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1.  Efficacy of acupuncture for chronic asthma: study protocol for a randomized controlled trial 
Trials  2015;16:424.
Although asthma symptoms can be temporarily controlled, it is recommended to use effective low-risk, non-drug strategies to constitute a significant advance in asthma management. Acupuncture has been traditionally used to treat asthma; however, the evidence for the efficacy of this treatment is still lacking. Previous clinical trials of acupuncture in treating asthma were limited by methodological defects; therefore, high-quality research is required.
This trial is designed as a multi-center, randomized, double-blind, parallel-group controlled trial. Patients with mild to moderate asthma will be randomly allocated to either a verum acupuncture plus as-needed salbutamol aerosol and/or prednisone tablets group or a sham acupuncture plus as-needed salbutamol aerosol and/or prednisone tablets group. Acupoints used in the verum acupuncture group are GV14 (Da Zhui), BL12 (Feng Men), BL13 (Fei Shu) and acupoints used in the sham acupuncture group are DU08 (Jin Suo), BL18 (Gan Shu), BL19 (Dan Shu). After a baseline period of 1 week, the patients in both groups will receive verum/sham acupuncture once every other day with a total of 20 treatment sessions in 6 weeks and a 3-month follow-up. The primary outcome will be measured by using the asthma control test and the secondary outcomes will be measured by using the percentage of symptom-free days, the average dosage of salbutamol aerosol and/or prednisone tablets, lung functions, daily asthma symptom scores, asthma quality of life questionnaire, and so on.
This trial will assess the effect of acupuncture on asthma and aims to provide reliable clinical evidence for the efficacy of acupuncture in treating asthma.
Trial registration Identifier: NCT01931696, registered on 26 August 2013
PMCID: PMC4581041  PMID: 26399399
Acupuncture; Chronic asthma; Efficacy; RCT; Study protocol
2.  PPL2ab neurons restore sexual responses in aged Drosophila males through dopamine 
Nature Communications  2015;6:7490.
Male sexual desire typically declines with ageing. However, our understanding of the neurobiological basis for this phenomenon is limited by our knowledge of the brain circuitry and neuronal pathways controlling male sexual desire. A number of studies across species suggest that dopamine (DA) affects sexual desire. Here we use genetic tools and behavioural assays to identify a novel subset of DA neurons that regulate age-associated male courtship activity in Drosophila. We find that increasing DA levels in a subset of cells in the PPL2ab neuronal cluster is necessary and sufficient for increased sustained courtship in both young and aged male flies. Our results indicate that preventing the age-related decline in DA levels in PPL2ab neurons alleviates diminished courtship behaviours in male Drosophila. These results may provide the foundation for deciphering the circuitry involved in sexual motivation in the male Drosophila brain.
We currently lack a detailed understanding of the neurobiological basis for the decline of male sexual desire with age. Here the authors demonstrate that restoring impaired dopaminergic signalling in a specific cluster of neurons in the Drosophila brain increases sexual behaviour in ageing male flies.
PMCID: PMC4491191  PMID: 26123524
3.  The anti-aging effects of Ludwigia octovalvis on Drosophila melanogaster and SAMP8 mice 
Age  2013;36(2):689-703.
We investigated the anti-aging effects of Ludwigia octovalvis (Jacq.) P. H. Raven (Onagraceae), an extract of which is widely consumed as a healthful drink in a number of countries. Using the fruit fly, Drosophila melanogaster, as a model organism, we demonstrated that L. octovalvis extract (LOE) significantly extended fly lifespan on a high, but not a low, calorie diet, indicating that LOE may regulate lifespan through a dietary restriction (DR)-related pathway. LOE also attenuated age-related cognitive decline in both flies and in the senescence-accelerated-prone 8 (SAMP8) mouse, without causing any discernable negative trade-offs, including water intake, food intake, fecundity, or spontaneous motor activity. LOE contained high levels of polyphenols and flavonoids, which possess strong DPPH radical scavenging activity, and was shown to attenuate paraquat-induced oxidative damage and lethality in flies. Gas chromatography–mass spectrometry (GC-MS) analyses identified 17 known molecules, of which β-sitosterol and squalene were the two most abundant. We further demonstrated that β-sitosterol was capable of extending lifespan, likely through activating AMP-activated protein kinase (AMPK) in the fat body of adult flies. Taken together, our data suggest that LOE is a potent anti-aging intervention with potential for treating age-related disorders.
