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1.  Biological Properties of Acidic Cosmetic Water from Seawater 
This current work was to investigate the biological effects of acidic cosmetic water (ACW) on various biological assays. ACW was isolated from seawater and demonstrated several bio-functions at various concentration ranges. ACW showed a satisfactory effect against Staphylococcus aureus, which reduced 90% of bacterial growth after a 5-second exposure. We used cultured human peripheral blood mononuclear cells (PBMCs) to test the properties of ACW in inflammatory cytokine release, and it did not induce inflammatory cytokine release from un-stimulated, normal PBMCs. However, ACW was able to inhibit bacterial lipopolysaccharide (LPS)-induced inflammatory cytokine TNF-α released from PBMCs, showing an anti-inflammation potential. Furthermore, ACW did not stimulate the rat basophilic leukemia cell (RBL-2H3) related allergy response on de-granulation. Our data presented ACW with a strong anti-oxidative ability in a superoxide anion radical scavenging assay. In mass spectrometry information, magnesium and zinc ions demonstrated bio-functional detections for anti-inflammation as well as other metal ions such as potassium and calcium were observed. ACW also had minor tyrosinase and melanin decreasing activities in human epidermal melanocytes (HEMn-MP) without apparent cytotoxicity. In addition, the cell proliferation assay illustrated anti-growth and anti-migration effects of ACW on human skin melanoma cells (A375.S2) indicating that it exerted the anti-cancer potential against skin cancer. The results obtained from biological assays showed that ACW possessed multiple bioactivities, including anti-microorganism, anti-inflammation, allergy-free, antioxidant, anti-melanin and anticancer properties. To our knowledge, this was the first report presenting these bioactivities on ACW.
PMCID: PMC3382787  PMID: 22754342
acidic cosmetic water (ACW); antioxidant activity; anti-microorganism; anti-inflammation; allergy-free; skin-whitening; anti-melanoma
2.  Carvedilol for Prevention of Atrial Fibrillation after Cardiac Surgery: A Meta-Analysis 
PLoS ONE  2014;9(4):e94005.
Postoperative atrial fibrillation (POAF) remains the most common complication after cardiac surgery. Current guidelines recommend β-blockers to prevent POAF. Carvedilol is a non-selective β-adrenergic blocker with anti-inflammatory, antioxidant, and multiple cationic channel blocking properties. These unique properties of carvedilol have generated interest in its use as a prophylaxis for POAF.
To investigate the efficacy of carvedilol in preventing POAF.
PubMed from the inception to September 2013 was searched for studies assessing the effect of carvedilol on POAF occurrence. Pooled relative risk (RR) with 95% confidence interval (CI) was calculated using random- or fixed-effect models when appropriate. Six comparative trials (three randomized controlled trials and three nonrandomized controlled trials) including 765 participants met the inclusion criteria.
Carvedilol was associated with a significant reduction in POAF (relative risk [RR] 0.49, 95% confidence interval [CI] 0.37 to 0.64, p<0.001). Subgroup analyses yielded similar results. In a subgroup analysis, carvedilol appeared to be superior to metoprolol for the prevention of POAF (RR 0.51, 95% CI 0.37 to 0.70, p<0.001). No evidence of heterogeneity was observed.
In conclusion, carvedilol may effectively reduce the incidence of POAF in patients undergoing cardiac surgery. It appeared to be superior to metoprolol. A large-scale, well-designed randomized controlled trial is needed to conclusively answer the question regarding the utility of carvedilol in the prevention of POAF.
PMCID: PMC3976381  PMID: 24705913
3.  DNAzyme-Based Probes for Telomerase Study in Early-Stage Cancer Detection 
Human telomerase is a polymerase enzyme that adds tandem repeats of DNA (TTAGGG) in the telomere regions. Since telomerase can be detected in immortalized, but not normal, somatic cells, it has been considered a selective target for cancer chemotherapy. In this paper, we describe a DNAzyme-based probe method to determine telomerase in cell lysates. Telomerase elongates the primer site on the probe. Subsequent addition of the PbII cofactor activates the DNAzyme, which cleaves the elongated fragment at the RNA site, releasing the probe for repetitive cycling and signal amplification. The cleaved fragment is detected by a reporter molecular beacon. Enzymatic amplification with rapid turnover allows detection of telomerase in the range of 0.1 μg to 1 μg cell lysate, with a 5-fold increase in signal level for cancer cells over normal cells. This probe design can provide a simple, yet rapid and sensitive, measurement of telomerase activity.
