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1.  Ancient Origins of RGK Protein Function: Modulation of Voltage-Gated Calcium Channels Preceded the Protostome and Deuterostome Split 
PLoS ONE  2014;9(7):e100694.
RGK proteins, Gem, Rad, Rem1, and Rem2, are members of the Ras superfamily of small GTP-binding proteins that interact with Ca2+ channel β subunits to modify voltage-gated Ca2+ channel function. In addition, RGK proteins affect several cellular processes such as cytoskeletal rearrangement, neuronal dendritic complexity, and synapse formation. To probe the phylogenetic origins of RGK protein–Ca2+ channel interactions, we identified potential RGK-like protein homologs in genomes for genetically diverse organisms from both the deuterostome and protostome animal superphyla. RGK-like protein homologs cloned from Danio rerio (zebrafish) and Drosophila melanogaster (fruit flies) expressed in mammalian sympathetic neurons decreased Ca2+ current density as reported for expression of mammalian RGK proteins. Sequence alignments from evolutionarily diverse organisms spanning the protostome/deuterostome divide revealed conservation of residues within the RGK G-domain involved in RGK protein – Cavβ subunit interaction. In addition, the C-terminal eleven residues were highly conserved and constituted a signature sequence unique to RGK proteins but of unknown function. Taken together, these data suggest that RGK proteins, and the ability to modify Ca2+ channel function, arose from an ancestor predating the protostomes split from deuterostomes approximately 550 million years ago.
doi:10.1371/journal.pone.0100694
PMCID: PMC4081519  PMID: 24992013
2.  Brain Pyroglutamate Amyloid-Beta is Produced by Cathepsin B and is Reduced by the Cysteine Protease Inhibitor E64d, Representing a Potential Alzheimer’s Disease Therapeutic 
Pyroglutamate amyloid-β peptides (pGlu-Aβ) are particularly pernicious forms of amyloid-β peptides (Aβ) present in Alzheimer’s disease (AD) brains. pGlu-Aβ peptides are N-terminally truncated forms of full-length Aβ peptides (flAβ(1-40/42)) in which the N-terminal glutamate is cyclized to pyroglutamate to generate pGlu-Aβ(3-40/42). β-secretase cleavage of amyloid-β precursor protein (AβPP) produces flAβ(1-40/42), but it is not yet known whether the β-secretase BACE1 or the alternative β-secretase cathepsin B (CatB) participate in the production of pGlu-Aβ. Therefore, this study examined the effects of gene knockout of these proteases on brain pGlu-Aβ levels in transgenic AβPPLon mice, which express AβPP isoform 695 and have the wild-type (wt) β-secretase activity found in most AD patients. Knockout or overexpression of the CatB gene reduced or increased, respectively, pGlu-Aβ(3-40/42), flAβ(1-40/42), and pGlu-Aβ plaque load, but knockout of the BACE1 gene had no effect on those parameters in the transgenic mice. Treatment of AβPPLon mice with E64d, a cysteine protease inhibitor of CatB, also reduced brain pGlu-Aβ(3-42), flAβ(1-40/42), and pGlu-Aβ plaque load. Treatment of neuronal-like chromaffin cells with CA074Me, an inhibitor of CatB, resulted in reduced levels of pGlu-Aβ(3-40) released from the activity-dependent, regulated secretory pathway. Moreover, CatB knockout and E64d treatment has been previously shown to improve memory deficits in the AβPPLon mice. These data illustrate the role of CatB in producing pGlu-Aβ and flAβ that participate as key factors in the development of AD. The advantages of CatB inhibitors, especially E64d and its derivatives, as alternatives to BACE1 inhibitors in treating AD patients are discussed.
doi:10.3233/JAD-131370
PMCID: PMC4059604  PMID: 24595198
pyroglutamate amyloid-β; cathepsin B; BACE1; AβPP; protease; transgenic AD mice; inhibitor; cysteine protease; secretion
3.  Engraftment Potential of Spheroid-Forming Hepatic Endoderm Derived from Human Embryonic Stem Cells 
Stem Cells and Development  2013;22(12):1818-1829.
