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1.  Spexin Enhances Bowel Movement through Activating L-type Voltage-dependent Calcium Channel via Galanin Receptor 2 in Mice 
Scientific Reports  2015;5:12095.
A novel neuropeptide spexin was found to be broadly expressed in various endocrine and nervous tissues while little is known about its functions. This study investigated the role of spexin in bowel movement and the underlying mechanisms. In functional constipation (FC) patients, serum spexin levels were significantly decreased. Consistently, in starved mice, the mRNA of spexin was significantly decreased in intestine and colon. Spexin injection increased the velocity of carbon powder propulsion in small intestine and decreased the glass beads expulsion time in distal colon in mice. Further, spexin dose-dependently stimulated the intestinal/colonic smooth muscle contraction. Galanin receptor 2 (GALR2) antagonist M871, but not Galanin receptor 3 (GALR3) antagonist SNAP37899, effectively suppressed the stimulatory effects of spexin on intestinal/colonic smooth muscle contraction, which could be eliminated by extracellular [Ca2+] removal and L-type voltage-dependentCa2+ channel (VDCC) inhibitor nifedipine. Besides, spexin dramatically increased the [Ca2+]i in isolated colonic smooth muscle cells. These data indicate that spexin can act on GALR2 receptor to regulate bowel motility by activating L-type VDCC. Our findings provide evidence for important physiological roles of spexin in GI functions. Selective action on spexin pathway might have therapeutic effects on GI diseases with motility disorders.
doi:10.1038/srep12095
PMCID: PMC4498193  PMID: 26160593
2.  Ghrelin inhibition of ethanol-induced gastric epithelial cell apoptosis is mediated by miR-21 
Aim: To investigate the underlying mechanism of ghrelin-induced gastro-protection in a cell culture model of ethanol-induced gastric epithelial cell injury. Methods: The human gastric epithelial cell line GES-1 was incubated with ghrelin (0.01-1 µM), 1 µM ghrelin and 1 µM D-Lys3-growth hormone releasing peptide-6 (GHRP-6), or 1 µM ghrelin and 400 nM antagomiR-21 for 24 h, followed by treatment with 8% ethanol for 3 h to induce apoptosis. Cell viability was determined by MTT assays and flow cytometry was used for detection of apoptosis rates. miR-21 transcription was analyzed by qRT-PCR and Akt, Bcl-2, Bax and caspase 3 expressions were measured by Western blot. Results: Flow cytometry and a quantitative RT-PCR analysis of the expression of miR-21 showed that ghrelin inhibited apoptosis in a dose dependent manner through a signaling pathway that was both growth hormone secretagogue receptor (GHS-R) and miR-21 dependent, as the antiapoptotic effect of ghrelin was blocked by both D-Lys3-GHRP-6 and antagomiR-21, respectively. Western blotting of Akt, Bcl-2, Bax, and caspase 3 showed that the levels of the antiapoptotic proteins, Akt and Bcl-2, in the cells pretreated with ghrelin alone were higher than those in the cells pretreated with D-Lys3-GHRP-6 or antagomiR-21. By contrast, the levels of the proapoptotic proteins, Bax and caspase 3, in the cells pretreated with ghrelin alone were lower than those in the cells pretreated with D-Lys3-GHRP-6 or antagomiR-21. Conclusion: Ghrelin inhibits GES-1 cell apoptosis through GHS-R-dependent signaling in which miR-21 activates the PI3K/Akt pathway, which upregulates Bcl-2 and downregulates Bax and caspase 3 expression.
PMCID: PMC4503028  PMID: 26191156
Ghrelin; miR-21; PI3K/Akt; apoptosis; gastric epithelial cells
3.  Effectiveness of Primary Androgen-Deprivation Therapy for Clinically Localized Prostate Cancer 
Journal of Clinical Oncology  2014;32(13):1324-1330.
Purpose
Primary androgen-deprivation therapy (PADT) is often used to treat clinically localized prostate cancer, but its effects on cause-specific and overall mortality have not been established. Given the widespread use of PADT and the potential risks of serious adverse effects, accurate mortality data are needed to inform treatment decisions.
Methods
We conducted a retrospective cohort study using comprehensive utilization and cancer registry data from three integrated health plans. All men were newly diagnosed with clinically localized prostate cancer. Men who were diagnosed between 1995 and 2008, were not treated with curative intent therapy, and received follow-up through December 2010 were included in the study (n = 15,170). We examined all-cause and prostate cancer-specific mortality as our main outcomes. We used Cox proportional hazards models with and without propensity score analysis.
