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1.  Vismodegib, an antagonist of hedgehog signaling, directly alters taste molecular signaling in taste buds 
Cancer Medicine  2014;4(2):245-252.
Vismodegib, a highly selective inhibitor of hedgehog (Hh) pathway, is an approved treatment for basal-cell carcinoma. Patients on treatment with vismodegib often report profound alterations in taste sensation. The cellular mechanisms underlying the alterations have not been studied. Sonic Hh (Shh) signaling is required for cell growth and differentiation. In taste buds, Shh is exclusively expressed in type IV taste cells, which are undifferentiated basal cells and the precursors of the three types of taste sensing cells. Thus, we investigated if vismodegib has an inhibitory effect on taste cell turnover because of its known effects on Hh signaling. We gavaged C57BL/6J male mice daily with either vehicle or 30 mg/kg vismodegib for 15 weeks. The gustatory behavior and immunohistochemical profile of taste cells were examined. Vismodegib-treated mice showed decreased growth rate and behavioral responsivity to sweet and bitter stimuli, compared to vehicle-treated mice. We found that vismodegib-treated mice had significant reductions in taste bud size and numbers of taste cells per taste bud. Additionally, vismodegib treatment resulted in decreased numbers of Ki67- and Shh-expressing cells in taste buds. The numbers of phospholipase Cβ2- and α-gustducin-expressing cells, which contain biochemical machinery for sweet and bitter sensing, were reduced in vismodegib-treated mice. Furthermore, vismodegib treatment resulted in reduction in numbers of T1R3, glucagon-like peptide-1, and glucagon-expressing cells, which are known to modulate sweet taste sensitivity. These results suggest that inhibition of Shh signaling by vismodegib treatment directly results in alteration of taste due to local effects in taste buds.
doi:10.1002/cam4.350
PMCID: PMC4329008  PMID: 25354792
Basal-cell carcinoma; sonic hedgehog; taste buds; taste perception; Vismodegib
2.  Molecular detection and genotypic characterization of Toxoplasma gondii infection in bats in four provinces of China 
Parasites & Vectors  2014;7(1):558.
Background
Toxoplasma gondii is an intracellular protozoan parasite that infects a wide variety of warm-blooded hosts, including humans. Limited information about T. gondii infection in bats is available in China. The objective of the present study was to determine prevalence and genetic characterization of T. gondii infection in bats in Jilin, Liaoning, Jiangxi and Guangdong provinces, China.
Methods
During May 2005 to August 2013, bats were sampled from Jilin, Liaoning, Jiangxi, and Guangdong provinces, China, and liver tissues were collected for the detection of T. gondii by a nested PCR targeting the B1 gene. The positive samples were genotyped at 11 genetic markers (SAG1, 5′-and 3′-SAG2, alternative SAG2, SAG3, BTUB, GRA6, L358, PK1, c22-8, c29-2, and Apico) using multilocus polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP).
Results
A total of 626 bats representing 10 species were examined for T. gondii infection, 38 (6.1%) were tested positive with by PCR, 8 positive DNA samples were completely genotyped, of which 3 samples (2 from Cynopterus sphinx, and 1 from Murina leucogaster) represented ToxoDB#10, and 5 samples (2 from Murina leucogaster, 2 from Myotis chinensis, and 1 from Rhinolophus ferrumequinum) belonged to ToxoDB#9 (http://toxodb.org/toxo/).
Conclusions
The present study revealed an overall T. gondii prevalence of 6.1% in bats from Jilin, Liaoning, Jiangxi and Guangdong provinces in China, and reported two T. gondii genotypes (ToxoDB#9 and #10) having a wide geographical distribution in China. These results provide new genetic information about T. gondii infection in bats, and have implications for better understanding of the genetic diversity of T. gondii in China and elsewhere.
doi:10.1186/s13071-014-0558-7
PMCID: PMC4258805  PMID: 25465220
Toxoplasma gondii; Bats; Prevalence; Genetic characterization; China
3.  Seroprevalence and Risk Factors Associated with Hepatitis E Virus Infection in Three Species of Pet Birds in Northwest China 
The Scientific World Journal  2014;2014:296285.
Hepatitis E virus (HEV), the causative agent of hepatitis E, has been reported in a wide variety of animals, including birds, but little is known of HEV infection in pet birds in northwest China. The objective of the present investigation was to examine HEV seroprevalence in three species of pet birds, namely, Eurasian siskin, Oriental skylark, and black-tailed grosbeak from Gansu. Serum samples collected from 685 pet birds from August 2011 to September 2012 were examined independently for the presence of antibodies against HEV. A total of 59 (8.31%) pet birds were tested positive for HEV antibodies by the commercially available enzyme immunoassay kits. Of these, the seroprevalence was diverse in different species pet birds; the most frequent level was 10.83% (39/360) in Eurasian siskin, followed by 6.57% (19/289) in Oriental skylark, and 2.29% (1/36) in black-tailed grosbeak. Age and collecting region of pet birds were the main risk factors associated with HEV infection. The present study firstly revealed the seroprevalence of HEV infection in three species of pet birds in northwest China, which provided the baseline data for taking comprehensive countermeasures and measures for effectively preventing and controlling HEV infection in birds.
doi:10.1155/2014/296285
PMCID: PMC4230193  PMID: 25530995
4.  Seroprevalence and Risk Factors of Chlamydia abortus Infection in Tibetan Sheep in Gansu Province, Northwest China 
The Scientific World Journal  2014;2014:193464.
