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1.  Investigating Factors Associated with Depression of Type 2 Diabetic Retinopathy Patients in China 
PLoS ONE  2015;10(7):e0132616.
Aims and objectives
To assess the depression status of type 2 diabetic retinopathy patients in Nantong China and to identify factors associated with depression.
Two hundred and ninety-four patients with type 2 diabetic retinopathy were recruited from the Affiliated Hospital of Nantong University. The severity of DR was measured in the worse eye. Depressive symptoms were assessed with the Center for Epidemiologic Studies Depression Scale (CES-D); the quality of life was measured with the Medical Outcomes Study Short Form 36 (SF-36). The logistic regression analyses were used to identify the independent factors of depression.
The mean age of the study subjects was 57.77 years (SD: 9.64). Approximately 35.7% of subjects reported depressive symptoms (n = 105).Multiple logistic regression analyses showed that female gender (p = 0.014), low monthly income (p = 0.01), poor vision in the better eye (P = 0.002), laser treatment history (p = 0.01) were significant risk factors for depression. The quality of life of individuals with CES-D score<16 was significantly better compared with individuals with CES-D score≥16.
The reported depressive symptoms among type 2 diabetic retinopathy population is higher in Nantong China. Gender, salary, vision acuity and treatment history were important risk factors linked to this disorder in the Chinese type 2 diabetic retinopathy population from Nantong. More attention by medical care personnel needs to be paid to the psychological health of this population.
PMCID: PMC4494704  PMID: 26151365
2.  Research of Herb-Partitioned Moxibustion for Primary Dysmenorrhea Patients Based on the LC-MS Metabonomics 
Objective. To explore the efficacy and mechanism of primary dysmenorrhea patients were treated with herb-partitioned moxibustion through metabonomics. Methods. 20 patients with primary dysmenorrhea were randomized into two groups, separately treated with herb-partitioned moxibustion at CV8 (shenque) and acupuncture at SP6 (sanyinjiao). After three menstrual cycles' treatment, the intensity of menstrual pain using VAS and the changes of metabolites of plasma using LC-MS were observed. Results. The VAS of two groups decreased with different descending range. Herb-partitioned moxibustion upregulated 20α-dihydroprogesterone, pregnenolone, prostaglandin E2 and γ-aminobutyric acid and downregulated the content of estrone and prostaglandin H2, while acupuncture upregulated pregnenolone and 20α-dihydroprogesterone and downregulated 2-methoxyestradiol-3-methylether, 15-hydroxyeicosatrienoic acid and 6-keto-prostaglandin. Discussion. It was effective in relieving the abdominal pain by these two therapies. Herb-partitioned moxibustion is superior to acupuncture for primary dysmenorrhea, which could be related to regulating the endocrine hormone.
PMCID: PMC4502312
3.  Meta-analysis of two Chinese populations identifies an autoimmune disease risk allele in 22q11.21 as associated with systemic lupus erythematosus 
Systemic lupus erythematosus (SLE) is a heterogeneous disease with a diverse spectrum of clinical symptoms, ranging from skin rash to end-organ damage. 22q11.21 has been identified as a susceptibility region for several autoimmune diseases, including SLE. However, detailed information for SLE association and the underlying functional mechanism(s) is still lacking.
Through meta-analysis of two genome-wide association studies (GWAS) on Han Chinese populations, comprising a total of 1,659 cases and 3,398 controls matched geographically, we closely examined the 22q11.21 region, especially on the reported single-nucleotide polymorphisms (SNPs) associated with different autoimmune diseases and their relationships. We further replicated the most significant associations of SNPs with SLE using 2,612 cases and 2,323 controls of Asian ancestry.
All reported SNPs in the 22q11.21 region with different autoimmune diseases were examined using the two GWAS data and meta-analysis results, and supportive evidence of association with SLE was found (meta-analysis: P_meta ≤ 7.27E-05), which might require further investigation. SNP rs2298428 was identified as the most significant SNP associated with SLE in this region (P_meta =2.70E-09). It showed independent effects through both stepwise and conditional logistic regression, and there is no evidence of other independent association signals for SLE in this region. The association of rs2298428 was further replicated in three cohorts from Hong Kong, Anhui and Thailand comprising a total of 2,612 cases and 2,323 controls (joint analysis of GWAS and replication result: P_all =1.31E-11, odds ratio =1.23). SNP rs2298428 was shown to be an expression quantitative locus for UBE2L3 gene in different cell types, with the risk allele (T) being correlated with higher expression of UBE2L3. This is consistent with earlier reports on higher expression of UBE2L3 in patients with SLE.