PMCID: PMC3755732  PMID: 23426940
DNAzyme; probe design; intramolecular probe; telomerase; lead ion
4.  Soluble Interleukin-6 Receptor-Mediated Innate Immune Response to DNA and RNA Viruses 
Journal of Virology  2013;87(20):11244-11254.
The interleukin-6 (IL-6) receptor, which exists as membrane-bound and soluble forms, plays critical roles in the immune response. The soluble IL-6 receptor (sIL6R) has been identified as a potential therapeutic target for preventing coronary heart disease. However, little is known about the role of this receptor during viral infection. In this study, we show that sIL6R, but not IL-6, is induced by viral infection via the cyclooxygenase-2 pathway. Interestingly, sIL6R, but not IL-6, exhibited extensive antiviral activity against DNA and RNA viruses, including hepatitis B virus, influenza virus, human enterovirus 71, and vesicular stomatitis virus. No synergistic effects on antiviral action were observed by combining sIL6R and IL-6. Furthermore, sIL6R mediated antiviral action via the p28 pathway and induced alpha interferon (IFN-α) by promoting the nuclear translocation of IFN regulatory factor 3 (IRF3) and NF-κB, which led to the activation of downstream IFN effectors, including 2′,5′-oligoadenylate synthetase (OAS), double-stranded RNA-dependent protein kinase (PKR), and myxovirus resistance protein (Mx). Thus, our results demonstrate that sIL6R, but not IL-6, plays an important role in the host antiviral response.
PMCID: PMC3807281  PMID: 23946454
5.  Isoflurane-induced spatial memory impairment by a mechanism independent of amyloid-beta levels and tau protein phosphorylation changes in aged rats 
Neurological research  2012;34(1):3-10.
The molecular mechanism of postoperative cognitive dysfunction is largely unknown. Isoflurane has been shown to promote Alzheimer’s disease neuropathogenesis. We set out to determine whether the effect of isoflurane on spatial memory is associated with amyloid-beta (A-beta) levels and tau phosphorylation in aged rats.
Eighteen-month-old male Sprague–Dawley rats were randomly assigned as anesthesia group (n = 31, received 1.4% isoflurane for 2 hours and had behavioral testing), training group (n = 20, received no anesthesia but had behavioral testing), and control group (n = 10, received no anesthesia and had no behavioral testing). Spatial memory was measured before and 2 days after the anesthesia by the Morris water maze. We divided the anesthesia group into an isoflurane-induced severe memory impairment group (SIG, n = 6) and a no severe memory impairment group (NSIG, n = 25), according to whether the escape latency was more than 1.96 stand deviation of that from the training group. Levels of A-beta and tau in the hippocampus were determined by enzyme-linked immunosorbent assay and quantitative western blot at the end of behavioral testing.
We found that isoflurane increased the escape latency in the SIG as compared to that in the training group and NSIG without affecting swimming speed. However, there were no differences in the levels of A-beta and tau among SIG, NSIG, training, and control groups.
Isoflurane may induce spatial memory impairment through non-A-beta or tau neuropathogenesis mechanisms in aged rats.
PMCID: PMC3971391  PMID: 22196855
Amyloid-beta; Hippocampus; Isoflurane; Morris water maze; Tau
6.  Distinct Pathways of ERK1/2 Activation by Hydroxy-Carboxylic Acid Receptor-1 
PLoS ONE  2014;9(3):e93041.
Mechanistic investigations have shown that, upon agonist activation, hydroxy-carboxylic acid receptor-1(HCA1) couples to a Gi protein and inhibits adenylate cyclase activity, leading to inhibition of liberation of free fatty acid. However, the underlying molecular mechanisms for HCA1 signaling remain largely unknown. Using CHO-K1 cells stably expressing HCA1, and L6 cells, which endogenously express rat HCA1 receptors, we found that activation of ERK1/2 by HCA1 was rapid, peaking at 5 min, and was significantly blocked by pertussis toxin. Furthermore, time course experiments with different kinase inhibitors demonstrated that HCA1 induced ERK1/2 activation via the extracellular Ca2+, PKC and IGF-I receptor transactivation-dependent pathways. In addition, we observed that pretreated the cells with M119K, an inhibitor of Gβγ subunit-dependent signaling, effectively attenuated the ERK1/2 activation triggered by HCA1, suggesting a critical role for βγ-subunits in HCA1-activated ERK1/2 phosphorylation. Furthermore, the present results also indicated that the arrestin2/3 were not required for ERK1/2 activation. In conclusion, our findings demonstrate that upon binding to agonist, HCA1 receptors initially activate Gi, leading to dissociation of the Gβγ subunit from activated Gi, and subsequently induce ERK1/2 activation via two distinct pathways: one PKC-dependent pathway and the other IGF-IR transactivation-dependent pathway. Our results provide the first in-depth evidence that defines the molecular mechanism of HCA1-mediated ERK1/2 activation.