Chlamydia abortus, an important pathogen in a variety of animals, is associated with abortion in sheep. In the present study, 1732 blood samples, collected from Tibetan sheep between June 2013 and April 2014, were examined by the indirect hemagglutination (IHA) test, aiming to evaluate the seroprevalence and risk factors of C. abortus infection in Tibetan sheep. 323 of 1732 (18.65%) samples were seropositive for C. abortus antibodies at the cut-off of 1 : 16. A multivariate logistic regression analysis was used to evaluate the risk factors associated with seroprevalence, which could provide foundation to prevent and control C. abortus infection in Tibetan sheep. Gender of Tibetan sheep was left out of the final model because it is not significant in the logistic regression analysis (P > 0.05). Region, season, and age were considered as major risk factors associated with C. abortus infection in Tibetan sheep. Our study revealed a widespread and high prevalence of C. abortus infection in Tibetan sheep in Gansu province, northwest China, with higher exposure risk in different seasons and ages and distinct geographical distribution.
doi:10.1155/2014/193464
PMCID: PMC4226191  PMID: 25401129
5.  High-Glucose Inhibits Human Fibroblast Cell Migration in Wound Healing via Repression of bFGF-Regulating JNK Phosphorylation 
PLoS ONE  2014;9(9):e108182.
One of the major symptoms of diabetes mellitus (DM) is delayed wound healing, which affects large populations of patients worldwide. However, the underlying mechanism behind this illness remains elusive. Skin wound healing requires a series of coordinated processes, including fibroblast cell proliferation and migration. Here, we simulate DM by application of high glucose (HG) in human foreskin primary fibroblast cells to analyze the molecular mechanism of DM effects on wound healing. The results indicate that HG, at a concentration of 30 mM, delay cell migration, but not cell proliferation. bFGF is known to promote cell migration that partially rescues HG effects on cell migration. Molecular and cell biology studies demonstrated that HG enhanced ROS production and repressed JNK phosphorylation, but did not affect Rac1 activity. JNK and Rac1 activation were known to be important for bFGF regulated cell migration. To further confirm DM effects on skin repair, a type 1 diabetic rat model was established, and we observed the efficacy of bFGF on both normal and diabetic rat skin repair. Furthermore, proteomic studies identified an increase of Annexin A2 protein nitration in HG-stressed fibroblasts and the nitration was protected by activation of bFGF signaling. Treatment with FGFR1 and JNK inhibitors delayed cell migration and increased Annexin A2 nitration levels, indicating that Annexin A2 nitration is modulated by bFGF signaling via activation of JNK. Together with these results, our data suggests that the HG-mediated delay of cell migration is linked to the inhibition of bFGF signaling, specifically through JNK suppression.
doi:10.1371/journal.pone.0108182
PMCID: PMC4171528  PMID: 25244316
6.  Implications of the Wnt5a/CaMKII Pathway in Retinoic Acid-Induced Myogenic Tongue Abnormalities of Developing Mice 
Scientific Reports  2014;4:6082.
Although proper tongue development is relevant to other structures in the craniofacial region, the molecular details of muscle development in tongue remain poorly understood. Here, we report that pregnant mice treated with retinoic acid (+RA) produce embryos with tongue malformation and a cleft palate. Histological analyses revealed that at E14.5, the tongues of +RA fetuses failed to descend and flatten. Ultrastructural analysis showed that at perinatal stage E18.5, the myofilaments failed to form normal structures of sarcomeres, and arranged disorderly in the genioglossus. The proliferation and levels of myogenic determination markers (Myf5 and MyoD) and myosin in the genioglossus were profoundly reduced. Wnt5a and Camk2d expressions were down-regulated, while levels of Tbx1, Ror2, and PKCδ were up-regulated in the tongues of +RA fetuses. In mock- and Wnt5a-transfected C2C12 (Wnt5a-C2C12) cells, Wnt5a overexpression impaired proliferation, and maintained Myf5 at a relative high level after RA treatment. Furthermore, Wnt5a overexpression positively correlated with levels of Camk2d and Ror2 in C2C12 cells after RA exposure. These data support the hypothesis that the Wnt5a/CaMKII pathway is directly involved in RA-induced hypoplasia and disorder of tongue muscles.
doi:10.1038/srep06082
PMCID: PMC4133706  PMID: 25124193
7.  Toxocara Seroprevalence among Clinically Healthy Individuals, Pregnant Women and Psychiatric Patients and Associated Risk Factors in Shandong Province, Eastern China 
Background
Toxocarosis is a widespread zoonosis caused by the ascarid nematodes Toxocara canis and Toxocara cati, which primarily infect dogs and cats, respectively. Most human infections with Toxocara are asymptomatic; however, some infected individuals may develop a serious illness and even death. Nevertheless, epidemiological knowledge regarding the prevalence and risks associated with Toxocara infection is limited in China. Therefore, we performed a cross-sectional pilot study and estimated the seroprevalence of Toxocara infection in humans in Shandong Province, eastern China for the first time, from June 2011 to July 2013, involving clinically healthy individuals, pregnant women and psychiatric patients, aiming to attract public attention to Toxocara infection.