Results
Overall, PADT was associated with neither a risk of all-cause mortality (hazard ratio [HR], 1.04; 95% CI, 0.97 to 1.11) nor prostate-cancer–specific mortality (HR, 1.03; 95% CI, 0.89 to 1.19) after adjusting for all sociodemographic and clinical characteristics. PADT was associated with decreased risk of all-cause mortality but not prostate-cancer–specific mortality. PADT was associated with decreased risk of all-cause mortality only among the subgroup of men with a high risk of cancer progression (HR, 0.88; 95% CI, 0.78 to 0.97).
Conclusion
We found no mortality benefit from PADT compared with no PADT for most men with clinically localized prostate cancer who did not receive curative intent therapy. Men with higher-risk disease may derive a small clinical benefit from PADT. Our study provides the best available contemporary evidence on the lack of survival benefit from PADT for most men with clinically localized prostate cancer.
doi:10.1200/JCO.2013.52.5782
PMCID: PMC3992722  PMID: 24638009
4.  Metabolomics Profiling to Investigate the Pharmacologic Mechanisms of Berberine for the Treatment of High-Fat Diet-Induced Nonalcoholic Steatohepatitis 
Objective. Berberine has been used to treat nonalcoholic steatohepatitis (NASH), which has been addressed in many studies. In this study, we investigated the molecular pharmacology mechanisms of berberine using metabolomic techniques. Methods. Sprague-Dawley rats were randomly divided into three groups (10 rats in each group): (i) normal control group; (ii) high-fat diet- (HFD-) induced NASH model group; and (iii) HFD berberine-treated group (i.d. 200 mg/kg). The handling procedure lasted eight weeks. Then, UPLC-Q-TOF/MS techniques coupled with histopathology and biochemical analyses were adopted to explore the mechanisms of berberine on the protective effects against NASH. Key Findings. (i) According to conventional test results, berberine treatment plays a fighting role in HFD-induced NASH due to its beneficial effects against insulin resistance, inflammation, and lipid metabolism. (ii) Based on UPLC-Q-TOF/MS techniques, metabolic profiles that involved sphingomyelin (SM), phosphatidylcholine (PC), lysophosphatidylcholine (LysoPC), 13-hydroperoxy-9, 11-octadecadienoic acid (13-HpODE), eicosatrienoic acid, docosatrienoic acid, and eicosenoic acid could provide potential metabolic biomarkers to address the pharmacological mechanisms of berberine. Conclusions. The parts of molecular pharmacological mechanisms of berberine for NASH treatment are related to the regulation of metabolic disruption involving phospholipid and unsaturated fatty acids in rats with NASH.
doi:10.1155/2015/897914
PMCID: PMC4421035  PMID: 25977701
5.  Synthesis and Anticancer Activity of 4β-Triazole-podophyllotoxin Glycosides 
A series of novel 4β-triazole-podophyllotoxin glycosides were synthesized by utilizing the Click reaction. Evaluation of cytotoxicity against a panel of five human cancer cell lines (HL-60, SMMC-7721, A-549, MCF-7, SW480) using MTT assay shows that most of these compounds show weak cytotoxicity. It was observed that compound 16 shows the highest activity with IC50 values ranging from 2.85 to 7.28 μM, which is more potent than the control drugs etoposide and cisplatin against four of five cancer cell lines tested. Compound 16 is characterized with an α-d-galactosyl residue directly linked to the triazole ring and a 4′-OH group on the E ring of the podophyllotoxin scaffold. HPLC investigation of representative compound indicates that incorporation of a sugar moiety seems to improve the chemical stability of the podophyllotoxin scaffold.
doi:10.1007/s13659-015-0057-3
PMCID: PMC4402586  PMID: 25869591
Podophyllotoxin; 4β-Triazole-podophyllotoxin; Glycosides; Click reaction; Anticancer; Synthesis
6.  Synthesis and Anticancer Activity of 4β-Triazole-podophyllotoxin Glycosides 
A series of novel 4β-triazole-podophyllotoxin glycosides were synthesized by utilizing the Click reaction. Evaluation of cytotoxicity against a panel of five human cancer cell lines (HL-60, SMMC-7721, A-549, MCF-7, SW480) using MTT assay shows that most of these compounds show weak cytotoxicity. It was observed that compound 16 shows the highest activity with IC50 values ranging from 2.85 to 7.28 μM, which is more potent than the control drugs etoposide and cisplatin against four of five cancer cell lines tested. Compound 16 is characterized with an α-d-galactosyl residue directly linked to the triazole ring and a 4′-OH group on the E ring of the podophyllotoxin scaffold. HPLC investigation of representative compound indicates that incorporation of a sugar moiety seems to improve the chemical stability of the podophyllotoxin scaffold.
doi:10.1007/s13659-015-0057-3
PMCID: PMC4402586  PMID: 25869591
Podophyllotoxin; 4β-Triazole-podophyllotoxin; Glycosides; Click reaction; Anticancer; Synthesis
7.  A novel FBN2 mutation in a Chinese family with congenital contractural arachnodactyly 
FEBS Open Bio  2015;5:163-166.