Transplantation and drug discovery programs for liver diseases are hampered by the shortage of donor tissue. While recent studies have shown that hepatic cells can be derived from human embryonic stem cells (hESCs), few cases have shown selective enrichment of hESC-derived hepatocytes and their integration into host liver tissues. Here we demonstrate that the dissociation and reaggregation procedure after an endodermal differentiation of hESC produces spheroids mainly consisted of cells showing hepatic phenotypes in vitro and in vivo. A combined treatment with Wnt3a and bone morphogenic protein 4 efficiently differentiated hESCs into definitive endoderm in an adherent culture. Dissociation followed by reaggregation of these cells in a nonadherent condition lead to the isolation of spheroid-forming cells that preferentially expressed early hepatic markers from the adherent cell population. Further differentiation of these spheroid cells in the presence of the hepatocyte growth factor, oncostatin M, and dexamethasone produced a highly enriched population of cells exhibiting characteristics of early hepatocytes, including glycogen storage, indocyanine green uptake, and synthesis of urea and albumin. Furthermore, we show that grafted spheroid cells express hepatic features and attenuate the serum aspartate aminotransferase level in a model of acute liver injury. These data suggest that hepatic progenitor cells can be enriched by the spheroid formation of differentiating hESCs and that these cells have engraftment potential to replace damaged liver tissues.
doi:10.1089/scd.2012.0401
PMCID: PMC3668500  PMID: 23373441
4.  Value of 18F-FDG PET-CT in surveillance of postoperative colorectal cancer patients with various carcinoembryonic antigen concentrations 
AIM: To evaluate the value of positron emission tomography (PET)/computerized tomography (CT) in surveillance of colorectal cancer (CRC) patients with different carcinoembryonic antigen (CEA) concentrations.
METHODS: One hundred and six postoperative CRC patients who had suspected recurrence or metastasis and received fluorodeoxyglucose (FDG) PET/CT within one week were included in this study. The final diagnosis was confirmed by histological examination or clinical follow-up over at least six months.
RESULTS: The sensitivity, specificity, and accuracy of FDG PET/CT were 95.2%, 82.6%, and 92.5%, and 94.8%, 81.4% and 92.8%, respectively, in the case- and lesion-based analyses. The sensitivity and accuracy of FDG PET/CT significantly differed from CT in both analyses (χ2 = 8.186, P = 0.004; χ2 =6.201, P = 0.013; χ2 =13.445, P = 0.000; χ2 =11.194, P = 0.001). In the lesion-based analysis, the sensitivity, specificity, and accuracy of FDG PET/CT in the abnormal CEA group were 97.8%, 82.6%, and 95.6%, compared with 81.3%, 80%, and 80.6% for patients with normal CEA levels. In case-based analysis, the sensitivity, specificity, and accuracy of FDG PET/CT were 97.2%, 77.8%, and 95% in abnormal CEA group. Only in lesion-based analysis, the sensitivity and accuracy of FDG PET/CT in the abnormal CEA group were significantly superior to those in the normal CEA group (χ2 =6.432, P = 0.011; χ2 =7.837, P = 0.005). FDG PET/CT changed the management in 45.8% of patients with positive scans.
CONCLUSION: FDG PET/CT showed superior diagnostic value and is an advisable option in surveillance of postoperative CRC patients with a vague diagnosis.
doi:10.3748/wjg.v20.i21.6608
PMCID: PMC4047348  PMID: 24914384
Colorectal cancer; Carcinoembryonic antigen; Fluorodeoxyglucose positron emission tomography/computed tomography; Recurrence; Metastasis
5.  Correlation of CD146 expression and clinicopathological characteristics in esophageal squamous cell carcinoma 
Oncology Letters  2014;8(2):859-863.
CD146, a cell adhesion molecule, is found in normal and tumor tissues. The level of its expression has been found to directly correlate with tumor progression and metastatic potential. The objective of this study was to investigate the expression of CD146 in esophageal squamous cell carcinoma (ESCC) and its correlation with clinicopathological parameters. Tumor specimens were collected from 63 patients with ESCC who underwent complete resection. We analyzed the CD146 expression levels in ESCC by immunohistochemistry. The expression of CD146 was detected and it was observed to correlate with clinicopathological parameters. Sixty-three cases of normal squamous mucosa were included for comparison. CD146 expression was identified in 46.0% (29/63) of the ESCC samples, and no positive (weak to moderate or moderate to strong) expression was found in the normal squamous epithelium samples (χ2=27.248; P<0.0001). CD146 expression was associated with lymph node metastasis (χ2=5.117; P=0.024) and advanced clinical stage (χ2=4.661; P=0.031). CD146 expression was one of the significant predictors of survival (hazard ratio, 2.838; 95% confidence interval 1.102–7.305). The overexpression of the CD146 gene was one of the important phenotypes and characteristics in ESCC carcinomatous change. We found that CD146 expression was associated with lymph node metastasis and advanced clinical stage, and was an indicator of poor prognosis in ESCC patients. CD146 may prove to be an important tumor marker for the individualized treatment for ESCC.
doi:10.3892/ol.2014.2227
PMCID: PMC4081421
CD146; esophageal squamous cell cancer; clinicopathological characteristics; immunohistochemistry
6.  β-Hydroxybutyrate Modulates N-Type Calcium Channels in Rat Sympathetic Neurons by Acting as an Agonist for the G-Protein-Coupled Receptor FFA3 
The Journal of Neuroscience  2013;33(49):19314-19325.