Methodology/Principle Findings
Seroprevalence of Toxocara was determined using an enzyme-linked immunosorbent assay based on a cross-sectional study conducted in Qingdao and Weihai, Shandong Province, eastern China. Factors potentially associated with Toxocara infection were identified by logistic regression analysis. The overall Toxocara seroprevalence among the study population (n = 2866) was 12.25%, and a significantly higher seroprevalence in psychiatric patients (16.40%, 73/445) than that in clinically healthy individuals (13.07%, 187/1431) and pregnant women (9.19%, 91/990) was revealed. Univariate analyses suggested that keeping dogs at home (OR = 0.06, 95% CI 0.05–0.08, P<0.001), contact with cats and dogs (OR = 0.42, 95% CI 0.33–0.53, P<0.001) and exposure with soil (OR = 0.37, 95% CI 0.28–0.49, P<0.001) were risk factors associated with Toxocara infection.
Conclusions/Significance
The present study revealed, for the first time, that human infection with Toxocara is common in eastern China, posing a significant public health concern. Increasing human and dog populations, population movements and climate change all will serve to increase the importance of this zoonosis. Further studies under controlled conditions are necessary to define potential morbidity associated with Toxocara infection.
Author Summary
Toxocarosis, a typical neglected and underestimated human health problem, is caused by the ascarid nematodes Toxocara canis and Toxocara cati, which primarily infect dogs and cats, respectively. Previous studies have reported an increased risk for Toxocara infection in humans worldwide, especially in children and psychiatric patients. This pilot study was aimed to investigate the Toxocara serology in clinically healthy individuals, pregnant women and psychiatric patients in Shandong Province, eastern China using an enzyme-linked immunosorbent assay. The overall Toxocara seroprevalence among the study population (n = 2866) was 12.25%, and a significantly higher seroprevalence in psychiatric patients (16.40%, 73/445) than that in clinically healthy individuals (13.07%, 187/1431) and pregnant women (9.19%, 91/990) was revealed. Keeping dogs at home, contact with cats and dogs, and exposure with soil were found to be associated with Toxocara infection. Our findings indicate that human infection with Toxocara is common in eastern China, posing a significant public health concern.
doi:10.1371/journal.pntd.0003082
PMCID: PMC4125144  PMID: 25101756
8.  Metabolic Dysfunction in Alzheimer’s Disease and Related Neurodegenerative Disorders 
Current Alzheimer research  2012;9(1):5-17.
Alzheimer’s disease and other related neurodegenerative diseases are highly debilitating disorders that affect millions of people worldwide. Efforts towards developing effective treatments for these disorders have shown limited efficacy at best, with no true cure to this day being present. Recent work, both clinical and experimental, indicates that many neurodegenerative disorders often display a coexisting metabolic dysfunction which may exacerbate neurological symptoms. It stands to reason therefore that metabolic pathways may themselves contain promising therapeutic targets for major neurodegenerative diseases. In this review, we provide an overview of some of the most recent evidence for metabolic dysregulation in Alzheimer’s disease, Huntington’s disease, and Parkinson’s disease, and discuss several potential mechanisms that may underlie the potential relationships between metabolic dysfunction and etiology of nervous system degeneration. We also highlight some prominent signaling pathways involved in the link between peripheral metabolism and the central nervous system that are potential targets for future therapies, and we will review some of the clinical progress in this field. It is likely that in the near future, therapeutics with combinatorial neuroprotective and ‘eumetabolic’ activities may possess superior efficacies compared to less pluripotent remedies.
PMCID: PMC4097094  PMID: 22329649
Neurodegenerative diseases; metabolic dysfunction; bodyweight; diabetes; glucose homeostasis; insulin; leptin; ghrelin; adiponectin; glucagon-like peptide 1; Alzheimer’s disease; Huntington’s disease; Parkinson’s disease
9.  3xTgAD mice exhibit altered behavior and elevated Aβ after chronic mild social stress 
Neurobiology of aging  2011;33(4):830.e1-830.12.