Highlights
•We identified a novel FBN2 mutation (C1406R) in a Chinese family with CCA.•The mutation presented in the patients of this family but not in unaffected members.•SIFT and PolyPhen analyses suggested that the mutation was pathogenic.•The mutation was located in the calcium-binding epidermal growth factor-like domain.
Congenital contractural arachnodactyly (CCA, OMIM: 121050) is an autosomal dominant condition that shares skeletal features with Marfan syndrome (MFS, OMIM: 154700), including contractures, arachnodactyly, dolichostenomelia, scoliosis, crumpled ears and pectus deformities but excluding the ocular and cardiovascular complications that characterize MFS. These two similar syndromes result from mutations in two genes belonging to the fibrillin family, FBN1 and FBN2, respectively. We successfully identified a novel FBN2 mutation (C1406R) in a Chinese family with CCA for over five generations. This mutation was detected in the patients of this family but not in the seven unaffected family members or 100 normal individuals. SIFT and PolyPhen analyses suggested that the mutation was pathogenic. We identified a missense mutation in the calcium binding-epidermal growth factor (cbEGF)-like domain. Our study extends the mutation spectrum of CCA and confirms a relationship between mutations in the FBN2 gene and the clinical findings of CCA.
doi:10.1016/j.fob.2015.02.005
PMCID: PMC4359973  PMID: 25834781
Congenital contractural arachnodactyly; CCA; Fibrillin2; FBN2
8.  The Th17/Treg Immune Balance in Ulcerative Colitis Patients with Two Different Chinese Syndromes: Dampness-Heat in Large Intestine and Spleen and Kidney Yang Deficiency Syndrome 
Objective. To investigate the Th17/Treg immune balance in the ulcerative colitis (UC) patients with two Chinese syndrome: dampness-heat in large intestine (DHLI) and spleen and kidney Yang deficiency (SKYD). Methods. Ninety UC patients (45 were diagnosed with DHLI and 45 with SKYD syndrome) and 23 healthy people were recruited. The serumIL-17 and TGF-β1 levels of these participants were measured with ELISA; the expression of IL-17 and TGF-β 1 in colonic mucosa tissue was determined with immunohistochemistry and the percentage of Th17 and Treg in peripheral blood with flow cytometry. Results. The levels of IL-17 and Th17 were significantly higher in both DHLI and SKYD groups than in healthy control group and higher in DHLI than in SKYD group (P < 0.05). The levels of TGF-β1 and Treg were significantly lower in the two UC patients groups than in healthy control group; and lower in SKYD group than in DHLI group (P < 0.05). Conclusions. UC with DHLI syndrome could be characterized by the elevation of Th17 and IL-17 levels, which indicated an accentuation of inflammatory reaction; UC with SKYD syndrome could be characterized by the reduction of serum Treg and TGF-β1 levels, which represented a depression of immune tolerance.
doi:10.1155/2015/264317
PMCID: PMC4359821  PMID: 25815027
9.  Two Novel Mutations in Myosin Binding Protein C Slow Causing Distal Arthrogryposis Type 2 in Two Large Han Chinese Families May Suggest Important Functional Role of Immunoglobulin Domain C2 
PLoS ONE  2015;10(2):e0117158.
Distal arthrogryposes (DAs) are a group of disorders that mainly involve the distal parts of the limbs and at least ten different DAs have been described to date. DAs are mostly described as autosomal dominant disorders with variable expressivity and incomplete penetrance, but recently autosomal recessive pattern was reported in distal arthrogryposis type 5D. Mutations in the contractile genes are found in about 50% of all DA patients. Of these genes, mutations in the gene encoding myosin binding protein C slow MYBPC1 were recently identified in two families with distal arthrogryposis type 1B. Here, we described two large Chinese families with autosomal dominant distal arthrogryposis type 2(DA2) with incomplete penetrance and variable expressivity. Some unique overextension contractures of the lower limbs and some distinctive facial features were present in our DA2 pedigrees. We performed follow-up DNA sequencing after linkage mapping and first identified two novel MYBPC1 mutations (c.1075G>A [p.E359K] and c.956C>T [p.P319L]) responsible for these Chinese DA2 families of which one introduced by germline mosacism. Each mutation was found to cosegregate with the DA2 phenotype in each family but not in population controls. Both substitutions occur within C2 immunoglobulin domain, which together with C1 and the M motif constitute the binding site for the S2 subfragment of myosin. Our results expand the phenotypic spectrum of MYBPC1-related arthrogryposis multiplex congenita (AMC). We also proposed the possible molecular mechanisms that may underlie the pathogenesis of DA2 myopathy associated with these two substitutions in MYBPC1.
doi:10.1371/journal.pone.0117158
PMCID: PMC4332675  PMID: 25679999
10.  Glycyrrhetinic acid induces G1-phase cell cycle arrest in human non-small cell lung cancer cells through endoplasmic reticulum stress pathway 
International Journal of Oncology  2015;46(3):981-988.