Free fatty acids receptor 3 (FFA3, GPR41) and 2 (FFA2, GPR43), for which the short-chain fatty acids (SCFAs) acetate and propionate are agonist, have emerged as important G-protein-coupled receptors influenced by diet and gut flora composition. A recent study (Kimura et al., 2011) demonstrated functional expression of FFA3 in the rodent sympathetic nervous system (SNS) providing a potential link between nutritional status and autonomic function. However, little is known of the source of endogenous ligands, signaling pathways, or effectors in sympathetic neurons. In this study, we found that FFA3 and FFA2 are unevenly expressed in the rat SNS with higher transcript levels in prevertebral (e.g., celiac-superior mesenteric and major pelvic) versus paravertebral (e.g., superior cervical and stellate) ganglia. FFA3, whether heterologously or natively expressed, coupled via PTX-sensitive G-proteins to produce voltage-dependent inhibition of N-type Ca2+ channels (Cav2.2) in sympathetic neurons. In addition to acetate and propionate, we show that β-hydroxybutyrate (BHB), a metabolite produced during ketogenic conditions, is also an FFA3 agonist. This contrasts with previous interpretations of BHB as an antagonist at FFA3. Together, these results indicate that endogenous BHB levels, especially when elevated under certain conditions, such as starvation, diabetic ketoacidosis, and ketogenic diets, play a potentially important role in regulating the activity of the SNS through FFA3.
doi:10.1523/JNEUROSCI.3102-13.2013
PMCID: PMC3850046  PMID: 24305827
7.  A Robust Protocol for Pd(II)-catalyzed C-3 Arylation of (1H) Indazoles and Pyrazoles: Total Synthesis of Nigellidine Hydrobromide 
C3-arylated indazole and pyrazoles are privileged structural motifs in agrochemicals and pharmaceuticals. C-3 C-H arylation of (1H) indazole and pyrazole has been a significant challenge due to the poor reactivity of the C-3 position. Herein, we report a practical Pd(II)/Phen catalyst and conditions for direct C-3 arylation of indazole and pyrazole with ArI or ArBr without using Ag additives as halide scavengers. The use of toluene, chlorobenzene, trifluoromethylbenzene and mesitylene as the solvent was found to be crucial for the selectivity and reactivity. We further demonstrate the robustness of this protocol through the first total synthesis of Nigellidine hydrobromide as well as expedient preparation of heterocycles structurally related to pesticides and drug molecules.
doi:10.1039/C3SC50184A
PMCID: PMC3656414  PMID: 23691269
8.  Reconstruction of a Columellar Defect With a Nasolabial Island Flap 
Columellar skin defects may be caused by excision of cutaneous malignancy, trauma, or tissue necrosis associated with surgery. Although columellar skin necrosis rarely occurs following rhinoplasty, this condition might be more common when using an external approach than a closed approach. Columellar skin incision performed with exaggerated tip augmentation may cause columellar necrosis. The nasolabial island flap, used unilaterally to cover columellar skin defects, is used for a single-stage reconstruction procedure and is generally not associated with the need for secondary surgeries. This technique is well suited for repairing columellar skin defects. We experienced a patient with columellar skin necrosis occurring after rhinoplasty which was reconstructed using a unilateral single-stage nasolabial island flap.
doi:10.3342/ceo.2014.7.2.142
PMCID: PMC4050088  PMID: 24917913
Island flap; Columellar defect; Rhinoplasty
9.  Prevalence of Chronic Sputum and Associated Factors in Korean Adults 
Journal of Korean Medical Science  2014;29(6):825-830.
Chronic sputum is a troublesome symptom in many respiratory diseases. The prevalence of chronic sputum varies from 1.2% to 13% according to the country. The purpose of this study was to estimate the prevalence of chronic sputum and to find its associated factors in a general Korean population. We analyzed the data of the Korea National Health and Nutrition Examination Survey 2010 and 2011. A total number of 6,783 subjects aged 40 yr or more were enrolled in this study with 3,002 men and 3,781 women. As a result, the prevalence of chronic sputum was 6.3% (n=430). Significant risk factors for chronic sputum by multivariate analysis were: age (≥70 yr) (odds ratio [OR], 1.954; 95% confidence interval [CI], 1.308-2.917), current smoking (OR, 4.496; 95% CI, 3.001-6.734), chronic obstructive pulmonary disease (COPD) (OR, 1.483; 95% CI, 1.090-2.018), and tuberculosis (OR, 1.959; 95% CI, 1.307-2.938). In conclusion, the prevalence of chronic sputum in Korea was in the intermediate range compared with other countries. Smoking is a preventable risk factor identified in this study, and major respiratory diseases, such as COPD and tuberculosis, should be considered in subjects with chronic sputum.