Association with distinct autoimmune diseases highlights the significance of this region in autoreactive responses and potentially shared functional mechanisms in these diseases.
Electronic supplementary material
The online version of this article (doi:10.1186/s13075-015-0577-6) contains supplementary material, which is available to authorized users.
PMCID: PMC4404227  PMID: 25880549
4.  Effect of combined application insulin and insulin detemir on continous glucose monitor in children with type 1 diabetes mellitus 
Insulin detemir is a soluble long-acting human insulin analogue at neutral pH with a unique mechanism of action, which could strengthen the effects of insulin. This study aims to explore the effects of insulin combined with insulin detemir on the continous glucose in children with type 1 diabetes mellitus. In this study, 150 patients with type 1 diabetes enrolled were included and randomly divided into 3 groups: insulin group (group A), insulin detemir group (group B) and insulin combined with insulin detemir group (group C). Each subject underwent 72 h of continuous glucose monitoring (CGM). MAGE, HbA1c and Noctumal Hypoglycemia levels were examined by using the ELISA kits. The body weight changes were also detected in this study. The results indicated that the information including age, body weight, disease duration and glucose level and HbA1c percentage on the start time point among three groups indicated no statistical differences. Insulin combined with insulin detemir decrease MAGE and HbA1c level in Group C compared to Group A and Group A (P < 0.05). Insulin combined with insulin detemir decreas noctumal hypoglycemia levels and body weight changes (P < 0.05). In conclusion, this study confirmed efficacy of insulin detemir by demonstrating non-inferiority of insulin detemir compared with insulin with respect to HbA1c, with an improved safety profile including significantly fewer hypoglycaemic episodes and less undesirable weight gain in children.
PMCID: PMC4443177  PMID: 26064343
Diabetes mellitus; insulin detemir; hypoglycemia; insulin therapy
5.  Investigating the role of DNA damage in tobacco smoking-induced spine degeneration 
Tobacco smoking is a key risk factor for spine degeneration. However, the underlying mechanism by which smoking induces degeneration is not known. Recent studies implicate DNA damage as a cause of spine and intervertebral disc degeneration. Because tobacco smoke contains many genotoxins, we hypothesized that tobacco smoking promotes spine degeneration by inducing cellular DNA damage.
To determine if DNA damage plays a causal role in smoking-induced spine degeneration.
To compare the effect of chronic tobacco smoke inhalation on intervertebral disc and vertebral bone in normal and DNA repair-deficient mice to determine the contribution of DNA damage to degenerative changes.
Two month-old wild-type (C57BL/6) and DNA repair-deficient Ercc1−/Δ mice were exposed to tobacco smoke by direct inhalation (4 cigarettes/day, 5 days/week for 7 weeks) to model first-hand smoking in humans. Total disc proteoglycan (PG) content (1,9-dimethylmethylene blue assay), PG synthesis (35S-sulfate incorporation assay), aggrecan proteolysis (immunoblotting analysis) and vertebral bone morphology (micro-computed tomography) were measured.
Exposure of wild-type mice to tobacco smoke led to a 19% increase in vertebral porosity and a 61% decrease in trabecular bone volume. Intervertebral discs of smoke-exposed animals also showed a 2.6-fold decrease in GAG content and a 8.1-fold decrease in new PG synthesis. These smoking-induced degenerative changes were similar but not worse in Ercc1−/Δ mice.
Short-term exposure to high levels of primary tobacco smoke inhalation promotes degeneration of vertebral bone and discs. Disc degeneration is primarily driven by reduced synthesis of proteoglycans needed for vertebral cushioning. Degeneration was not exacerbated in congenic DNA repair-deficient mice indicating that DNA damage per se does not have a significant causal role in driving smoke-induced spine degeneration.
PMCID: PMC3944725  PMID: 24211096
Tobacco smoking; Intervertebral disc degeneration; Matrix proteoglycans; Aggrecan; Matrix metalloproteinases; DNA damage repair
6.  Optimization of 4-(N-Cycloamino)phenylquinazolines as a Novel Class of Tubulin-Polymerization Inhibitors Targeting the Colchicine Site 
Journal of medicinal chemistry  2014;57(4):1390-1402.