Glycyrrhetinic acid (GA) is a natural compound extracted from liquorice, which is often used in traditional Chinese medicine. The purpose of the present study was to investigate the antitumor effect of GA in human non-small cell lung cancer (NSCLC), and its underlying mechanisms in vitro. We have shown that GA suppressed the proliferation of A549 and NCI-H460 cells. Flow cytometric analysis showed that GA arrested cell cycle in G0/G1 phase without inducing apoptosis. Western blot analysis indicated that GA mediated G1-phase cell cycle arrest by upregulation of cyclin-dependent kinase inhibitors (CKIs) (p18, p16, p27 and p21) and inhibition of cyclins (cyclin-D1, -D3 and -E) and cyclin-dependent kinases (CDKs) (CDK4, 6 and 2). GA also maintained pRb phosphorylation status, and inhibited E2F transcription factor 1 (E2F-1) in both cell lines. GA upregulated the unfolded proteins, Bip, PERK and ERP72. Accumulation of unfolded proteins in the endoplasmic reticulum (ER) triggered the unfolded protein response (UPR), which could be the mechanism by which GA inhibited cell proliferation in NSCLC cells. GA then coordinated the induction of ER chaperones, which decreased protein synthesis and induced cell cycle arrest in the G1 phase. This study provides experimental evidence to support the development of GA as a chemotherapeutic agent for NSCLC.
doi:10.3892/ijo.2015.2819
PMCID: PMC4324580  PMID: 25573651
glycyrrhetinic acid; cell cycle arrest; ER stress; NSCLC
11.  The Shared Crosstalk of Multiple Pathways Involved in the Inflammation between Rheumatoid Arthritis and Coronary Artery Disease Based on a Digital Gene Expression Profile 
PLoS ONE  2014;9(12):e113659.
Rheumatoid arthritis (RA) and coronary artery disease (CAD) are both complex inflammatory diseases, and an increased prevalence of CAD and a high rate of mortality have been observed in RA patients. But the molecular mechanism of inflammation that is shared between the two disorders is unclear. High-throughput techniques, such as transcriptome analysis, are becoming important tools for genetic biomarker discovery in highly complex biological samples, which is critical for the diagnosis, prognosis, and treatment of disease. In the present study, we reported one type of transcriptome analysis method: digital gene expression profiling of peripheral blood mononuclear cells of 10 RA patients, 10 CAD patients and 10 healthy people. In all, 213 and 152 differently expressed genes (DEGs) were identified in RA patients compared with normal controls (RA vs. normal) and CAD patients compared with normal controls (CAD vs. normal), respectively, with 73 shared DEGs between them. Using this technique in combination with Ingenuity Pathways Analysis software, the effects on inflammation of four shared canonical pathways, three shared activated predicted upstream regulators and three shared molecular interaction networks were identified and explored. These shared molecular mechanisms may provide the genetic basis and potential targets for optimizing the application of current drugs to more effectively treat these diseases simultaneously and for preventing one when the other is diagnosed.
doi:10.1371/journal.pone.0113659
PMCID: PMC4267808  PMID: 25514790
12.  Smoking and Adverse Maternal and Child Health Outcomes in Brazil 
Nicotine & Tobacco Research  2013;15(11):1797-1804.
Introduction:
Numerous studies from high-income countries document the causal relationship between cigarette smoking during pregnancy and adverse maternal and child health (MCH) outcomes. Less research has been conducted in low and middle income countries, but a burgeoning literature can be found for Brazil.
Methods:
We review Brazilian studies of the prevalence of maternal smoking, the relative risk of smoking-attributable adverse MCH outcomes, and present new estimates for these outcomes, using the attributable fraction method.
Results:
We found that Brazilian studies of the relative risks of smoking-attributable adverse MCH outcomes were broadly consistent with previous reviews. Based on a comparison of maternal smoking over time, smoking during pregnancy has declined by about 50% over the last 20 years in Brazil. For 2008, we estimate that 5,352 cases of spontaneous abortion, 10,929 cases of preterm birth, 20,717 cases of low birth weight, and 29 cases of sudden infant death syndrome are attributable to maternal smoking. Between 1989 and 2008, the percent of smoking-attributable adverse MCH outcomes in Brazil was at least halved.