Graphical Abstract
doi:10.3346/jkms.2014.29.6.825
PMCID: PMC4055817  PMID: 24932085
Chronic Sputum; Prevalence; Associated Factor
10.  Pd(II)-Catalyzed Ortho- or Meta-C–H Olefination of Phenol Derivatives 
A combination of weakly coordinating auxiliaries and ligand acceleration allows for the development of both ortho- and meta-selective C–H olefination of phenol derivatives. These reactions demonstrate the feasibility of directing C–H functionalizations when functional groups are distal to target C–H bonds. The meta-C–H functionalization of electron-rich phenol derivatives is unprecedented and orthogonal to previous electrophilic substitution of phenols in terms of regioselectivity. These methods are also applied to functionalize α-phenoxyacetic acids, a fibrate class of drug scaffolds.
doi:10.1021/ja400659s
PMCID: PMC3685289  PMID: 23614807
11.  Whole Genome Sequence-Based Analysis of a Model Complex Trait, High Density Lipoprotein Cholesterol 
Nature genetics  2013;45(8):899-901.
We describe initial steps for interrogating whole genome sequence (WGS) data to characterize the genetic architecture of a complex trait, such as high density lipoprotein cholesterol (HDL-C). We estimate that common variation contributes more to HDL-C heritability than rare variation, and screening for Mendelian dyslipidemia variants identified individuals with extreme HDL-C. WGS analyses highlight the value of regulatory and non-protein coding regions of the genome in addition to protein coding regions.
doi:10.1038/ng.2671
PMCID: PMC4030301  PMID: 23770607
12.  Identification of Two Novel Mutations in the PHEX Gene in Chinese Patients with Hypophosphatemic Rickets/Osteomalacia 
PLoS ONE  2014;9(5):e97830.
Objective
X-linked dominant hypophosphatemia (XLH) is the most prevalent form of inherited rickets/osteomalacia in humans. The aim of this study was to identify PHEX gene mutations and describe the clinical features observed in 6 unrelated Chinese families and 3 sporadic patients with hypophosphatemic rickets/osteomalacia.
Methods
For this study, 45 individuals from 9 unrelated families of Chinese Han ethnicity (including 16 patients and 29 normal phenotype subjects), and 250 healthy donors were recruited. All 22 exons and exon-intron boundaries of the PHEX gene were amplified by polymerase chain reaction (PCR) and directly sequenced.
Results
The PHEX mutations were detected in 6 familial and 3 sporadic hypophosphatemic rickets/osteomalacia. Altogether, 2 novel mutations were detected: 1 missense mutation c.1183G>C in exon 11, resulting in p.Gly395Arg and 1 missense mutation c.1751A>C in exon 17, resulting in p.His584Pro. No mutations were found in the 250 healthy controls.
Conclusions
Our study increases knowledge of the PHEX gene mutation types and clinical phenotypes found in Chinese patients with XLH, which is important for understanding the genetic basis of XLH. The molecular diagnosis of a PHEX genetic mutation is of great importance for confirming the clinical diagnosis of XLH, conducting genetic counseling, and facilitating prenatal intervention, especially in the case of sporadic patients.
doi:10.1371/journal.pone.0097830
PMCID: PMC4024000  PMID: 24836714
13.  Epigenetic regulation of cholinergic receptor M1 (CHRM1) by histone H3K9me3 impairs Ca2+ signaling in Huntington’s disease 
Acta neuropathologica  2013;125(5):727-739.
Huntington’s disease (HD) is an autosomal dominant neurodegenerative disease caused by an expanded trinucleotide CAG repeat in the gene coding for huntingtin (Htt). Deregulation of chromatin remodeling is linked to the pathogenesis of HD but the mechanism remains elusive. In order to identify what genes are deregulated by trimethylated histone H3K9 (H3K9me3)-dependent heterochromatin, we performed H3K9me3-ChIP genome-wide sequencing combined with RNA-sequencing followed by platform integration analysis in stable striatal HD cell lines (STHdhQ7/7 and STHdhQ111/111 cells). We found that genes involving neuronal synaptic transmission including cholinergic receptor M1 (CHRM1), cell motility, and neuronal differentiation pathways are down regulated while their promoter regions are highly occupied with H3K9me3 in HD. Moreover, we found that repression of CHRM1 gene expression by H3K9me3 impairs Ca2+-dependent neuronal signal transduction in stable cell lines expressing mutant HD protein. Thus, our data indicates that the epigenetic modifications, such as aberrant H3K9me3-dependent heterochromatin plasticity, directly contribute to the pathogenesis of HD.