The 6-methoxy-1,2,3,4-tetrahydroquinoline moiety in prior leads 2-chloro- and 2-methyl-4-(6-methoxy-3,4-dihydroquinolin-1(2H)-yl)quinazoline (1a and 1b) was modified to produce 4-(N-cycloamino)quinazolines (4a–c and 5a–m). The new compounds were evaluated in cytotoxicity and tubulin inhibition assays, resulting in the discovery of new tubulin-polymerization inhibitors. 7-Methoxy-4-(2-methylquinazolin-4-yl)-3,4-dihydroquinoxalin- 2(1H)-one (5f), the most potent compound, exhibited high in vitro cytotoxic activity (GI50 1.9–3.2 nM), significant potency against tubulin assembly (IC50 0.77 μM), and substantial inhibition of colchicine binding (99% at 5 μM). In mechanism studies, 5f caused cell arrest in G2/M phase, disrupted microtubule formation, and competed mostly at the colchicine site on tubulin. Compound 5f and N-methylated analogue 5g were evaluated in nude mouse MCF7 xenograft models to validate their antitumor activity. Compound 5g displayed significant in vivo activity (tumor inhibitory rate 51%) at a dose of 4 mg/kg without obvious toxicity, whereas 5f unexpectedly resulted in toxicity and death at the same dose.
PMCID: PMC3983391  PMID: 24502232
7.  Prevalence of Suicide Attempts among College Students in China: A Meta-Analysis 
PLoS ONE  2015;10(2):e0116303.
Suicide is the leading cause of death among 15–34 year olds in China, but no national data are available on the suicide and suicide attempts rates of college students, a sub-group of youth with 23 million. Several studies have reported the prevalence of suicide attempts among college students, however, no meta-analysis pooling the prevalence of suicide attempts is found.
Objective and Methods
This study aims to estimate the pooled prevalence of suicide attempts among college students in China. The relevant studies up to August 2014 were systematically searched via electronic databases (PubMed-Medline, Embase, Chinese Wanfang database, Chinese National Knowledge Infrastructure and Chinese VIP database). We only selected original articles that either reported the prevalence of suicide attempts or sufficient data for calculating the prevalence.
A total of 29 eligible studies, with 88,225 college students, were finally included. The maximum and minimum reported prevalences of suicide attempts among college students in China were 0.4% and 10.5%, respectively. The pooled prevalence of suicide attempts was 2.8% (95%CI: 2.3%–3.3%). Subgroup analyses showed that the pooled estimate of prevalence of life time suicide attempts was 2.7% (95%CI: 2.1%–3.3%), and 12-month suicide attempts was 2.9% (95%CI: 2.0%–3.8%). The prevalence for males was 2.4% (95%CI: 1.8%–3.0%), and for females was 2.7% (95%CI: 1.9%–3.7%). The prevalences among college students in grade 1 through 4 were 2.8% (95%CI: 1.7%–3.8%), 1.8% (95%CI: 1.2%–2.3%), 2.0% (95%CI: 0.8%–3.1%), and 2.9% (95%CI: 0.1%–6.7%), respectively. The prevalences among college students from rural and urban areas were 5.1% (95%CI: 2.8%–7.5%) and 3.7% (95%CI: 1.4%–5.9%), respectively.
2.8% prevalence of suicide attempts and more than 600,000 suicide attempters among college students indicate that suicide attempt among college students is an important public health problem in China. More attention should be paid to the current situation.
PMCID: PMC4321993  PMID: 25664661
8.  Optimization of 4-(N-Cycloamino)phenylquinazolines as a Novel Class of Tubulin-Polymerization Inhibitors Targeting the Colchicine Site 
Journal of Medicinal Chemistry  2014;57(4):1390-1402.
The 6-methoxy-1,2,3,4-tetrahydroquinoline moiety in prior leads 2-chloro- and 2-methyl-4-(6-methoxy-3,4-dihydroquinolin-1(2H)-yl)quinazoline (1a and 1b) was modified to produce 4-(N-cycloamino)quinazolines (4a–c and 5a–m). The new compounds were evaluated in cytotoxicity and tubulin inhibition assays, resulting in the discovery of new tubulin-polymerization inhibitors. 7-Methoxy-4-(2-methylquinazolin-4-yl)-3,4-dihydroquinoxalin- 2(1H)-one (5f), the most potent compound, exhibited high in vitro cytotoxic activity (GI50 1.9–3.2 nM), significant potency against tubulin assembly (IC50 0.77 μM), and substantial inhibition of colchicine binding (99% at 5 μM). In mechanism studies, 5f caused cell arrest in G2/M phase, disrupted microtubule formation, and competed mostly at the colchicine site on tubulin. Compound 5f and N-methylated analogue 5g were evaluated in nude mouse MCF7 xenograft models to validate their antitumor activity. Compound 5g displayed significant in vivo activity (tumor inhibitory rate 51%) at a dose of 4 mg/kg without obvious toxicity, whereas 5f unexpectedly resulted in toxicity and death at the same dose.