Conclusions:
The results show that over a 20-year period, during which Brazil implemented numerous effective tobacco control measures, the country experienced a dramatic decrease in both maternal smoking prevalence and smoking-attributable adverse MCH outcomes. Countries that implement effective tobacco control measures can expect to reduce both maternal smoking and adverse MCH outcomes, thereby improving the public health.
doi:10.1093/ntr/ntt073
PMCID: PMC3842128  PMID: 23873977
13.  Irisin Promotes Human Umbilical Vein Endothelial Cell Proliferation through the ERK Signaling Pathway and Partly Suppresses High Glucose-Induced Apoptosis 
PLoS ONE  2014;9(10):e110273.
Irisin is a newly discovered myokine that links exercise with metabolic homeostasis. It is involved in modest weight loss and improves glucose intolerance. However, the direct effects and mechanisms of irisin on vascular endothelial cells (ECs) are not fully understood. In the current study, we demonstrated that irisin promoted Human Umbilical Vein Endothelial Cell (HUVEC) proliferation. It was further demonstrated that this pro-proliferation effect was mediated by irisin-induced activation of extracellular signal–related kinase (ERK) signaling pathways. Inhibition of ERK signaling with U0126 decreased the pro-proliferation effect of irisin on HUVECs. It was also demonstrated that irisin reduced high glucose-induced apoptosis by up-regulating Bcl-2 expression and down-regulating Bax, Caspase-9 and Caspase-3 expression. In summary, these results suggested that irisin plays a novel role in sustaining endothelial homeostasis by promoting HUVEC proliferation via the ERK signaling pathway and protects the cell from high glucose-induced apoptosis by regulating Bcl-2,Bax and Caspase expression.
doi:10.1371/journal.pone.0110273
PMCID: PMC4206299  PMID: 25338001
14.  Arsenic trioxide induces apoptosis of human gastrointestinal cancer cells 
AIM: To investigate the changes in apoptosis in gastrointestinal cancer cells from patients with gastrointestinal cancers treated with arsenic trioxide (As2O3); and to study the possible molecular mechanisms of such changes by detecting the expression levels of p53 and Bcl-2.
METHODS: Twenty patients with gastrointestinal adenocarcinoma based on endoscopic and biopsy findings (ten patients with gastric cancer and ten patients with colorectal cancer) who received treatment in our hospital between August 2007 and December 2008 were included in this study. None of the patients had received anti-tumour agents prior to As2O3 treatment. As2O3 was administered intravenously at a dose of 0.01 g/d diluted with 5% glucose in normal saline for 2-3 h for 3 consecutive days before surgery. Morphological changes associated with apoptosis of gastrointestinal cancer cells were observed by light microscopy. Changes in the apoptotic index induced by As2O3 were investigated using the terminal deoxynucleotidyl transferase dUTP nick end labelling method. Expression levels of p53 and Bcl-2 proteins in gastrointestinal cancer tissues were determined by immunohistochemistry.
RESULTS: The apoptotic index of human gastrointestinal cancer cells was higher in cells from patients treated with As2O3 than in those not treated (P < 0.05). p53 protein expression in gastrointestinal tissues was unchanged by As2O3 (P > 0.05). However, Bcl-2 protein expression in gastrointestinal tissues was down-regulated by As2O3 (P < 0.01).
CONCLUSION: These results demonstrate that As2O3 treatment in patients with gastrointestinal cancers can induce apoptosis in gastrointestinal cancer cells and down-regulate Bcl-2 protein expression.
doi:10.3748/wjg.v20.i18.5505
PMCID: PMC4017065  PMID: 24833880
Gastrointestinal cancer; Arsenic trioxide; Apoptosis; p53; Bcl-2
15.  Duration of Breastfeeding and Childhood Obesity: A Generalized Propensity Score Approach 
Health Services Research  2012;48(2 Pt 1):628-651.
Objective
To estimate the effect of breastfeeding duration on childhood obesity.
Data Source
The Child Development Supplement (CDS) of the Panel Study of Income Dynamics (PSID). The PSID provides extensive data on the income and well-being of a representative sample of U.S. families from 1968 to the present. The CDS collects information on the children in PSID families ranging from cognitive, behavioral, and health status to their family and neighborhood environment. The first two waves of the CDS were conducted in 1997 and 2002, respectively. The data provide information on 3,271 children and their mothers.
Study Design
We use the generalized propensity score to adjust for confounding based on continuous treatment, and the general additive model to analyze the adjusted association between treatment and the outcome conditional on the propensity score. The main outcome is the body mass index (BMI) directly assessed during the in-person interview in 2002. Covariates include family, maternal, and child characteristics, many of which were measured in the year the child was born.
Principal Findings
After using propensity scores to adjust for confounding, the relationship between breastfeeding duration and childhood BMI is trivially small across a range of model specifications, and none of them is statistically significant except the unadjusted model.