PMCID: PMC3966839  PMID: 24671202
7.  Postsynaptic Target Specific Synaptic Dysfunctions in the CA3 Area of BACE1 Knockout Mice 
PLoS ONE  2014;9(3):e92279.
Beta-amyloid precursor protein cleaving enzyme 1 (BACE1), a major neuronal β-secretase critical for the formation of β-amyloid (Aβ) peptide, is considered one of the key therapeutic targets that can prevent the progression of Alzheimer’s disease (AD). Although a complete ablation of BACE1 gene prevents Aβ formation, we previously reported that BACE1 knockouts (KOs) display presynaptic deficits, especially at the mossy fiber (MF) to CA3 synapses. Whether the defect is specific to certain inputs or postsynaptic targets in CA3 is unknown. To determine this, we performed whole-cell recording from pyramidal cells (PYR) and the stratum lucidum (SL) interneurons in the CA3, both of which receive excitatory MF terminals with high levels of BACE1 expression. BACE1 KOs displayed an enhancement of paired-pulse facilitation at the MF inputs to CA3 PYRs without changes at the MF inputs to SL interneurons, which suggests postsynaptic target specific regulation. The synaptic dysfunction in CA3 PYRs was not restricted to excitatory synapses, as seen by an increase in the paired-pulse ratio of evoked inhibitory postsynaptic currents from SL to CA3 PYRs. In addition to the changes in evoked synaptic transmission, BACE1 KOs displayed a reduction in the frequency of miniature excitatory and inhibitory postsynaptic currents (mEPSCs and mIPSCs) in CA3 PYRs without alteration in mEPSCs recorded from SL interneurons. This suggests that the impairment may be more global across diverse inputs to CA3 PYRs. Our results indicate that the synaptic dysfunctions seen in BACE1 KOs are specific to the postsynaptic target, the CA3 PYRs, independent of the input type.
PMCID: PMC3956924  PMID: 24637500
8.  Proteomics Analysis of Normal and Senescent NG108-15 Cells: GRP78 Plays a Negative Role in Cisplatin-Induced Senescence in the NG108-15 Cell Line 
PLoS ONE  2014;9(3):e90114.
Accelerated senescence (ACS) leading to proliferative arrest is a physiological mechanism of the DNA damage response that occurs during tumor therapy. Our experiment was designed to detect unknown genes that may play important roles in cisplatin-induced senescence and to illustrate the related senescence mechanism. Using 2-dimension electrophoresis (2-DE), we identified 5 protein spots with different expression levels in the normal and senescent NG108-15 cells. According to MALDI-TOF MS analysis, the 5 proteins were determined to be peptidylprolyl isomerase A (PPIA), peroxiredoxin 1 (PRX1), glutathione S-transferase mu 1 (GSTM1), vimentin (VIM) and glucose-regulated protein 78 (GRP78). Then, we investigated how cisplatin-induced senescence was mediated by GRP78 in the NG108-15 cells. Knockdown of GRP78 significantly increased P53 expression in NG108-15 cells. Additionally, 2-deoxy-D-glucose (2DG)-induced GRP78 overexpression protected the NG108-15 cells from cisplatin-induced senescence, which was accompanied by the obvious suppression of P53 and p-CDC2 expression. Inhibition of Ca2+ release from endoplasmic reticulum (ER) stores was also found to be associated with the anti-senescence effect of 2DG-induced GRP78 overexpression. In conclusion, we found 5 proteins that were differentially expressed in normal NG108-15 cells and senescent NG108-15 cells. GRP78 plays an important role in cisplatin-induced senescence in NG108-15 cells, mainly through its regulation of P53 expression and ER calcium efflux.
PMCID: PMC3951507  PMID: 24621580
9.  Genetic Diversity and Population Demography of the Chinese Crocodile Lizard (Shinisaurus crocodilurus) in China 
PLoS ONE  2014;9(3):e91570.