Electronic supplementary material
The online version of this article (doi:10.1007/s11357-013-9606-z) contains supplementary material, which is available to authorized users.
PMCID: PMC4039272  PMID: 24338263
Ludwigia octovalvis; Dietary restriction; Lifespan; AMPK
4.  Nucleotide synthesis is regulated by cytoophidium formation during neurodevelopment and adaptive metabolism 
Biology Open  2014;3(11):1045-1056.
The essential metabolic enzyme CTP synthase (CTPsyn) can be compartmentalised to form an evolutionarily-conserved intracellular structure termed the cytoophidium. Recently, it has been demonstrated that the enzymatic activity of CTPsyn is attenuated by incorporation into cytoophidia in bacteria and yeast cells. Here we demonstrate that CTPsyn is regulated in a similar manner in Drosophila tissues in vivo. We show that cytoophidium formation occurs during nutrient deprivation in cultured cells, as well as in quiescent and starved neuroblasts of the Drosophila larval central nervous system. We also show that cytoophidia formation is reversible during neurogenesis, indicating that filament formation regulates pyrimidine synthesis in a normal developmental context. Furthermore, our global metabolic profiling demonstrates that CTPsyn overexpression does not significantly alter CTPsyn-related enzymatic activity, suggesting that cytoophidium formation facilitates metabolic stabilisation. In addition, we show that overexpression of CTPsyn only results in moderate increase of CTP pool in human stable cell lines. Together, our study provides experimental evidence, and a mathematical model, for the hypothesis that inactive CTPsyn is incorporated into cytoophidia.
PMCID: PMC4232762  PMID: 25326513
CTP synthase; cytoophidium; intracellular compartmentation; CTP; Drosophila; neurogenesis
5.  Müllerian inhibiting substance is anterogradely transported and does not attenuate avulsion-induced death of hypoglossal motor neurons 
Experimental neurology  2010;231(2):304-308.
Müllerian Inhibiting Substance (MIS, Anti-Müllerian hormone) is a gonadal hormone that contributes to the subtle sex-biases in the nervous system. Mature neurons of both sexes also produce MIS, suggesting that MIS may be a paracrine regulator of adult neural networks. We report here that murine hypoglossal motor neurons produce MIS and its receptors, MISRII and bone morphogenetic protein receptor 1A (BMPR1A, ALK3), but differentially transport them, with only MIS being detectable in axons. The production of MIS and its receptors were rapidly down regulated after axonal damage, which is a characteristic of genes involved in mature neuronal function. MIS is a survival factor for embryonic spinal motor neurons, but the rate of cell loss after hypoglossal nerve avulsion was normal in Mis−/− mice and was not attenuated by intraventricular administration of MIS. These observations suggest that MIS may be involved in anterograde rather than autocrine or retrograde regulation of neurons.
PMCID: PMC3797533  PMID: 21195071
Axonal transport; Avulsion; MISRII; ALK3
6.  Lie Group Analysis of the Photo-Induced Fluorescence of Drosophila Oogenesis with the Asymmetrically Localized Gurken Protein 
PLoS ONE  2013;8(6):e65143.
Lie group analysis of the photo-induced fluorescence of Drosophila oogenesis with the asymmetrically localized Gurken protein has been performed systematically to assess the roles of ligand-receptor complexes in follicle cells. The (2×2) matrix representations resulting from the polarized tissue spectra were employed to characterize the asymmetrical Gurken distributions. It was found that the fluorescence of the wild-type egg shows the Lie point symmetry X23 at early stages of oogenesis. However, due to the morphogen regulation by intracellular proteins and extracellular proteins, the fluorescence of the embryogenesis with asymmetrically localized Gurken expansions exhibits specific symmetry features: Lie point symmetry Z1 and Lie point symmetry X1. The novel approach developed herein was successfully used to validate that the invariant-theoretical characterizations are consonant with the observed asymmetric fluctuations during early embryological development.