Conclusions
The causal link between duration of breastfeeding and childhood obesity has not been established. Any recommendation of promoting breastfeeding to reduce childhood obesity is premature.
doi:10.1111/j.1475-6773.2012.01456.x
PMCID: PMC3626344  PMID: 22924637
Breastfeeding duration; childhood obesity; generalized propensity score (GPS); generalized additive model (GAM); confounding
16.  Rheumatoid Arthritis with Deficiency Pattern in Traditional Chinese Medicine Shows Correlation with Cold and Hot Patterns in Gene Expression Profiles 
In our precious study, the correlation between cold and hot patterns in traditional Chinese medicine (TCM) and gene expression profiles in rheumatoid arthritis (RA) has been explored. Based on TCM theory, deficiency pattern is another key pattern diagnosis among RA patients, which leads to a specific treatment principle in clinical management. Therefore, a further analysis was performed aiming at exploring the characteristic gene expression profile of deficiency pattern and its correlation with cold and hot patterns in RA patients by bioinformatics analysis approach based on gene expression profiles data detected with microarray technology. The TCM deficiency pattern-related genes network comprises 7 significantly, highly connected regions which are mainly involved in protein transcription processes, protein ubiquitination, toll-like receptor activated NF-κB regulated gene transcription and apoptosis, RNA clipping, NF-κB signal, nucleotide metabolism-related apoptosis, and immune response processes. Toll-like receptor activated NF-κB regulated gene transcription and apoptosis pathways are potential specific pathways related to TCM deficiency patterns in RA patients; TCM deficiency pattern is probably related to immune response. Network analysis can be used as a powerful tool for detecting the characteristic mechanism related to specific TCM pattern and the correlations between different patterns.
doi:10.1155/2013/248650
PMCID: PMC3794642  PMID: 24174973
17.  Expression Profiling and Proteomic Analysis of JIN Chinese Herbal Formula in Lung Carcinoma H460 Xenografts 
Many traditional Chinese medicine (TCM) formulae have been used in cancer therapy. The JIN formula is an ancient herbal formula recorded in the classic TCM book Jin Kui Yao Lue (Golden Chamber). The JIN formula significantly delayed the growth of subcutaneous human H460 xenografted tumors in vivo compared with the growth of mock controls. Gene array analysis of signal transduction in cancer showed that the JIN formula acted on multiple targets such as the mitogen-activated protein kinase, hedgehog, and Wnt signaling pathways. The coformula treatment of JIN and diamminedichloroplatinum (DDP) affected the stress/heat shock pathway. Proteomic analysis showed 36 and 84 differentially expressed proteins between the mock and DDP groups and between the mock and JIN groups, respectively. GoMiner analysis revealed that the differentially expressed proteins between the JIN and mock groups were enriched during cellular metabolic processes, and so forth. The ones between the DDP and mock groups were enriched during protein-DNA complex assembly, and so forth. Most downregulated proteins in the JIN group were heat shock proteins (HSPs) such as HSP90AA1 and HSPA1B, which could be used as markers to monitor responses to the JIN formula therapy. The mechanism of action of the JIN formula on HSP proteins warrants further investigation.
doi:10.1155/2013/160168
PMCID: PMC3770002  PMID: 24066008
18.  TGFA and IRF6 Contribute to the Risk of Nonsyndromic Cleft Lip with or without Cleft Palate in Northeast China 
PLoS ONE  2013;8(8):e70754.
Nonsyndromic cleft lip with or without cleft palate (NSCL/P) are common birth defects with a complex etiology. Multiple interacting loci and possible environmental factors influence the risk of NSCL/P. 12 single nucleotide polymorphisms (SNPs) in 7 candidate genes were tested using an allele-specific primer extension for case-control and case-parent analyses in northeast China in 236 unrelated patients, 185 mothers and 154 fathers, including 128 complete trios, and 400 control individuals. TGFA and IRF6 genes showed a significant association with NSCL/P. In IRF6, statistical evidence of an association between rs2235371 (p = 0.003), rs2013162 (p<0.0001) and NSCL/P was observed in case-control analyses. Family based association tests (FBATs) showed over-transmission of the C allele at the rs2235371 polymorphism (p = 0.007). In TGFA, associations between rs3771494, rs3771523 (G3822A), rs11466285 (T3851C) and NSCL/P were observed in case-control and FBAT analyses. Associations between other genes (BCL3, TGFB3, MTHFR, PVRL1 and SUMO1) and NSCL/P were not detected.
doi:10.1371/journal.pone.0070754
PMCID: PMC3735505  PMID: 23940636
19.  Dendrowardol C, a novel sesquiterpenoid from Dendrobium wardianum Warner 
Dendrowardol C (1)—a novel sesquiterpenoid, with an unprecedented 4/5/6/6 tetracyclic carbon backbone, together with two known cyclopacamphane-type sesquiterpenoids; dendronobilin I (2) and dendrobane A (3) were isolated from the stems of Dendrobium wardianum Warner. The structure of 1 was established on the basis of spectroscopic data and the absolute configuration was determined by single-crystal X-ray diffraction crystallography. The hypothetical biosynthetic pathway of 1 was postulated. Compound 1 showed no cytotoxic activity against human tumor cell lines HL-60, SMMC-7721, A-549, MCF-7, and SW480.