The Chinese crocodile lizard Shinisaurus crocodilurus is a critically endangered species, listed in Appendix II of CITES. Its populations and habitat in China have undergone significant changes in recent years. Understanding the genetic variability and phylogeography of this species is very important for successful conservation. In this study, samples were taken from 11 wild ponds and two captive populations in China. We sequenced mitochondrial CYTB, partial ND6, and partial tRNA-Glu and genotyped 10 microsatellite loci. Our analyses of these data showed low genetic variability, no strong isolation caused by distance, and a lack of a phylogeographic structure in this species. Based on our results, the basal divergence between two clades of S. crocodilurus in China may have been caused by the formation of the Pearl River system. We found a population expansion in one of these clades. Microsatellite analysis indicated the presence of three clusters, separated by significant genetic differences. We found that most individuals in the two captive populations were from the Luokeng (Guangdong) and Guangxi wild source populations, respectively.
PMCID: PMC3950216  PMID: 24618917
10.  Anesthetics Isoflurane and Desflurane Differently Affect Mitochondrial Function, Learning, and Memory 
Annals of neurology  2012;72(4):630.
There are approximately 8.5 million Alzheimer disease (AD) patients who need anesthesia and surgery care every year. The inhalation anesthetic isoflurane, but not desflurane, has been shown to induce caspase activation and apoptosis, which are part of AD neuropathogenesis, through the mitochondria-dependent apoptosis pathway. However, the in vivo relevance, underlying mechanisms, and functional consequences of these findings remain largely to be determined.
We therefore set out to assess the effects of isoflurane and desflurane on mitochondrial function, cytotoxicity, learning, and memory using flow cytometry, confocal microscopy, Western blot analysis, immunocytochemistry, and the fear conditioning test.
Here we show that isoflurane, but not desflurane, induces opening of mitochondrial permeability transition pore (mPTP), increase in levels of reactive oxygen species, reduction in levels of mitochondrial membrane potential and adenosine-5′-triphosphate, activation of caspase 3, and impairment of learning and memory in cultured cells, mouse hippocampus neurons, mouse hippocampus, and mice. Moreover, cyclosporine A, a blocker of mPTP opening, attenuates isoflurane-induced mPTP opening, caspase 3 activation, and impairment of learning and memory. Finally, isoflurane may induce the opening of mPTP via increasing levels of reactive oxygen species.
These findings suggest that desflurane could be a safer anesthetic for AD patients as compared to isoflurane, and elucidate the potential mitochondria-associated underlying mechanisms, and therefore have implications for use of anesthetics in AD patients, pending human study confirmation.
PMCID: PMC3942786  PMID: 23109162
11.  Whole-Exome Sequencing Identifies ALMS1, IQCB1, CNGA3, and MYO7A Mutations in Patients with Leber Congenital Amaurosis 
Human mutation  2011;32(12):1450-1459.
It has been well documented that mutations in the same retinal disease gene can result in different clinical phenotypes due to difference in the mutant allele and/or genetic background. To evaluate this, a set of consanguineous patient families with Leber congenital amaurosis (LCA) that do not carry mutations in known LCA disease genes was characterized through homozygosity mapping followed by targeted exon/whole-exome sequencing to identify genetic variations. Among these families, a total of five putative disease-causing mutations, including four novel alleles, were found for six families. These five mutations are located in four genes, ALMS1, IQCB1, CNGA3, and MYO7A. Therefore, in our LCA collection from Saudi Arabia, three of the 37 unassigned families carry mutations in retinal disease genes ALMS1, CNGA3, and MYO7A, which have not been previously associated with LCA, and 3 of the 37 carry novel mutations in IQCB1, which has been recently associated with LCA. Together with other reports, our results emphasize that the molecular heterogeneity underlying LCA, and likely other retinal diseases, may be highly complex. Thus, to obtain accurate diagnosis and gain a complete picture of the disease, it is essential to sequence a larger set of retinal disease genes and combine the clinical phenotype with molecular diagnosis.
PMCID: PMC3943164  PMID: 21901789
Leber congenital amaurosis; LCA; whole-exome sequencing; SNP; padlock
12.  Selective anesthesia-induced neuroinflammation in developing mouse brain and cognitive impairment 
Anesthesiology  2013;118(3):502-515.
Recent population studies have suggested that children with multiple exposures to anesthesia and surgery at an early age are at an increased risk of cognitive impairment. We therefore have established an animal model with multiple versus single exposures of anesthetic(s) in young versus adult mice, aiming to distinguish the role of different anesthesia in cognitive impairment.
Six day and 60 day-old mice were exposed to various anesthesia regimen. We then determined the effects of the anesthesia on learning and memory function, levels of pro-inflammatory cytokine interleukin-6 and tumor necrosis factor-α in brain tissues, and the amount of ionized calcium binding adaptor molecule 1 positive cells, the marker of microglia activation, in the hippocampus.