PMCID: PMC3686808  PMID: 23840317
7.  BMP4 Is a Peripherally-Derived Factor for Motor Neurons and Attenuates Glutamate-Induced Excitotoxicity In Vitro 
PLoS ONE  2013;8(3):e58441.
Bone morphogenetic proteins (BMPs), members of the transforming growth factor-beta (TGF-β) superfamily, have been shown to play important roles in the nervous system, including neuronal survival and synaptogenesis. However, the physiological functions of BMP signaling in the mammalian neuromuscular system are not well understood. In this study, we found that proteins of the type II bone morphogenetic receptors (BMPRII) were detected at the neuromuscular junction (NMJ), and one of its ligands, BMP4, was expressed by Schwann cells and skeletal muscle fibers. In double-ligated nerves, BMP4 proteins accumulated at the proximal and distal portions of the axons, suggesting that Schwann cell- and muscle fiber-derived BMP4 proteins were anterogradely and retrogradely transported by motor neurons. Furthermore, BMP4 mRNA was down-regulated in nerves but up-regulated in skeletal muscles following nerve ligation. The motor neuron-muscle interactions were also demonstrated using differentiated C2C12 muscle cells and NG108-15 neurons in vitro. BMP4 mRNA and immunoreactivity were significantly up-regulated in differentiated C2C12 muscle cells when the motor neuron-derived factor, agrin, was present in the culture. Peripherally-derived BMP4, on the other hand, promotes embryonic motor neuron survival and protects NG108-15 neurons from glutamate-induced excitotoxicity. Together, these data suggest that BMP4 is a peripherally-derived factor that may regulate the survival of motor neurons.
PMCID: PMC3589418  PMID: 23472198
8.  Autophagy-related gene 7 is downstream of heat shock protein 27 in the regulation of eye morphology, polyglutamine toxicity, and lifespan in Drosophila 
Autophagy and molecular chaperones both regulate protein homeostasis and maintain important physiological functions. Atg7 (autophagy-related gene 7) and Hsp27 (heat shock protein 27) are involved in the regulation of neurodegeneration and aging. However, the genetic connection between Atg7 and Hsp27 is not known.
The appearances of the fly eyes from the different genetic interactions with or without polyglutamine toxicity were examined by light microscopy and scanning electronic microscopy. Immunofluorescence was used to check the effect of Atg7 and Hsp27 knockdown on the formation of autophagosomes. The lifespan of altered expression of Hsp27 or Atg7 and that of the combination of the two different gene expression were measured.
We used the Drosophila eye as a model system to examine the epistatic relationship between Hsp27 and Atg7. We found that both genes are involved in normal eye development, and that overexpression of Atg7 could eliminate the need for Hsp27 but Hsp27 could not rescue Atg7 deficient phenotypes. Using a polyglutamine toxicity assay (41Q) to model neurodegeneration, we showed that both Atg7 and Hsp27 can suppress weak, toxic effect by 41Q, and that overexpression of Atg7 improves the worsened mosaic eyes by the knockdown of Hsp27 under 41Q. We also showed that overexpression of Atg7 extends lifespan and the knockdown of Atg7 or Hsp27 by RNAi reduces lifespan. RNAi-knockdown of Atg7 expression can block the extended lifespan phenotype by Hsp27 overexpression, and overexpression of Atg7 can extend lifespan even under Hsp27 knockdown by RNAi.
We propose that Atg7 acts downstream of Hsp27 in the regulation of eye morphology, polyglutamine toxicity, and lifespan in Drosophila.
PMCID: PMC3483682  PMID: 22621211
Atg7; Hsp27; Neurodegeneration; Lifespan; Drosophila
9.  Uterotrophic effects of cow milk in immature ovariectomized Sprague–Dawley rats 
Milk contains considerable quantities of estrogens and progesterone and as such may be one of the risk factors for hormone-related cancers. To determine the hormonal effects of commercial and traditional types of milk, we performed uterotrophic tests.