doi:10.1007/s00401-013-1103-z
PMCID: PMC3633717  PMID: 23455440
H3K9me3; epigenomes; Huntington’s disease; cholinergic receptor M1; heterochromatin
14.  Mite and Booklouse Fauna From Vacuumed Dust Samples From Beijing 
A significant-source of allergens come from house dust that contain particles derived from arthropods, molds, and pet dander. This study evaluated mite and booklouse fauna from vacuumed dust samples in Beijing China (a temperate zone). Our survey was carried out in Beijing in the homes of mite allergic patients who visited our Allergy Department. In total, 38 homes were selected for the collection of dust samples by vacuuming, from December 2008 to January 2010. The flotation method was used to isolate mites from house dust. Permanent slides were prepared for mite specimens and mites were identified and counted under a microscope. In total, 1,798 separate mite and insect specimens were found in 345 dust samples taken from 38 homes. A total of 95 individual Dermatophagoides (D) siboney were detected in 35 dust samples from 19 homes (representing 5.3% of all mite and insect species found in house dust); in addition, this mite was found to co-exist with D. farinae (Hughes, 1961) in 33 dust samples. Our results demonstrated the presence D. siboney that co-existed with D. farinae in house dust in Beijing China (a temperate zone).
doi:10.4168/aair.2014.6.3.257
PMCID: PMC4021245  PMID: 24843802
Dermatophagoides siboney; Dermatophagoides farinae; domestic mites
15.  Serum Leptin and Adiponectin Levels in Korean Patients with Psoriasis 
Journal of Korean Medical Science  2014;29(5):729-734.
Psoriasis is a disorder caused by genetic and immunological factors. Leptin, a peptide hormone secreted predominantly from adipose tissue, regulates energy intake and expenditure, as well as the T-helper response. There have been conflicting reports regarding serum levels of leptin and adiponectin in patients with psoriasis. In the present study, we measured serum levels of leptin and adiponectin in Korean patients with psoriasis. Twenty-four patients with psoriasis and fifteen control subjects were included in the study. Serum leptin and adiponectin levels were determined by an immunometric sandwich enzyme-linked immunosorbent assay (ELISA). The mean serum leptin concentration in patients with psoriasis was higher than in controls, and the difference was statistically significant. In contrast, serum adiponectin levels in patients with psoriasis were significantly decreased compared with healthy controls. Leptin levels in vitamin D-deficient patients were statistically significantly higher than in vitamin D-sufficient patients. Serum adiponectin concentrations showed a negative correlation with body mass index (BMI) and psoriasis area and severity index (PASI) in patients with psoriasis. In conclusion, the present study demonstrated that leptin and adiponectin may play a role in the immunopathogenesis of psoriasis and may be useful biomarkers indicating severity of psoriasis in Korean patients.
Graphical Abstract
doi:10.3346/jkms.2014.29.5.729
PMCID: PMC4024941  PMID: 24851032
Adiponectin; Leptin; Metabolic Syndrome; Psoriasis
16.  Efficacy of Bicalutamide 150-mg Monotherapy Compared With Combined Androgen Blockade in Patients With Locally Advanced Prostate Cancer 
Korean Journal of Urology  2014;55(5):315-320.
Purpose
We compared the efficacy, survival rate, and adverse events between bicalutamide 150-mg monotherapy and combined androgen blockade (CAB) in men with locally advanced prostate cancer.
Materials and Methods
From March 2003 to July 2012, we retrospectively included 74 patients who were treated for more than 3 months and were followed up for more than 6 months. 25 men were treated with bicalutamide 150-mg only (group 1) and 49 men received CAB (group 2). Serum prostate-specific antigen (PSA) change, survival rate, and adverse events were compared between the 2 groups.
Results
The PSA levels before and after treatment were 37.0±32.8 ng/mL and 9.5±27.0 ng/mL in group 1 (p<0.001) and 50.2±40.0 ng/mL and 20.0±35.8 ng/mL in group 2 (p<0.001). Mean survival rates were 78.9% in group 1 and 52.3% in group 2 (p=0.055). There were no statistically significant differences in adverse events between the 2 groups (p=0.304). The International Index of Erectile Function 5 (IIEF-5) score before treatment was 19.3±5.9 in group 1 and 18.3±5.8 in group 2 (p=0.487). The IIEF-5 score after treatment was 17.1±6.3 in group 1 and 14.0±6.1 in group 2, which was a statistically significant difference (p=0.036).