Here we show that anesthesia with 3% sevoflurane two hours daily for three days induced cognitive impairment and neuroinflammation [e.g., increased interleukin-6 levels: 151% ± 2.3 (mean ± SD) versus 100% ± 9.0, P = 0.035, n = 6] in young, but not adult, mice. Anesthesia with 3% sevoflurane two hours daily for one day and 9% desflurane two hours daily for three days induced neither cognitive impairment nor neuroinflammation. Finally, an enriched environment and anti-inflammation treatment (ketorolac) ameliorated the sevoflurane anesthesia-induced cognitive impairment.
Anesthesia-induced cognitive impairment may depend on developmental stage, anesthetic agent, and the number of exposures. These findings also suggest the cellular basis and the potential prevention and treatment strategies for the anesthesia-induced cognitive impairment, which may ultimately lead to safer anesthesia care and better postoperative outcomes for children.
PMCID: PMC3580002  PMID: 23314110
13.  Mebendazole Reduces Vascular Smooth Muscle Cell Proliferation and Neointimal Formation Following Vascular Injury in Mice 
PLoS ONE  2014;9(2):e90146.
Mebendazole is an antihelminthic drug that exerts its effects via interference with microtubule function in parasites. To determine the utility of mebendazole as a potential treatment for vascular diseases involving proliferation of vascular smooth muscle cells, the effects of mebendazole on vascular smooth muscle cell proliferation were tested in vitro and in a mouse model of arterial injury. In vitro, mebendazole inhibited proliferation and migration of murine vascular smooth muscle cells and this was associated with altered intracellular microtubule organization. To determine in vivo effects of mebendazole following vascular injury, femoral arterial wire injury was induced in wild-type mice treated with either mebendazole or placebo control. Compared with placebo-treated mice, mebendazole-treated mice formed less neointima at the site of injury. Mebendazole is effective at inhibiting vascular smooth muscle cell proliferation and migration, and neointimal formation following arterial injury in mice.
PMCID: PMC3937425  PMID: 24587248
14.  Regulation of Drosophila Eye Development by the Transcription Factor Sine oculis 
PLoS ONE  2014;9(2):e89695.
Homeodomain transcription factors of the Sine oculis (SIX) family direct multiple regulatory processes throughout the metazoans. Sine oculis (So) was first characterized in the fruit fly Drosophila melanogaster, where it is both necessary and sufficient for eye development, regulating cell survival, proliferation, and differentiation. Despite its key role in development, only a few direct targets of So have been described previously. In the current study, we aim to expand our knowledge of So-mediated transcriptional regulation in the developing Drosophila eye using ChIP-seq to map So binding regions throughout the genome. We find 7,566 So enriched regions (peaks), estimated to map to 5,952 genes. Using overlap between the So ChIP-seq peak set and genes that are differentially regulated in response to loss or gain of so, we identify putative direct targets of So. We find So binding enrichment in genes not previously known to be regulated by So, including genes that encode cell junction proteins and signaling pathway components. In addition, we analyze a subset of So-bound novel genes in the eye, and find eight genes that have previously uncharacterized eye phenotypes and may be novel direct targets of So. Our study presents a greatly expanded list of candidate So targets and serves as basis for future studies of So-mediated gene regulation in the eye.
PMCID: PMC3934907  PMID: 24586968
15.  Comprehensive molecular diagnosis of 179 Leber congenital amaurosis and juvenile retinitis pigmentosa patients by targeted next generation sequencing 
Journal of medical genetics  2013;50(10):674-688.
Leber congenital amaurosis (LCA) and juvenile retinitis pigmentosa (RP) are inherited retinal diseases that cause early onset severe visual impairment. An accurate molecular diagnosis can refine the clinical diagnosis and allow gene specific treatments.
We developed a capture panel that enriches the exonic DNA of 163 known retinal disease genes. Using this panel, we performed targeted next generation sequencing (NGS) for a large cohort of 179 unrelated and prescreened patients with the clinical diagnosis of LCA or juvenile RP. Systematic NGS data analysis, Sanger sequencing validation, and segregation analysis were utilised to identify the pathogenic mutations. Patients were revisited to examine the potential phenotypic ambiguity at the time of initial diagnosis.
Pathogenic mutations for 72 patients (40%) were identified, including 45 novel mutations. Of these 72 patients, 58 carried mutations in known LCA or juvenile RP genes and exhibited corresponding phenotypes, while 14 carried mutations in retinal disease genes that were not consistent with their initial clinical diagnosis. We revisited patients in the latter case and found that homozygous mutations in PRPH2 can cause LCA/juvenile RP. Guided by the molecular diagnosis, we reclassified the clinical diagnosis in two patients.