Chronic stress may be a risk factor for developing Alzheimer’s disease (AD), but most studies of the effects of stress in models of AD utilize acute adverse stressors of questionable clinical relevance. The goal of this work was to determine how chronic psychosocial stress affects behavioral and pathological outcomes in an animal model of AD, and to elucidate underlying mechanisms. A triple-transgenic mouse model of AD (3xTgAD mice) and nontransgenic control mice were used to test for an affect of chronic mild social stress on blood glucose, plasma glucocorticoids, plasma insulin, anxiety and hippocampal Aβ, ptau and BDNF levels. Despite the fact that both control and 3xTgAD mice experienced rises in corticosterone during episodes of mild social stress, at the end of the 6 week stress period 3xTgAD mice displayed increased anxiety, elevated levels of Aβ oligomers and intraneuronal Aβ, and decreased BDNF levels, whereas control mice did not. Findings suggest 3xTgAD mice are more vulnerable than control mice to chronic psychosocial stress, and that such chronic stress exacerbates Aβ accumulation and impairs neurotrophic signaling.
doi:10.1016/j.neurobiolaging.2011.07.005
PMCID: PMC4074356  PMID: 21855175
Alzheimer’s disease; amyloid oligomers; psychosocial stress; corticosterone; hippocampus; BDNF
10.  Metabolic and hormonal signatures in pre-manifest and manifest Huntington's disease patients 
Huntington's disease (HD) is an inherited neurodegenerative disorder typified by involuntary body movements, and psychiatric and cognitive abnormalities. Many HD patients also exhibit metabolic changes including progressive weight loss and appetite dysfunction. Here we have investigated metabolic function in pre-manifest and manifest HD subjects to establish an HD subject metabolic hormonal plasma signature. Individuals at risk for HD who have had predictive genetic testing showing the cytosine-adenine-guanine (CAG) expansion causative of HD, but who do not yet present signs and symptoms sufficient for the diagnosis of manifest HD are said to be “pre-manifest.” Pre-manifest and manifest HD patients, as well as both familial and non-familial controls, were evaluated for multiple peripheral metabolism signals including circulating levels of hormones, growth factors, lipids, and cytokines. Both pre-manifest and manifest HD subjects exhibited significantly reduced levels of circulating growth factors, including growth hormone and prolactin. HD-related changes in the levels of metabolic hormones such as ghrelin, glucagon, and amylin were also observed. Total cholesterol, HDL-C, and LDL-C were significantly decreased in HD subjects. C-reactive protein was significantly elevated in pre-manifest HD subjects. The observation of metabolic alterations, even in subjects considered to be in the pre-manifest stage of HD, suggests that in addition, and prior, to overt neuronal damage, HD affects metabolic hormone secretion and energy regulation, which may shed light on pathogenesis, and provide opportunities for biomarker development.
doi:10.3389/fphys.2014.00231
PMCID: PMC4066441  PMID: 25002850
Huntington's disease; pre-manifest; metabolic hormones; lipids; peripheral energy metabolism
11.  Seroprevalence and genetic characterization of Toxoplasma gondii in three species of pet birds in China 
Parasites & Vectors  2014;7:152.
Background
Toxoplasmosis, caused by the protozoan parasite Toxoplasma gondii, is one of the most common zoonosis worldwide, affecting a wide range of warm-blooded mammals and birds worldwide. However, no information on T. gondii infection in pet birds in China is available. Therefore, this study was performed to determine the prevalence of T. gondii infection in pet birds in Gansu province, China.
Methods
A total of 687 blood samples were collected from pet birds (Carduelis spinus, Alauda gulgula, Cocothraustes migratorlus) in three representative administrative regions in Gansu province, northwest China between August 2011 and September 2012 T. gondii antibodies were determined using the modified agglutination test (MAT). Genomic DNA was extracted from the brain tissues of seropositive pet birds and T. gondii B1 gene was amplified using a semi-nested PCR.DNA samples giving positive B1 amplification were then genetically characterized using multi-locus PCR-RFLP.
Results
The overall T. gondii seroprevalence was 11.21% (77/687). C. spinus had the highest T. gondii seroprevalence (11.65%), followed by A. arvensis (11.39%) and C. migratorlus (5.26%), these differences were not statistically significant (P > 0.05). Of 77 DNA samples, 8 were positive for the T. gondii B1 gene, four showed complete genotyping results. Only one genotype (the Type II variant: ToxoDB genotype #3) was identified.
Conclusions
The results of the present survey indicated the presence of T. gondii infection in pet birds in Gansu province, China. These data provide base-line information for the execution of control strategies against T. gondii infection in pet birds. To our knowledge, this is the first report documenting the occurrence of T. gondii prevalence and genotype in pet birds in China.
doi:10.1186/1756-3305-7-152
PMCID: PMC3974739  PMID: 24690251
Toxoplasma gondii; Toxoplasmosis; Pet birds; Seroprevalence; Genetic characterization
12.  Stage-specific differential gene expression profiling and functional network analysis during morphogenesis of diphyodont dentition in miniature pigs, Sus Scrofa 
BMC Genomics  2014;15:103.
Background
Our current knowledge of tooth development derives mainly from studies in mice, which have only one set of non-replaced teeth, compared with the diphyodont dentition in humans. The miniature pig is also diphyodont, making it a valuable alternative model for understanding human tooth development and replacement. However, little is known about gene expression and function during swine odontogenesis. The goal of this study is to undertake the survey of differential gene expression profiling and functional network analysis during morphogenesis of diphyodont dentition in miniature pigs. The identification of genes related to diphyodont development should lead to a better understanding of morphogenetic patterns and the mechanisms of diphyodont replacement in large animal models and humans.