Conclusions
The PSA change, mean survival rate, and adverse events in patients with locally advanced prostate cancer treated with bicalutamide 150-mg and CAB did not differ significantly. However, sexual function was better in the bicalutamide 150-mg group. Therefore, bicalutamide 150-mg monotherapy could be considered as a treatment for locally advanced prostate cancer in patients concerned about sexual function.
doi:10.4111/kju.2014.55.5.315
PMCID: PMC4026657  PMID: 24868335
Bicalutamide; Prostatic neoplasms; Therapy
17.  Effects of therapeutic massage on gait and pain after delayed onset muscle soreness 
Unfamiliar or sudden exercise can induce delayed onset muscle soreness (DOMS) within 12–24 h. So, several researchers have reported various interventions to treat DOMS. Massage is generally known to eliminate muscle fatigue. However, effect of massage after DOMS is still not clear. We investigated whether the massage is effective on pain and gait after DOMS. The participants were divided into a control group (n= 10) with DOMS and an experimental group (n= 11) with the massage treated after DOMS. We induced DOMS by taking isotonic exercise with going up and down 20 times in 5-story building. We applied the massage and assessment on gastrocnemius of dominant foot. The change of gait and pain was assessed using gaitrite and algometer. In the present results, the massage on gastrocnemius after DOMS showed significant difference in pain (P< 0.05). Also, there was a significant difference in gait (P< 0.05), especially, spatial parameters (distance, step length, stride length) and temporal parameters (ambulation, heel on off time, stride velocity). Moreover, the pain relief after massage-treated in DOMS correlated with gait. These results suggest that the massage on gastrocnemius after DOMS has influence on pain and gait performance. Therefore, massage can be applied as intervention for delayed onset muscle soreness.
doi:10.12965/jer.140106
PMCID: PMC4025548  PMID: 24877051
Delayed onset muscle soreness; Massage; Gastrocnemius; Gait; Pain
18.  Genome-wide microRNA expression profiles in hippocampus of rats with chronic temporal lobe epilepsy 
Scientific Reports  2014;4:4734.
The expression and functions of microRNAs (miRNAs) in chronic temporal lobe epilepsy (TLE), the most common type of refractory epilepsy in adults, are poorly understood currently. In this study, status epilepticus evoked by amygdala stimulation was used to establish rat chronic TLE model. Two months later, high-throughput sequencing was employed to investigate miRNA expression profile in rat hippocampus, and six miRNAs were confirmed to be differentially expressed. Kyoto Encyclopedia of Genes and Genomes pathway analysis indicated that most of the target genes for these six miRNAs were associated with neuronal apoptosis. Meanwhile, the levels of miR-423-3p and miR-296-5p were correlated with the activity of caspase-3, an apoptosis indicator. Additionally, the loading of miR-423-3p was increased in RNA-induced silencing complex whilst caspase-6, a target of miR-423-3p, was reduced in chronic TLE rats. Collectively, our findings suggest that miRNAs may exert anti-apoptotic effects in chronic TLE.
doi:10.1038/srep04734
PMCID: PMC3994440  PMID: 24751812
19.  Ovariectomy Results in Variable Changes in Nociception, Mood and Depression in Adult Female Rats 
PLoS ONE  2014;9(4):e94312.
Decline in the ovarian hormones with menopause may influence somatosensory, cognitive, and affective processing. The present study investigated whether hormonal depletion alters the nociceptive, depressive-like and learning behaviors in experimental rats after ovariectomy (OVX), a common method to deplete animals of their gonadal hormones. OVX rats developed thermal hyperalgesia in proximal and distal tail that was established 2 weeks after OVX and lasted the 7 weeks of the experiment. A robust mechanical allodynia was also occurred at 5 weeks after OVX. In the 5th week after OVX, dilute formalin (5%)-induced nociceptive responses (such as elevating and licking or biting) during the second phase were significantly increased as compared to intact and sham-OVX females. However, chronic constriction injury (CCI) of the sciatic nerve-induced mechanical allodynia did not differ as hormonal status (e.g. OVX and ovarian intact). Using formalin-induced conditioned place avoidance (F-CPA), which is believed to reflect the pain-related negative emotion, we further found that OVX significantly attenuated F-CPA scores but did not alter electric foot-shock-induced CPA (S-CPA). In the open field and forced swimming test, there was an increase in depressive-like behaviors in OVX rats. There was no detectable impairment of spatial performance by Morris water maze task in OVX rats up to 5 weeks after surgery. Estrogen replacement retrieved OVX-induced nociceptive hypersensitivity and depressive-like behaviors. This is the first study to investigate the impacts of ovarian removal on nociceptive perception, negative emotion, depressive-like behaviors and spatial learning in adult female rats in a uniform and standard way.