Forty-five rats were ovariectomized and divided into three groups of 15 animals each. The animals were kept for 7 days on powdered chow and one of three different liquids: commercial milk (C), traditional milk (T), or water. At autopsy, wet and dry uterine weights were determined. The cell heights of the uterine epithelium and endometrium were determined. The uterine 5-bromo-2-deoxyuridine (BrdU) labeling index of the epithelium and endometrium gland epithelium was also assessed.
The weights of wet and dry uterus were 142 ± 13 and 112 ± 10 mg in the C group, 114 ± 30 and 91 ± 24 mg in the T group, and 87 ± 6 and 69 ± 5 mg in the W group. Significant differences in wet and dry uterus weights were found between all pairs of groups. The ratio of the wet uterine weight to body weight was significantly higher in the C and T groups than in the W group. The heights of the uterine epithelium and endometrium were higher and BrdU labeling index was greater in the C group than in the T and W groups.
Commercially available milk and traditional milk have uterotrophic effects on young ovariectomized rats. Our findings indicate that these uterotrophic effects in the milk groups were partly due to the estrogen and progesterone in the milk.
PMCID: PMC2854339  PMID: 19957059
Cow milk; Estrogen; Ovariectomized rat; Progesterone; Uterotrophic assay
10.  D-Cbl Binding to Drk Leads to Dose-Dependent Down-Regulation of EGFR Signaling and Increases Receptor-Ligand Endocytosis 
PLoS ONE  2011;6(2):e17097.
Proper control of Epidermal Growth Factor Receptor (EGFR) signaling is critical for normal development and regulated cell behaviors. Abnormal EGFR signaling is associated with tumorigenic process of various cancers. Complicated feedback networks control EGFR signaling through ligand production, and internalization-mediated destruction of ligand-receptor complexes. Previously, we found that two isoforms of D-Cbl, D-CblS and D-CblL, regulate EGFR signaling through distinct mechanisms. While D-CblL plays a crucial role in dose-dependent down-regulation of EGFR signaling, D-CblS acts in normal restriction of EGFR signaling and does not display dosage effect. Here, we determined the underlying molecular mechanism, and found that Drk facilitates the dose-dependent regulation of EGFR signaling through binding to the proline-rich motif of D-CblL, PR. Furthermore, the RING finger domain of D-CblL is essential for promoting endocytosis of the ligand-receptor complex. Interestingly, a fusion protein of the two essential domains of D-CblL, RING- PR, is sufficient to down-regulate EGFR signal in a dose-dependent manner by promoting internalization of the ligand, Gurken. Besides, RING-SH2Drk, a fusion protein of the RING finger domain of D-Cbl and the SH2 domain of Drk, also effectively down-regulates EGFR signaling in Drosophila follicle cells, and suppresses the effects of constitutively activated EGFR. The RING-SH2Drk suppresses EGFR signaling by promoting the endosomal trafficking of ligand-receptor complexes, suggesting that Drk plays a negative role in EGFR signaling by enhancing receptor endocytosis through cooperating with the RING domain of D-Cbl. Interfering the recruitment of signal transducer, Drk, to the receptor by the RING-SH2Drk might further reduces EGFR signaling. The fusion proteins we developed may provide alternative strategies for therapy of cancers caused by hyper-activation of EGFR signaling.
PMCID: PMC3038869  PMID: 21340027
11.  Prevalence of Risk Factors for Cardiovascular Disease and Their Associations with Diet and Physical Activity in Suburban Beijing, China 
Journal of Epidemiology  2010;20(3):237-243.
We calculated new prevalences of risk factors for cardiovascular disease (CVD) and examined their associations with dietary habits and physical activity in a suburban area of Beijing—one of the most urbanized cities in China.
In 2007, a cross-sectional survey of a representative sample of 19 003 suburban residents aged 18 to 76 years was conducted. Dietary and anthropometric data were collected by questionnaire, and blood pressure, fasting blood glucose, and serum lipids were measured.