We have identified a novel gene and a large number of novel mutations that are associated with LCA/juvenile RP. Our results highlight the importance of molecular diagnosis as an integral part of clinical diagnosis.
PMCID: PMC3932025  PMID: 23847139
16.  Unregistered Biological Words Recognition by Q-Learning with Transfer Learning 
The Scientific World Journal  2014;2014:173290.
Unregistered biological words recognition is the process of identification of terms that is out of vocabulary. Although many approaches have been developed, the performance approaches are not satisfactory. As the identification process can be viewed as a Markov process, we put forward a Q-learning with transfer learning algorithm to detect unregistered biological words from texts. With the Q-learning, the recognizer can attain the optimal solution of identification during the interaction with the texts and contexts. During the processing, a transfer learning approach is utilized to fully take advantage of the knowledge gained in a source task to speed up learning in a different but related target task. A mapping, required by many transfer learning, which relates features from the source task to the target task, is carried on automatically under the reinforcement learning framework. We examined the performance of three approaches with GENIA corpus and JNLPBA04 data. The proposed approach improved performance in both experiments. The precision, recall rate, and F score results of our approach surpassed those of conventional unregistered word recognizer as well as those of Q-learning approach without transfer learning.
PMCID: PMC3950481
17.  Meta-Analysis of Peripheral Blood Apolipoprotein E Levels in Alzheimer’s Disease 
PLoS ONE  2014;9(2):e89041.
Peripheral blood Apolipoprotein E (ApoE) levels have been proposed as biomarkers of Alzheimer’s disease (AD), but previous studies on levels of ApoE in blood remain inconsistent. This meta-analysis was designed to re-examine the potential role of peripheral ApoE in AD diagnosis and its potential value as a candidate biomarker.
We conducted a systematic literature search of MEDLINE, EMBASE, the Cochrane library, and BIOSIS previews for case-control studies measuring ApoE levels in serum or plasma from AD subjects and healthy controls. The pooled weighted mean difference (WMD) and 95% confidence interval (CI) were used to estimate the association between ApoE levels and AD risk.
Eight studies with a total of 2250 controls and 1498 AD cases were identified and analyzed. The pooled WMD from a random-effect model of AD participants compared with the healthy controls was −5.59 mg/l (95% CI: [−8.12, −3.06]). The overall pattern in WMD was not varied by characteristics of study, including age, country, assay method, publication year, and sample type.
Our meta-analysis supports a lowered level of blood ApoE in AD patients, and indicates its potential value as an important risk factor for AD. Further investigation employing standardized assay for ApoE measurement are still warranted to uncover the precise role of ApoE in the pathophysiology of AD.
PMCID: PMC3928366  PMID: 24558469
18.  Fluoxetine Pretreatment Promotes Neuronal Survival and Maturation after Auditory Fear Conditioning in the Rat Amygdala 
PLoS ONE  2014;9(2):e89147.
The amygdala is a critical brain region for auditory fear conditioning, which is a stressful condition for experimental rats. Adult neurogenesis in the dentate gyrus (DG) of the hippocampus, known to be sensitive to behavioral stress and treatment of the antidepressant fluoxetine (FLX), is involved in the formation of hippocampus-dependent memories. Here, we investigated whether neurogenesis also occurs in the amygdala and contributes to auditory fear memory. In rats showing persistent auditory fear memory following fear conditioning, we found that the survival of new-born cells and the number of new-born cells that differentiated into mature neurons labeled by BrdU and NeuN decreased in the amygdala, but the number of cells that developed into astrocytes labeled by BrdU and GFAP increased. Chronic pretreatment with FLX partially rescued the reduction in neurogenesis in the amygdala and slightly suppressed the maintenance of the long-lasting auditory fear memory 30 days after the fear conditioning. The present results suggest that adult neurogenesis in the amygdala is sensitive to antidepressant treatment and may weaken long-lasting auditory fear memory.
PMCID: PMC3923882  PMID: 24551236
19.  Effects of Thapsigargin on the Proliferation and Survival of Human Rheumatoid Arthritis Synovial Cells 
The Scientific World Journal  2014;2014:605416.