Results
The temporal gene expression profiles during early diphyodont development in miniature pigs were detected with the Affymetrix Porcine GeneChip. The gene expression data were further evaluated by ANOVA as well as pathway and STC analyses. A total of 2,053 genes were detected with differential expression. Several signal pathways and 151 genes were then identified through the construction of pathway and signal networks.
Conclusions
The gene expression profiles indicated that spatio-temporal down-regulation patterns of gene expression were predominant; while, both dynamic activation and inhibition of pathways occurred during the morphogenesis of diphyodont dentition. Our study offers a mechanistic framework for understanding dynamic gene regulation of early diphyodont development and provides a molecular basis for studying teeth development, replacement, and regeneration in miniature pigs.
doi:10.1186/1471-2164-15-103
PMCID: PMC3937075  PMID: 24498892
Gene expression profile; Diphyodont; Odontogenesis; Miniature pig
13.  Seroprevalence of Toxoplasma gondii Infection in Sows in Hunan Province, China 
The Scientific World Journal  2014;2014:347908.
Toxoplasma gondii infections are prevalent in animals and humans worldwide. Although the prevalence of T. gondii has been reported in many animals in China, little is known of T. gondii infection in sows. Antibodies to T. gondii in sows in Hunan province, subtropical China, were examined using indirect hemagglutination test (IHAT). Overall, 31.3% (373/1191) of the examined sows were seropositive for T. gondii. Among 11 representative regions of Hunan province, the seroprevalence ranged from 14.8% to 45.1%. In addition, the T. gondii seroprevalence was higher in summer (37.4%) and autumn (34.9%) than in spring (24.6%) and winter (23.9%). Regarding different antibody titers, the seroprevalence ranged from 1.8% (titer ≥ 1 : 1024) to 17.4% (titer = 1 : 64). The findings of the present investigation revealed the high seroprevalence of T. gondii in sows in Hunan province, China, which poses a potential risk for T. gondii infection in humans and animals in this province. Therefore, effective measures should be taken to prevent and control toxoplasmosis of pigs in this province. This is the first report of the comprehensive survey of T. gondii seroprevalence in sows in Hunan Province, subtropical China.
doi:10.1155/2014/347908
PMCID: PMC3932812  PMID: 24683331
14.  Combined thoracoscopic and laparoscopic minimally invasive esophagectomy 
Journal of Thoracic Disease  2014;6(2):152-155.
With the improvement in thoracoscopic and laparoscopic surgery, thoracoscopic and laparoscopic esophagectomy (TLE), a minimally invasive approach, has attracted increasing attention as an alternative to open three-field esophagectomy. From June 2012 to October 2013, 90 patients underwent laparoscopic and thoracoscopic resection of esophageal carcinoma in our department. The VATS esophagectomy technique described here is the approach currently employed in the department of thoracic surgery at Sichuan Provincial People’s Hospital of China.
doi:10.3978/j.issn.2072-1439.2014.02.04
PMCID: PMC3944189  PMID: 24605230
Thoracoscopic and laparoscopic; minimally invasive; esophagectomy
15.  Altered Lipid and Salt Taste Responsivity in Ghrelin and GOAT Null Mice 
PLoS ONE  2013;8(10):e76553.
Taste perception plays an important role in regulating food preference, eating behavior and energy homeostasis. Taste perception is modulated by a variety of factors, including gastric hormones such as ghrelin. Ghrelin can regulate growth hormone release, food intake, adiposity, and energy metabolism. Octanoylation of ghrelin by ghrelin O-acyltransferase (GOAT) is a specific post-translational modification which is essential for many biological activities of ghrelin. Ghrelin and GOAT are both widely expressed in many organs including the gustatory system. In the current study, overall metabolic profiles were assessed in wild-type (WT), ghrelin knockout (ghrelin−/−), and GOAT knockout (GOAT−/−) mice. Ghrelin−/− mice exhibited decreased food intake, increased plasma triglycerides and increased ketone bodies compared to WT mice while demonstrating WT-like body weight, fat composition and glucose control. In contrast GOAT−/− mice exhibited reduced body weight, adiposity, resting glucose and insulin levels compared to WT mice. Brief access taste behavioral tests were performed to determine taste responsivity in WT, ghrelin−/− and GOAT−/− mice. Ghrelin and GOAT null mice possessed reduced lipid taste responsivity. Furthermore, we found that salty taste responsivity was attenuated in ghrelin−/− mice, yet potentiated in GOAT−/− mice compared to WT mice. Expression of the potential lipid taste regulators Cd36 and Gpr120 were reduced in the taste buds of ghrelin and GOAT null mice, while the salt-sensitive ENaC subunit was increased in GOAT−/− mice compared with WT mice. The altered expression of Cd36, Gpr120 and ENaC may be responsible for the altered lipid and salt taste perception in ghrelin−/− and GOAT−/− mice. The data presented in the current study potentially implicates ghrelin signaling activity in the modulation of both lipid and salt taste modalities.
doi:10.1371/journal.pone.0076553
PMCID: PMC3790684  PMID: 24124572
16.  Long-Term Artificial Sweetener Acesulfame Potassium Treatment Alters Neurometabolic Functions in C57BL/6J Mice 
PLoS ONE  2013;8(8):e70257.
