotide polymorphisms covering the whole alpha-2B-adrenergic receptor (ADRA2B) gene and investigated their associations with response inhibition in a relatively large healthy Chinese sample (N=421). The results revealed significant genetic effects of the ADRA2B conserved haplotype polymorphisms on response inhibition as measured by stop-signal reaction time (SSRT) (F(2, 418)=5.938, p=0.003). Individuals with the AAGG/AAGG genotype (n=89; mean SSRT=170.2 ms) had significantly shorter SSRTs than did those with either the CCAC/AAGG genotype (n=216; mean SSRT=182.4 ms; uncorrected p=0.03; corrected p=0.09) or the CCAC/CCAC genotype (n=116; mean SSRT=195.8 ms; corrected p<0.002, Cohen's d=0.51). This finding provides the first evidence from association research in support of a critical role of the norepinephrine neurotransmission system in response inhibition. A better understanding of the genetic basis of response inhibition would allow us to develop more effective diagnosis, treatment, and prevention of deficient or underdeveloped response inhibition as well as its related prevalent neuropsychiatric disorders.
PMCID: PMC3306871  PMID: 22218095
ADRA2B gene; response inhibition; stop-signal task; haplotype; norepinephrine neurotransmission system; addiction and substance abuse; alcohol and alcoholism; behavioral science; neuropharmacology; mifepristone; yohimbine; reinstatement; ethanol; self-administration; glucocorticoids
22.  Differential expression of beta-catenin and dickkopf-1 in the third trimester placentas from normal and preeclamptic pregnancies: a comparative study 
Beta-catenin is a key nuclear effector of Wnt signaling which could be antagonized by dickkopf-1(DKK1). Beta-catenin and DKK1 are involved in a variety of biological processes; however, their expression in the placenta with severe preeclampsia (PE) has not been elucidated. This study was aimed to detect the localization and compare the expression of beta-catenin and DKK1 in normal and preeclamptic placenta.
Sixty pregnant women who underwent cesarean section were enrolled in this study, including 30 healthy pregnant women in the control group and 30 preeclamptic women in the severe PE group. Real-time polymerase chain reaction (real-time-PCR) and western blot were employed to detect the beta-catenin and DKK1 mRNA and protein expression levels, respectively, and their locations were evaluated by immunohistochemistry (IHC).
Our results indicated that beta-catenin and DKK1 were expressed predominantly in the syncytiotrophoblast and the extravillous trophoblast (EVT). The beta-catenin mRNA and protein expressions were significantly decreased, whereas the DKK1 significantly increased in preeclamptic placental tissues compared to normal placental controls.
In conclusion, decreased beta-catenin expression, as well as DKK1 over-expression might be associated with the process of the pathogenesis of PE. Further studies would elucidate their exact roles in the pathogenesis of PE.
PMCID: PMC3599361  PMID: 23452984
Severe preeclampsia; Beta-catenin; Dickkof-1; Placenta
23.  Retrotransposon activation contributes to fragile X premutation rCGG-mediated neurodegeneration 
Human Molecular Genetics  2011;21(1):57-65.
Fragile X-associated tremor/ataxia syndrome (FXTAS) is a neurodegenerative disorder associated with fragile X premutation carriers. Previous studies have shown that fragile X rCGG repeats are sufficient to cause neurodegeneration and that the rCGG-repeat-binding proteins Pur α and heterogeneous nuclear ribonucleoprotein (hnRNP) A2/B1 could modulate rCGG-mediated neuronal toxicity. Mobile genetic elements or their remnants populate the genomes, and the activities of these elements are tightly controlled for the fitness of host genomes in different organisms. Here we provide both biochemical and genetic evidence to show that the activation of a specific retrotransposon, gypsy, can modulate rCGG-mediated neurodegeneration in an FXTAS Drosophila model. We find that one of the rCGG-repeat-binding proteins, hnRNP A2/B1, is involved in this process via interaction with heterochromatin protein 1. Knockdown of gypsy RNA by RNAi could suppress the neuronal toxicity caused by rCGG repeats. These data together point to a surprisingly active role for retrotransposition in neurodegeneration.
PMCID: PMC3235010  PMID: 21940752
24.  Interferons in Sjögren’s Syndrome: Genes, Mechanisms, and Effects 
Sjögren’s syndrome (SS) is a common, progressive autoimmune exocrinopathy distinguished by dry eyes and mouth and affects ∼0.7% of the European population. Overexpression of transcripts induced by interferons (IFN), termed as an “IFN signature,” has been found in SS patients. Four microarray studies have been published in SS that identified dysregulated genes within type I IFN signaling in either salivary glands or peripheral blood of SS patients. The mechanism of this type I IFN activation is still obscure, but several possible explanations have been proposed, including virus infection-initiated and immune complex-initiated type I IFN production by plasmacytoid dendritic cells. Genetic predisposition to increased type I IFN signaling is supported by candidate gene studies showing evidence for association of variants within IFN-related genes. Once activated, IFN signaling may contribute to numerous aspects of SS pathophysiology, including lymphocyte infiltration into exocrine glands, autoantibody production, and glandular cell apoptosis. Thus, dysregulation of IFN pathways is an important feature that can be potentially used as a serum biomarker for diagnosis and targeting of new treatments in this complex autoimmune disease.
PMCID: PMC3778845  PMID: 24062752
interferon signature; Sjögren’s syndrome; gene expression profiling; microarrays; type I interferon; genetic association; mechanisms; biomarker
25.  Treatment of Multiple Sclerosis With Chinese Scalp Acupuncture 
Chinese scalp acupuncture is a contemporary acupuncture technique with just 40 years of history. It integrates traditional Chinese needling methods with Western medical knowledge of the cerebral cortex and has been proven to be a very effective technique for treating multiple sclerosis (MS) and other central nervous system disorders. A 65-year-old male patient who had had MS for 20 years was treated with Chinese scalp acupuncture. The motor area, sensory area, foot motor and sensory area, balance area, hearing and dizziness area, and tremor area were stimulated once a week for 10 weeks, then once a month for six sessions. After the 16 treatments, the patient showed remarkable improvements. He was able to stand and walk without any problems. The numbness and tingling in his limbs did not bother him anymore. He had more energy and had not experienced incontinence of urine or dizziness after the first treatment. He was able to return to work full time. At this writing, the patient has been in remission for 26 months. This case demonstrates that Chinese scalp acupuncture can be a very effective treatment for patients with MS. Chinese scalp acupuncture holds the potential to expand treatment options for MS in both conventional and complementary or integrative therapies. It can not only relieve symptoms, increase the patient's quality of life, and slow and reverse the progression of physical disability but also reduce the number of relapses and help patients with multiple sclerosis to remain in remission.
PMCID: PMC3833581  PMID: 24278838
Multiple sclerosis; Chinese scalp acupuncture; remission

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