A series of experiments have been carried out to investigate the effects of different concentrations of thapsigargin (0, 0.001, 0.1, and 1 μM) on the proliferation and survival of human rheumatoid arthritis synovial cells (MH7A). The results showed that thapsigargin can block the cell proliferation in human rheumatoid arthritis synovial cells in a time- and dose-dependent manner. Results of Hoechst staining suggested that thapsigargin may induce cell apoptosis in MH7A cells in a time- and dose-dependent manner, and the percentages of cell death reached 44.6% at thapsigargin concentration of 1 μM treated for 4 days compared to the control. The protein and mRNA levels of cyclin D1 decreased gradually with the increasing of thapsigargin concentration and treatment times. Moreover, the protein levels of mTORC1 downstream indicators pS6K and p4EBP-1 were reduced by thapsigargin treatment at different concentrations and times, which should be responsible for the reduced cyclin D1 expressions. Our results revealed that thapsigargin may effectively impair the cell proliferation and survival of MH7A cells. The present findings will help to understand the molecular mechanism of fibroblast-like synoviocytes proliferations and suggest that thapsigargin is of potential for the clinical treatment of rheumatoid arthritis.
PMCID: PMC3934453
20.  Amyloid Formation in Heterogeneous Environments: Islet Amyloid Polypeptide Glycosaminoglycan Interactions 
Journal of molecular biology  2012;425(3):492-505.
Amyloid formation plays an important role in a broad range of diseases and the search for amyloid inhibitors is an active area of research. Amyloid formation takes places in a heterogeneous environment in vivo with the potential for interactions with membranes and with components of the extracellular matrix. Naturally occurring amyloid deposits are associated with sulfated proteoglycans and other factors. However, the vast majority of in vitro assays of amyloid formation and amyloid inhibition are conducted in homogeneous solution where the potential for interactions with membranes or sulfated proteoglycans is lacking and it is possible that different results may be obtained in heterogeneous environments. We show that variants of islet amyloid polypeptide, which are non-amyloidgenic in homogeneous solution, can be readily induced to form amyloid in the presence of glycosaminoglycans. Glycosaminoglycans are found to be more effective than anionic lipid vesicles at inducing amyloid formation on a per charge basis. Several known inhibitors of IAPP amyloid formation are shown to be less effective in the presence of glycosaminoglycans.
PMCID: PMC3753189  PMID: 23154166
IAPP; amylin; glycosaminoglycan; extracellular matrix; amyloid; inhibitor
21.  Evaluation of specific fecal protein biochips for the diagnosis of colorectal cancer 
AIM: To develop and initially test a potential fecal protein biochip for the screening of colorectal cancer (CRC).
METHODS: Fecal protein from 20 colorectal cancer patients and 20 healthy controls were extracted from all of the fecal samples and screened for proteomic differences using a Biotin label-based protein array. Candidate proteins were then verified by ELISA. Finally, we will select out the significant protein and a seven-target multiplex fecal protein biochip was generated and tested for 20 fecal samples to determine the effectiveness of the biochip on identifying CRC. And the value of the protein biochip would be discussed.
RESULTS: After tested by protein biochip of the fecal protein from 20 colorectal cancer patients and 20 healthy controls and levels of calprotectin, M2-pyruvatekinase, angiopoietin-2, fibroblast growth factor-23 (FGF-23), proteins of the matrix metalloproteinase, thrombopoietin (TPO) and interleukin-13 (IL-13) were significantly different between CRC and healthy controls. The sensitivity of all the seven proteins combined was 0.7, specificity was 0.4, and area under the receiver operating characteristics was 0.729. The most promising combinations of test proteins were FGF-23, TPO, and IL-13, reaching a sensitivity of 0.7 and a specificity of 0.7. The combination of FGF-23 and TPO scored highest with sensitivity of 0.7 and specificity of 0.8. Its mean that the combination of FGF-23 and TPO has the highest value for the diagnosis of CRC in our study.
CONCLUSION: A protein biochip composed of proteins found to be elevated in the feces of colorectal cancer patients has great potential as a noninvasive diagnostic for colorectal cancer. The addition of new protein biomarkers and technologies, as they are discovered, is an excellent avenue of future research.
PMCID: PMC3921516  PMID: 24574808
Protein biochip; Feces; Colorectal cancer; Fibroblast growth factor-23; Thrombopoietin
22.  Heterogeneous Differential Evolution for Numerical Optimization 
The Scientific World Journal  2014;2014:318063.
Differential evolution (DE) is a population-based stochastic search algorithm which has shown a good performance in solving many benchmarks and real-world optimization problems. Individuals in the standard DE, and most of its modifications, exhibit the same search characteristics because of the use of the same DE scheme. This paper proposes a simple and effective heterogeneous DE (HDE) to balance exploration and exploitation. In HDE, individuals are allowed to follow different search behaviors randomly selected from a DE scheme pool. Experiments are conducted on a comprehensive set of benchmark functions, including classical problems and shifted large-scale problems. The results show that heterogeneous DE achieves promising performance on a majority of the test problems.