doi:10.1371/journal.pone.0094312
PMCID: PMC3978042  PMID: 24710472
20.  Cryptotanshinone Reverses Reproductive and Metabolic Disturbances in PCOS Model Rats via Regulating the Expression of CYP17 and AR 
Objective. To explore the effect of Cryptotanshinone on reversing the reproductive and metabolic disturbances in polycystic ovary syndrome (PCOS) model rats and the possible regulatory mechanisms. Methods. PCOS model rats were induced by subcutaneous injection of dehydroepiandrosterone (DHEA) and verified by histological screening of vaginal exfoliated cells. After Cryptotanshinone intervention, the rats' body weight and ovary morphological were observed; the serum biochemical assessments were analyzed by radioimmunoassay (RIA) and key genes and proteins related with anabolism of androgen and insulin were detected by Real-Time PCR and Immunohistochemical (IHC). Results. The estrous cyclicity of PCOS model rats was significantly recovered by Cryptotanshinone. The body weight, ovarian coefficient, and ovarian morphology had been improved and the serum biochemical indicators including testosterone (T), androstenedione (A2), luteinizing hormone (LH), LH/follicle stimulating hormone (FSH), sexual binding globulin (SHBG), low density cholesterol (LDL-C), fasting insulin (FINS) were reversed after Cryptotanshinone intervention. Specifically, the levels of Cytochrome P450, 17-a hydroxylase/17,20 lyase (CYP17), and androgen receptor (AR) were downregulated significantly. Conclusions. Our data suggest that Cryptotanshinone could rebalance reproductive and metabolic disturbances in PCOS model rats and could be a potential therapeutic agent for the treatment of PCOS.
doi:10.1155/2014/670743
PMCID: PMC3996859  PMID: 24799941
21.  Nanoparticles for targeted delivery of antioxidant enzymes to the brain after cerebral ischemia and reperfusion injury 
Stroke is one of the major causes of death and disability in the United States. After cerebral ischemia and reperfusion injury, the generation of reactive oxygen species (ROS) and reactive nitrogen species may contribute to the disease process through alterations in the structure of DNA, RNA, proteins, and lipids. We generated various nanoparticles (liposomes, polybutylcyanoacrylate (PBCA), or poly(lactide-co-glycolide) (PLGA)) that contained active superoxide dismutase (SOD) enzyme (4,000 to 20,000 U/kg) in the mouse model of cerebral ischemia and reperfusion injury to determine the impact of these molecules. In addition, the nanoparticles were untagged or tagged with nonselective antibodies or antibodies directed against the N-methyl-𝒟-aspartate (NMDA) receptor 1. The nanoparticles containing SOD protected primary neurons in vitro from oxygen-glucose deprivation (OGD) and limited the extent of apoptosis. The nanoparticles showed protection against ischemia and reperfusion injury when applied after injury with a 50% to 60% reduction in infarct volume, reduced inflammatory markers, and improved behavior in vivo. The targeted nanoparticles not only showed enhanced protection but also showed localization to the CA regions of the hippocampus. Nanoparticles alone were not effective in reducing infarct volume. These studies show that targeted nanoparticles containing protective factors may be viable candidates for the treatment of stroke.
doi:10.1038/jcbfm.2012.209
PMCID: PMC3618396  PMID: 23385198
anti-oxidants; antibody; cerebral ischemia; nanoparticles; superoxide dismutase
22.  Comparison of laparoscopy and laparotomy for the management of early-stage ovarian cancer: surgical and oncological outcomes 
Journal of Gynecologic Oncology  2014;25(2):111-117.
Objective
To investigate the surgical and oncological outcomes of laparoscopic surgery compared with laparotomy for the treatment of early-stage ovarian cancer.
Methods
Data from patients who underwent surgical management for early-stage ovarian cancer between 2006 and 2012 were retrospectively reviewed. All patients presented with stage I or II disease, and underwent comprehensive staging surgery consisting of a total hysterectomy, bilateral salpingo-oophorectomy, pelvic and para-aortic lymphadenectomy, omentectomy, and peritoneal cytology.
Results
Seventy-seven patients who underwent laparoscopic surgery (24 patients) or laparotomy (53 patients) were identified. Surgery for none of the patients was converted from laparoscopy to laparotomy. The mean operation time was shorter and the estimated blood loss was lower in the laparoscopy group than in the laparotomy group, though the differences were not statistically significant (193 min vs. 224 min, p=0.127; 698 mL vs. 973 mL, p=0.127). There were no differences in the intraoperative or postoperative complications. During a mean follow-up period of 31 months, tumor recurrence occurred in 4 patients: 2 (8.3%) in the laparoscopy group and 2 (3.8%) in the laparotomy group. The mean disease-free survival was 59 months after laparoscopy and 66 months after laparotomy (p=0.367).