With the prevalence of obesity, artificial, non-nutritive sweeteners have been widely used as dietary supplements that provide sweet taste without excessive caloric load. In order to better understand the overall actions of artificial sweeteners, especially when they are chronically used, we investigated the peripheral and central nervous system effects of protracted exposure to a widely used artificial sweetener, acesulfame K (ACK). We found that extended ACK exposure (40 weeks) in normal C57BL/6J mice demonstrated a moderate and limited influence on metabolic homeostasis, including altering fasting insulin and leptin levels, pancreatic islet size and lipid levels, without affecting insulin sensitivity and bodyweight. Interestingly, impaired cognitive memory functions (evaluated by Morris Water Maze and Novel Objective Preference tests) were found in ACK-treated C57BL/6J mice, while no differences in motor function and anxiety levels were detected. The generation of an ACK-induced neurological phenotype was associated with metabolic dysregulation (glycolysis inhibition and functional ATP depletion) and neurosynaptic abnormalities (dysregulation of TrkB-mediated BDNF and Akt/Erk-mediated cell growth/survival pathway) in hippocampal neurons. Our data suggest that chronic use of ACK could affect cognitive functions, potentially via altering neuro-metabolic functions in male C57BL/6J mice.
doi:10.1371/journal.pone.0070257
PMCID: PMC3737213  PMID: 23950916
17.  Prevalence and Genetic Characterization of Toxoplasma gondii in House Sparrows (Passer domesticus) in Lanzhou, China 
The prevalence of Toxoplasma gondii infection in birds has epidemiological significance because birds are indeed considered as a good indicator of environmental contamination by T. gondii oocysts. In this study, the prevalence of T. gondii in 313 house sparrows in Lanzhou, northwestern China was assayed by the modified agglutination test (MAT). Antibodies to T. gondii were positive in 39 (12.46%) of 313 samples (MAT titer ≥ 1:5). Tissues of heart, brain, and lung from the 39 seropositive house sparrows were tested for T. gondii DNA, 11 of which were found to be positive for the T. gondii B1 gene by PCR amplification. These positive DNA samples were typed at 9 genetic markers, including 8 nuclear loci, i.e., SAG1, 5'- and 3'-SAG2, alternative SAG2, SAG3, GRA6, L358, PK1, c22-8 and an apicoplast locus Apico. Of them, 4 isolates were genotyped with complete data for all loci, and 2 genotypes (Type II variants; ToxoDB #3 and a new genotype) were identified. These results showed that there is a potential risk for human infection with T. gondii in this region. To our knowledge, this is the first report of T. gondii seroprevalence in house sparrows in China.
doi:10.3347/kjp.2013.51.3.363
PMCID: PMC3712113  PMID: 23864750
Toxoplasma gondii; sparrow; seroprevalence; PCR-RFLP typing; northwestern China
18.  Age-Related Changes in Mouse Taste Bud Morphology, Hormone Expression, and Taste Responsivity 
Normal aging is a complex process that affects every organ system in the body, including the taste system. Thus, we investigated the effects of the normal aging process on taste bud morphology, function, and taste responsivity in male mice at 2, 10, and 18 months of age. The 18-month-old animals demonstrated a significant reduction in taste bud size and number of taste cells per bud compared with the 2- and 10-month-old animals. The 18-month-old animals exhibited a significant reduction of protein gene product 9.5 and sonic hedgehog immunoreactivity (taste cell markers). The number of taste cells expressing the sweet taste receptor subunit, T1R3, and the sweet taste modulating hormone, glucagon-like peptide-1, were reduced in the 18-month-old mice. Concordant with taste cell alterations, the 18-month-old animals demonstrated reduced sweet taste responsivity compared with the younger animals and the other major taste modalities (salty, sour, and bitter) remained intact.