PMCID: PMC3933298
23.  Mesenchymal stem cell-based cell engineering with multifunctional mesoporous silica nanoparticles for tumor delivery 
Biomaterials  2012;34(7):1772-1780.
Stem cell engineering, the manipulation and control of cells, harnesses tremendous potential for diagnosis and therapy of disease; however, it is still challenging to impart multifunctionalization onto stem cells to achieve both. Here we describe a mesenchymal stem cell (MSC)-based multifunctional platform to target orthotopic glioblastoma by integrating the tumor targeted delivery of mesenchymal stem cells and the multimodal imaging advantage of mesoporous silica nanoparticles (MSNs). Rapid cellular uptake, long retention time and stability of particles exemplify the potential that the combination of MSNs and MSCs has as a stem cell-based multifunctional platform. Using such a platform, we verified tumor-targeted delivery of MSCs by in vivo multimodal imaging in an orthotopic U87MG glioblastoma model, displaying higher tumor uptake than particles without MSCs. As a proof-of-concept, this MSC platform opens a new vision for multifunctional applications of cell products by combining the superiority of stem cells and nanoparticles for actively targeted delivery.
PMCID: PMC3538138  PMID: 23228423
Mesenchymal stem cells (MSCs); mesoporous silica nanoparticles (MSNs); cell engineering; multimodal imaging; targeted delivery
24.  Duration of Shh signaling contributes to mDA neuron diversity 
Developmental biology  2012;374(1):115-126.
Sonic hedgehog (Shh) signaling is critical for various developmental processes including specification of the midbrain dopamine (mDA) neurons in the ventral mesencephalon (vMes). While the timing of Shh and its response gene Gli1 segregates mDA neurons, their overall lineage contribution to mDA neurons heavily overlaps. Here, we demonstrate that the same set of mDA neuron progenitors sequentially respond to Shh signaling (Gli1 expression), induce Shh expression, and then turn off Shh responsiveness. Thus, at any given developmental stage, cells rarely co-express Shh and Gli1. Using ShhCre:GFP mice to delete the Smoothened receptor in the Shh pathway, we demonstrate that the loss of Shh signaling in Shh expressing cells results in a transient increase in proliferation and subsequent depletion of mDA neuron progenitors in the posterior vMes due to the facilitated cell cycle exit. Moreover, the change in duration of Shh signaling in vMes progenitors altered the timing of the contribution to the ventral tegmental area (VTA) and the substantia nigra pars compacta (SNc) mDA neurons. Taken together, our investigation on the relationship between the Shh-secreting and -responding cells revealed an intricate regulation of induction and cessation of Shh signaling that influences the distribution of mDA neurons in the VTA and SNc.
PMCID: PMC3548960  PMID: 23201023
Sonic hedgehog; Gli1; Midbrain dopamine neurons; Substantia nigra pars compacta; Ventral tegmental area; Genetic inducible fate mapping
25.  Late Life Leisure Activities and Risk of Cognitive Decline 
Studies concerning the effect of different types of leisure activities on various cognitive domains are limited. This study tests the hypothesis that mental, physical, and social activities have a domain-specific protection against cognitive decline.
A cohort of a geographically defined population in China was examined in 2003–2005 and followed for an average of 2.4 years. Leisure activities were assessed in 1,463 adults aged 65 years and older without cognitive or physical impairment at baseline, and their cognitive performances were tested at baseline and follow-up examinations.
High level of mental activity was related to less decline in global cognition (β = −.23, p < .01), language (β = −.11, p < .05), and executive function (β = −.13, p < .05) in ANCOVA models adjusting for age, gender, education, history of stroke, body mass index, Apolipoprotein E genotype, and baseline cognition. High level of physical activity was related to less decline in episodic memory (β = −.08, p < .05) and language (β = −.15, p < .01). High level of social activity was associated with less decline in global cognition (β = −.11, p < .05). Further, a dose-response pattern was observed: although participants who did not engage in any of the three activities experienced a significant global cognitive decline, those who engaged in any one of the activities maintained their cognition, and those who engaged in two or three activities improved their cognition. The same pattern was observed in men and in women.
Leisure activities in old age may protect against cognitive decline for both women and men, and different types of activities seem to benefit different cognitive domains.
PMCID: PMC3598354  PMID: 22879456
Cognitive function; Leisure activities; Mental activity; Physical activity; Social activity

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