Conclusion
Laparoscopic surgery seems to be adequate and feasible for the treatment of early-stage ovarian cancer with comparable results to laparotomy in terms of the surgical outcomes and oncological safety.
doi:10.3802/jgo.2014.25.2.111
PMCID: PMC3996260  PMID: 24761214
Early-stage ovarian cancer; Laparoscopy surgery; Laparotomy staging
23.  Theory of Mind as a Mediator of Reasoning and Facial Emotion Recognition: Findings from 200 Healthy People 
Psychiatry Investigation  2013;11(2):105-111.
Objective
It was proposed that the ability to recognize facial emotions is closely related to complex neurocognitive processes and/or skills related to theory of mind (ToM). This study examines whether ToM skills mediate the relationship between higher neurocognitive functions, such as reasoning ability, and facial emotion recognition.
Methods
A total of 200 healthy subjects (101 males, 99 females) were recruited. Facial emotion recognition was measured through the use of 64 facial emotional stimuli that were selected from photographs from the Korean Facial Expressions of Emotion (KOFEE). Participants were requested to complete the Theory of Mind Picture Stories task and Standard Progressive Matrices (SPM).
Results
Multiple regression analysis showed that the SPM score (t=3.19, p=0.002, β=0.22) and the overall ToM score (t=2.56, p=0.011, β=0.18) were primarily associated with a total hit rate (%) of the emotion recognition task. Hierarchical regression analysis through a three-step mediation model showed that ToM may partially mediate the relationship between SPM and performance on facial emotion recognition.
Conclusion
These findings imply that higher neurocognitive functioning, inclusive of reasoning, may not only directly contribute towards facial emotion recognition but also influence ToM, which in turn, influences facial emotion recognition. These findings are particularly true for healthy young people.
doi:10.4306/pi.2014.11.2.105
PMCID: PMC4023082  PMID: 24843363
Facial emotion; Theory of mind; Analogical reasoning; Neurocognition; Social cognition
24.  Stiff-Person Syndrome: Case Series 
Journal of Movement Disorders  2014;7(1):19-21.
Stiff-person syndrome (SPS) is a rare disorder, characterized by progressive fluctuating muscular rigidity and spasms. Glutamic acid decarboxylase (GAD) antibody is primarily involved in the pathogenesis of SPS and SPS is strongly associated with other autoimmune disease. Here we report three cases of patients with classical SPS finally confirmed by high serum level of GAD antibodies. All of our patients respond favorably to gamma amino butyric acid-enhancing drugs and immunotherapies.
doi:10.14802/jmd.14004
PMCID: PMC4051723  PMID: 24926406
Stiff-person syndrome; Glutamic acid decarboxylase antibody; Autoimmune disease
25.  Effect of gender differences on the regulation of renal ischemia-reperfusion-induced inflammation in mice 
Molecular Medicine Reports  2014;9(6):2061-2068.
Inflammation is a key mediator of renal ischemia-reperfusion (IR) injury. Gender disparities have been reported in acute and chronic kidney disease. In particular, males are considered to be more susceptible to renal ischemic injury compared with females according to animal studies. The purpose of the present study was to investigate the effect of gender on the renal inflammatory response following acute renal IR injury in mice. Experiments were performed in male and female C57BL/6 mice. Two weeks prior to the study, castration or ovariectomy were performed and testosterone propionate (100 μg/kg) or 17β-estradiol (100 μg/kg) was injected. Acute kidney injury (AKI) was induced by bilateral clamping of the renal pedicle for 23 min. Histological examination, western blot analysis and quantitative polymerase chain reaction were performed. In the acute renal IR injury model, the female mice were more resistant to kidney injury compared with the male mice. However, castration of the male mice reduced the levels of IR-induced tubular injury and macrophage infiltration compared with those in the injured male mice. Supplementation of testosterone reversed this protective effect in the male AKI model. Depletion of estrogen in the female mice increased the levels of IR-induced tubular injury and macrophage infiltration compared with those in the injured female mice. However, supplementation of estrogen in the ovariectomized female mice attenuated the IR-induced tubular injury and reduced the levels of macrophage infiltration. The expression levels of inflammatory cytokines, including tumor necrosis factor-α, monocyte chemotactic protein-1, interferon-γ and chemokine (C-C motif) ligand 17, were elevated in the male AKI mice compared with those in the control male mice, and were attenuated by castration. Estrogen depletion in the female mice significantly increased the expression levels of the renal inflammatory cytokines compared with those in the injured female mice, and were attenuated by estrogen supplementation in the ovariectomized female mice. These results suggested that the male gender confers greater susceptibility to IR renal injury due to an enhanced inflammatory response.
doi:10.3892/mmr.2014.2089
PMCID: PMC4055478  PMID: 24682292
gender; disparity; acute kidney injury; inflammation

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