Electronic Supplementary Material
Supplementary material is available for this article at 10.1007/s13659-013-0024-9 and is accessible for authorized users.
doi:10.1007/s13659-013-0024-9
PMCID: PMC4131667
Dendrobium wardianum Warner; sesquiterpenoid; dendrowardol; X-ray
20.  Chemical components of Dendrobium crepidatum and their neurite outgrowth enhancing activities 
15 compounds, including two new ones crepidatuols A (1) and B (2) were isolated from the stems of Dendrobium crepidatum. The planar structures of these compounds were elucidated by spectroscopic methods (NMR, MS, UV, and IR) and comparison with those from literatures. 10 compounds were send for enhancing activities on nerve growth factor (NGF) medicated neurite outgrowth in PC12 cells and the results indicated that crepidatuol A (1), confusarin and 3-(2-acetoxy-5-methoxy)-phenylpropanol showed enhancing activities at the concentration of 10.0 µM.
Electronic Supplementary Material
Supplementary material is available for this article at 10.1007/s13659-012-0103-3 and is accessible for authorized users.
doi:10.1007/s13659-012-0103-3
PMCID: PMC4131658
Orchidaceae; Dendrobium crepidatum; bibenzyl; neurite outgrowth enhancing activity
21.  Xiaoqinglong Granules as Add-On Therapy for Asthma: Latent Class Analysis of Symptom Predictors of Response 
Xiaoqinglong granules (XQLG) has been shown to be an effective therapy in asthma animal models. We reviewed the literature and conducted this study to assess the impact of XQLG as an add-on therapy to treatment with fluticasone/salmeterol (seretide) in adult patients with mild-to-moderate, persistent asthma. A total of 178 patients were randomly assigned to receive XQLG and seretide or seretide plus placebo for 90 days. Asthma control was assessed by asthma control test (ACT), symptoms scores, FEV1, and PEF. Baseline patient-reported Chinese medicine (CM)-specific symptoms were analyzed to determine whether the symptoms may be possible indicators of treatment response by conducting latent class analysis (LCA). There was no statistically significant difference in ACT score between two groups. In the subset of 70 patients with symptoms defined by CM criteria, XQLG add-on therapy was found to significantly increase the levels of asthma control according to global initiative for asthma (GINA) guidelines (P = 0.0329). There was no significant difference in another subset of 100 patients with relatively low levels of the above-mentioned symptoms (P = 0.1291). Results of LCA suggest that patients with the six typical symptoms defined in CM may benefit from XQLG.
doi:10.1155/2013/759476
PMCID: PMC3574648  PMID: 23431348
22.  Ganoderma lucidum polysaccharides counteract inhibition on CD71 and FasL expression by culture supernatant of B16F10 cells upon lymphocyte activation 
Immune responses to tumor-associated antigens are often detectable in tumor-bearing hosts, but they fail to eliminate malignant cells or prevent development of metastases. Tumor cells produce factors such as interleukin-10, transforming growth factor-β1 and vascular endothelial growth factor (VEGF) that suppress the function of immune cells or induce apoptosis of immune cells. Culture supernatant of tumor cells may contain these immunosuppressive factors which suppress lymphocyte activation. CD71 and FasL are two important molecules that are expressed upon lymphocyte activation. Counteraction against suppression CD71 and FasL expression upon lymphocyte activation may benefit tumor control. A potential component with this effect is Ganoderma lucidum polysaccharides (Gl-PS). In this study, Gl-PS was used on lymphocytes incubating with culture supernatant of B16F10 melanoma cells (B16F10-CS) in the presence of phytohemagglutinin. Following induction with phytohemagglutinin, B16F10-CS suppressed CD71 expression in lymphocytes (as detected by immunofluorescence and flow cytometry), proliferation in lymphocytes (as detected by MTT assay), and FasL expression in lymphocytes (as detected by immunocytochemistry and western blot analysis), while Gl-PS fully or partially counteracted these suppressions. Gl-PS showed counteractive effects against suppression induced by B16F10-CS on CD71 and FasL expression upon lymphocyte activation, suggesting the potential of Gl-PS to facilitate cancer immunotherapy.