doi:10.1093/gerona/glr192
PMCID: PMC3410661  PMID: 22056740
Taste buds; Aging; Sweet taste; Glucagon-like peptide-1; T1R3
19.  BRET Biosensor Analysis of Receptor Tyrosine Kinase Functionality 
Bioluminescence resonance energy transfer (BRET) is an improved version of earlier resonance energy transfer technologies used for the analysis of biomolecular protein interaction. BRET analysis can be applied to many transmembrane receptor classes, however the majority of the early published literature on BRET has focused on G protein-coupled receptor (GPCR) research. In contrast, there is limited scientific literature using BRET to investigate receptor tyrosine kinase (RTK) activity. This limited investigation is surprising as RTKs often employ dimerization as a key factor in their activation, as well as being important therapeutic targets in medicine, especially in the cases of cancer, diabetes, neurodegenerative, and respiratory conditions. In this review, we consider an array of studies pertinent to RTKs and other non-GPCR receptor protein–protein signaling interactions; more specifically we discuss receptor-protein interactions involved in the transmission of signaling communication. We have provided an overview of functional BRET studies associated with the RTK superfamily involving: neurotrophic receptors [e.g., tropomyosin-related kinase (Trk) and p75 neurotrophin receptor (p75NTR)]; insulinotropic receptors [e.g., insulin receptor (IR) and insulin-like growth factor receptor (IGFR)] and growth factor receptors [e.g., ErbB receptors including the EGFR, the fibroblast growth factor receptor (FGFR), the vascular endothelial growth factor receptor (VEGFR) and the c-kit and platelet-derived growth factor receptor (PDGFR)]. In addition, we review BRET-mediated studies of other tyrosine kinase-associated receptors including cytokine receptors, i.e., leptin receptor (OB-R) and the growth hormone receptor (GHR). It is clear even from the relatively sparse experimental RTK BRET evidence that there is tremendous potential for this technological application for the functional investigation of RTK biology.
doi:10.3389/fendo.2013.00046
PMCID: PMC3620488  PMID: 23577003
receptor tyrosine kinase; RTK; protein–protein interaction; neurotrophic; insulin receptor; insulin-like growth factor receptor; epidermal growth factor receptor; cytokine receptors
20.  Correction: Altered Hypothalamic Protein Expression in a Rat Model of Huntington's Disease 
PLoS ONE  2012;7(11):10.1371/annotation/677c26e3-ce52-4837-853a-63c4ed7d72c0.
doi:10.1371/annotation/677c26e3-ce52-4837-853a-63c4ed7d72c0
PMCID: PMC3552740
21.  Altered Hypothalamic Protein Expression in a Rat Model of Huntington's Disease 
PLoS ONE  2012;7(10):e47240.
Huntington's disease (HD) is a neurodegenerative disorder, which is characterized by progressive motor impairment and cognitive alterations. Changes in energy metabolism, neuroendocrine function, body weight, euglycemia, appetite function, and circadian rhythm can also occur. It is likely that the locus of these alterations is the hypothalamus. We used the HD transgenic (tg) rat model bearing 51 CAG repeats, which exhibits similar HD symptomology as HD patients to investigate hypothalamic function. We conducted detailed hypothalamic proteome analyses and also measured circulating levels of various metabolic hormones and lipids in pre-symptomatic and symptomatic animals. Our results demonstrate that there are significant alterations in HD rat hypothalamic protein expression such as glial fibrillary acidic protein (GFAP), heat shock protein-70, the oxidative damage protein glutathione peroxidase (Gpx4), glycogen synthase1 (Gys1) and the lipid synthesis enzyme acylglycerol-3-phosphate O-acyltransferase 1 (Agpat1). In addition, there are significant alterations in various circulating metabolic hormones and lipids in pre-symptomatic animals including, insulin, leptin, triglycerides and HDL, before any motor or cognitive alterations are apparent. These early metabolic and lipid alterations are likely prodromal signs of hypothalamic dysfunction. Gaining a greater understanding of the hypothalamic and metabolic alterations that occur in HD, could lead to the development of novel therapeutics for early interventional treatment of HD.
doi:10.1371/journal.pone.0047240
PMCID: PMC3475691  PMID: 23094041
22.  Herbal Extracts Combination (WNK) Prevents Decline in Spatial Learning and Memory in APP/PS1 Mice through Improvement of Hippocampal Aβ Plaque Formation, Histopathology, and Ultrastructure 
To investigate the cognitive enhancement effect of WNK, an extracts combination of P. ginseng,  G. biloba, and C. sativus L. and possible mechanisms, 5-month-old APP/PS1 transgenic mice were used in this study. After 3 months of administration, all mice received Morris water maze (MWM) training and a probe test. Mouse brain sections were detected by immunohistochemistry, HE staining, and transmission electron microscopy. MWM results showed significant difference between transgenic mice and nontransgenic littermates (P < 0.05, P < 0.01). WNK-treated mice exhibited enhanced maze performance over the training progression, especially better spatial memory retention in probe test compared to transgenic mice (P < 0.05, P < 0.01) and better spatial learning and memory at the fourth day of MWM test compared to EGB761- (G. biloba extract-) treated ones (P < 0.05). Hippocampal Aβ plaque burden significantly differed between APP/PS1 and littermate mice (P < 0.001), while decreased Aβ plaque appeared in WNK- or EGB761-treated transgenic brains (P < 0.05). Neurodegenerative changes were evident from light microscopic and ultrastructural observations in transgenic brains, which were improved by WNK or EGB761 treatment. These data indicate WNK can reduce the decline in spatial cognition, which might be due to its effects on reducing Aβ plaque formation and ameliorating histopathology and ultrastructure in hippocampus of APP/PS1 mouse brain.
doi:10.1155/2012/478190
PMCID: PMC3395307  PMID: 22811746
23.  First report of Toxoplasma gondii infection in market-sold adult chickens, ducks and pigeons in northwest China 
Parasites & Vectors  2012;5:110.