The age-standardized prevalences of the CVD risk factors overweight/obesity, diabetes, hypertension, dyslipidemia, and metabolic syndrome (MS) were 31.9%, 6.1%, 33.6%, 30.3%, and 11.6%, respectively. The adjusted odd ratios (95% confidence interval [CI]) of overweight/obesity, diabetes, hypertension, dyslipidemia, and MS for participants who were physically active, as compared with those who were not physically active, were 0.67 (0.47 to 0.85), 0.87 (0.80 to 0.95), 0.92 (0.87 to 0.98), 0.89 (0.82 to 0.96), and 0.74 (0.62 to 0.89), respectively. The adjusted odds ratios (95% CI) of hypertension and MS for participants with a high intake of salt, as compared with those without a high intake of salt, were 1.72 (1.29 to 2.03) and 1.48 (1.16 to 1.77), respectively. In addition, participants who consumed a high-fat diet were more likely to be overweight/obese and dyslipidemic, whereas vegetarians had less risk of overweight/obesity, diabetes, hypertension, dyslipidemia, and MS.
In this population of adults living in suburban Beijing, there were relatively high prevalences of the CVD risk factors overweight/obesity, diabetes, hypertension, dyslipidemia, and MS. Healthy dietary habits and physical activity may reduce the risks of these conditions.
PMCID: PMC3900847  PMID: 20431234
cardiovascular disease; risk factors; associations; dietary habits; physical activity
12.  Myocardial deletion of Smad4 using a novel α skeletal muscle actin Cre recombinase transgenic mouse causes misalignment of the cardiac outflow tract 
SMAD4 acts as the converging point for TGFβ and BMP signaling in heart development. Here, we investigated the role of SMAD4 in heart development using a novel α skeletal muscle actin Cre recombinase (MuCre) transgenic mouse strain. Lineage tracing using MuCre/ROSA26LacZ reporter mice indicated strong Cre-recombinase expression in developing and adult heart and skeletal muscles. In heart development, significant MuCre expression was noted at E11.5 in the atrial, ventricular, outflow tract and atrioventricular canal myocardium, but not in the endocardial cushions. MuCre-driven conditional deletion of Smad4 in mice caused double outlet right ventricle (DORV), ventricular septal defect (VSD), impaired trabeculation and thinning of ventricular myocardium, and mid-gestational embryonic lethality. In conclusion, MuCre mice effectively delete genes in both heart and skeletal muscles, thus enabling the discovery that myocardial Smad4 deletion causes misalignment of the outflow tract and DORV.
PMCID: PMC2945925  PMID: 20877696
heart; myogenesis; transforming growth factor beta; SMAD; Marfan syndrome.
13.  Promoting Effects of Milk on the Development of 7,12-dimethylbenz(a)anthracene (DMBA)-induced Mammary Tumors in Rats 
To assess the effect of milk on the development of 7,12-dimethylbenz(a)anthracene (DMBA)-induced mammary tumors, 48 female Sprague-Dawley rats treated with DMBA were divided into 3 groups and given 1 of 3 test solutions for 20 weeks as their drinking liquid: milk, estrone sulfate solution or tap water. The milk group showed a significantly great incidence (75%) in tumor development compared with the water group (38%) and was comparable to the estrone sulfate group (69%). Mean tumor number per rat in the milk group was significantly higher than that in the water group (p=0.009). We classified the mammary tumors into three histological types: intraductal papilloma, fibroadenoma, and adenocarcinoma. Although the percent of intraductal papilloma and fibroadenoma was almost same among the three groups, malignant tumor was found only in the milk and estrone sulfate groups. In conclusion, our results indicate that milk as well as estrone sulfate promotes the development of DMBA-induced mammary tumors in rat and could be associated with the occurrence of adenocarcinoma.
PMCID: PMC1874511  PMID: 17576434
mammary tumor; milk; smooth muscle actin; proliferating cell nuclear antigen; estrogen receptor

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