doi:10.3892/etm.2013.931
PMCID: PMC3628224  PMID: 23596479
tumor; lymphocyte activation; Ganoderma lucidum; polysaccharides; FasL; CD71
23.  Traditional Chinese Medicine-Based Network Pharmacology Could Lead to New Multicompound Drug Discovery 
Current strategies for drug discovery have reached a bottleneck where the paradigm is generally “one gene, one drug, one disease.” However, using holistic and systemic views, network pharmacology may be the next paradigm in drug discovery. Based on network pharmacology, a combinational drug with two or more compounds could offer beneficial synergistic effects for complex diseases. Interestingly, traditional chinese medicine (TCM) has been practicing holistic views for over 3,000 years, and its distinguished feature is using herbal formulas to treat diseases based on the unique pattern classification. Though TCM herbal formulas are acknowledged as a great source for drug discovery, no drug discovery strategies compatible with the multidimensional complexities of TCM herbal formulas have been developed. In this paper, we highlighted some novel paradigms in TCM-based network pharmacology and new drug discovery. A multiple compound drug can be discovered by merging herbal formula-based pharmacological networks with TCM pattern-based disease molecular networks. Herbal formulas would be a source for multiple compound drug candidates, and the TCM pattern in the disease would be an indication for a new drug.
doi:10.1155/2012/149762
PMCID: PMC3541710  PMID: 23346189
24.  Effect of Combining Therapy with Traditional Chinese Medicine-Based Psychotherapy and Herbal Medicines in Women with Menopausal Syndrome: A Randomized Controlled Clinical Trial 
This multicenter, randomized, controlled clinical study was designed to address the effectiveness of combined traditional-Chinese-medicine- (TCM-) based psychotherapy and Chinese herbal medicine (CHM) in the treatment of menopausal syndrome. Altogether 424 eligible women diagnosed as menopausal syndrome and categorized as Kidney-Yin/Kidney-Yang deficiency pattern in TCM were randomly assigned into 4 groups and accepted TCM-based psychotherapy (PSY), CHM, PSY + CHM, or placebo therapies, respectively, for 12 weeks, and another 12 weeks were taken as the followup. Kupperman Index (KI) and the Menopause-Specific Quality of Life (MENQOL) with its four subscales (vasomotor, physical, psychosocial, and sexual) were employed for efficacy assessment. Results showed that 400 participants completed 12-week treatment, of which 380 finished the record of KI and MENQOF at week 24. The average adjusted number of KI score decreased between baseline and 12 weeks in all groups. Statistically significant differences were detected in the average adjusted change between the PSY + CHM group and placebo at overall time points (P < 0.05). No severe adverse events occurred in each group and no significant differences were indicated between any of the three groups and placebo in adverse event proportion. We concluded that TCM psychotherapy combined with CHM has a favorable outcome in treating menopausal syndrome.
doi:10.1155/2012/354145
PMCID: PMC3523610  PMID: 23304198
25.  Inhibition of β-catenin Signaling by Nongenomic Action of Orphan Nuclear Receptor Nur77 
Oncogene  2011;31(21):2653-2667.
Dysregulation of β-catenin turnover due to mutations of its regulatory proteins including APC and p53 is implicated in the pathogenesis of cancer. Thus, intensive effort is being made to search for alternative approaches to reduce abnormally activated β-catenin in cancer cells. Nur77, an orphan member of the nuclear receptor superfamily, plays a role in the growth and apoptosis of cancer cells. Here, we reported that Nur77 could inhibit transcriptional activity of β-catenin by inducing β-catenin degradation via proteasomal degradation pathway that is GSK3β and Siah-1 independent. Nur77 induction of β-catenin degradation required both the N-terminal region of Nur77, which was involved in Nur77 ubiquitination, and the C-terminal region, which was responsible for β-catenin binding. Nur77/ΔDBD, a Nur77 mutant lacking its DNA-binding domain, resided in the cytoplasm, interacted with β-catenin, and induced β-catenin degradation, demonstrating that Nur77-mediated β-catenin degradation was independent of its DNA-binding and transactivation and might occur in the cytoplasm. In addition, we reported our identification of two digitalis-like compounds (DLCs), H-9 and ATE-i2-b4, which potently induced Nur77 expression and β-catenin degradation in SW620 colon cancer cells expressing mutant APC protein in vitro and in animals. DLC-induced Nur77 protein was mainly found in the cytoplasm, and inhibition of Nur77 nuclear export by the CRM1-dependent nuclear export inhibitor leptomycin B or Jun N-terminal kinase inhibitor prevented the effect of DLC on inducing β-catenin degradation. Together, our results demonstrate that β-catenin can be degraded by cytoplasmic Nur77 through their interaction and identify H-9 and ATE-i2-b4 as potent activators of the Nur77-mediated pathway for β-catenin degradation.
doi:10.1038/onc.2011.448
PMCID: PMC3257393  PMID: 21986938
Nur77; β-catenin; Nongenomic; Cardenolide; Cancer

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