Background
Toxoplasma gondii infection is a global concern, affecting a wide range of warm-blooded animals and humans worldwide, including poultry. Domestic and companion birds are considered to play an important role in the transmission of T. gondii to humans and other animals. However, little information on T. gondii infection in domestic birds in Lanzhou, northwest China was available. Therefore, this study was performed to determine the seroprevalence of T. gondii infection in domestic birds in Lanzhou, northwest China.
Methods
In the present study, the seroprevalence of T. gondii antibodies in 413 (305 caged and 108 free-range) adult chickens, 334 (111 caged and 223 free-range) adult ducks and 312 adult pigeons in Lanzhou, northwest China, were examined using the modified agglutination test (MAT).
Results
30 (7.26%) chickens, 38 (11.38%) ducks and 37 (11.86%) pigeons were found to be positive for T. gondii antibodies at the cut-off of 1:5. The prevalences in caged and free-range chickens were 6.23% and 10.19% respectively, however, statistical analysis showed that the difference was not significant (P > 0.05). The seroprevalences in caged and free-range ducks were 6.31% and 13.90% respectively, but the difference was not statistically significant (P > 0.05).
Conclusions
The results of the present survey indicated the presence of T. gondii infection in adult chickens, ducks and pigeons sold for meat in poultry markets in Lanzhou, northwest China, which poses a potential risk for T. gondii infection in humans and other animals in this region. This is the first seroprevalence study of T. gondii infection in domestic birds in this region.
doi:10.1186/1756-3305-5-110
PMCID: PMC3414767  PMID: 22676311
24.  Ghrelin receptor signaling: a promising therapeutic target for metabolic syndrome and cognitive dysfunction 
The neuroendocrine hormone ghrelin is an octanoylated 28-residue peptide that exerts numerous physiological functions. Ghrelin exerts its effects on the body mainly through a highly conserved G protein-coupled receptor known as the growth hormone secretagagogue receptor subtype 1a (GHS-R1a). Ghrelin and GSH-R1a are widely expressed in both peripheral and central tissues/organs, and ghrelin signaling plays a critical role in maintaining energy balance and neuronal health. The multiple orexigenic effects of ghrelin and its receptor have been studied in great detail, and GHS-R1a-mediated ghrelin signaling has long been a promising target for the treatment of metabolic disorders, such as obesity. In addition to its well-characterized metabolic effects, there is also mounting evidence that ghrelin-mediated GHS-R1a signaling exerts neuroprotective effects on the brain. In this review, we will summarize some of the effects of ghrelin-mediated GSH-R1a signaling on peripheral energy balance and cognitive function. We will also discuss the potential pharmacotherapeutic role of GSH-R1a-mediated ghrelin signaling for the treatment of complex neuroendocrine disorders.
PMCID: PMC2967656  PMID: 20632971
Cognitive function; energy balance; ghrelin; growth hormone secretagagogue receptor; memory; metabolic disorders; neuroprotection; obesity
25.  Attenuated Salmonella choleraesuis-mediated RNAi targeted to conserved regions against foot-and-mouth disease virus in guinea pigs and swine 
Veterinary Research  2010;41(3):30.
In this study, specific sequences within three genes (3D, VP4 and 2B) of the foot-and-mouth disease virus (FMDV) genome were determined to be effective RNAi targets. These sequences are highly conserved among different serotype viruses based on sequence analysis. Small interfering RNA (siRNA)-expressing plasmids (p3D-NT19, p3D-NT56, pVP4-NT19, pVP4-NT65 and p2B-NT25) were constructed to express siRNA targeting 3D, VP4 and 2B, respectively. The antiviral potential of these siRNA for various FMDV isolates was investigated in baby hamster kidney (BHK-21) cells and suckling mice. The results show that these siRNA inhibited virus yield 10- to 300-fold for different FMDV isolates of serotype O and serotype Asia I at 48 h post infection in BHK-21 cells compared to control cells. In suckling mice, p3D-NT56 and p2B-NT25 delayed the death of mice. Twenty percent to 40% of the animals that received a single siRNA dose survived 5 days post infection with serotype O or serotype Asia I. We used an attenuated Salmonella choleraesuis (C500) vaccine strain, to carry the plasmid that expresses siRNA directed against the polymerase gene 3D (p3D-NT56) of FMDV. We used guinea pigs to evaluate the inhibitory effects of recombinant S. cho (p3D-NT56/S. cho) on FMDV infection. The results show that 80% of guinea pigs inoculated with 109 CFU of p3D-NT56/S. cho and challenged 36 h later with 50 ID50 of homologous FMDV were protected. We also measured the antiviral activity of p3D-NT56/S. cho in swine. The results indicate that 100% of the animals treated with 5 × 109 CFU of p3D-NT56/S. cho were protected in 9 days.
doi:10.1051/vetres/2010002
PMCID: PMC2826090  PMID: 20167192
foot-and-mouth disease virus; RNA interference; Salmonella choleraesuis; conserved sequence; swine

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