PMCID: PMC3983391  PMID: 24502232
9.  An Updated Meta-Analysis: Risk Conferred by Glutathione S-Transferases (GSTM1 and GSTT1) Polymorphisms to Age-Related Cataract 
Journal of Ophthalmology  2015;2015:103950.
Purpose. To study the effects of glutathione S-transferase M1 (GSTM1) and T1 (GSTT1) polymorphisms on age-related cataract (ARC). Methods. After a systematic literature search, all relevant studies evaluating the association between GSTs polymorphisms and ARC were included. Results. Fifteen studies on GSTM1 and nine studies on GSTT1 were included in this meta-analysis. In the pooled analysis, a significant association between null genotype of GSTT1 and ARC was found (OR = 1.229, 95% CI = 1.057–1.429, and P = 0.007). In subgroup analysis, the association between cortical cataract (CC) and GSTM1 null genotype was statistically significant (OR = 0.713, 95% CI = 0.598–0.850, and P < 0.001). In addition, GSTM1 null genotype was significantly associated with ARC causing risk to individuals working indoors and not individuals working outdoors. The association between GSTT1 null genotype and risk of ARC was statistically significant in Asians (OR = 1.442, 95% CI = 1.137–1.830, and P = 0.003) but not in Caucasians. Conclusions. GSTM1 positive genotype is associated with increased risk of CC and loses the protective role in persons who work outdoors. Considering the ethnic variation, GSTT1 null genotype is found to be associated with increased risk of ARC in Asians but not in Caucasians.
PMCID: PMC4322823  PMID: 25692031
10.  Novel KIF6 Polymorphism Increases Susceptibility to Type 2 Diabetes Mellitus and Coronary Heart Disease in Han Chinese Men 
Journal of Diabetes Research  2014;2014:871439.
Objectives. The effect of the KIF6 polymorphism Trp719Arg on the risk of T2DM and T2DM with CHD remains unclear. Methods. 946 unrelated subjects of Han Chinese origin were recruited, comprising 346 controls, 312 T2DM, and 288 T2DM + CHD patients. Genotyping was performed by high-resolution melting curve analysis using real-time qPCR. The impact of the variant on T2DM/T2DM + CHD and gene-sex interaction were evaluated by stepwise multiple regression analysis. Results. The frequencies of the Trp719 allele in T2DM and T2DM + CHD patients were similar to the control group, whereas significantly increased 719Arg allele frequencies were observed in male T2DM and T2DM + CHD patients compared with the corresponding control group. Further sex partition analysis revealed that only male 719Arg allele carriers had approximately 3-fold and 5-fold higher risk of T2DM and T2DM + CHD, respectively, than noncarriers. There was also a significant association between carriers and higher TG and lower HDL-C levels. Conclusion. The KIF6 719Arg allele may increase the risk of T2DM and T2DM + CHD only in Han Chinese men by modulating lipid metabolism, especially with regard to TG and HDL.
PMCID: PMC4297624  PMID: 25629058
11.  Effects of different concentrations of tetramethylpyrazine, an active constituent of Chinese herb, on human corneal epithelial cell damaged by hydrogen peroxide 
To discuss the effects of different concentrations of tetramethylpyrazine (TMP), an active constituent of Chinese herb, on damaged Shandong human corneal epithelial cell (SDHCEC) induced by hydrogen peroxide.
We detected the combined effects of TMP with concentrations ranging from 4 mg/mL to 0.03 mg/mL and 800 µM hydrogen peroxide on SDHCEC. The methyl thiazolyl tetrazolium (MTT) assay was processed at 3, 6 and 12h separately while the detection of cell apoptosis at 6h only by flow cytometry.
The viability of SDHCEC with 0.5 mg/mL, 0.25 mg/mL, 0.125 mg/mL and 0.06 mg/mL TMP joint with 800 µM hydrogen peroxide at 3h and 6h was significantly higher than that with 800 µM hydrogen peroxide only, P<0.05. However, except 0.25 mg/mL, TMP with other concentrations joint with 800 µM hydrogen peroxide at 12h could not significantly inhibit decreased SDHCEC viability induced by 800 µM hydrogen peroxide. At 12h, TMP of 0.5 mg/mL, 0.25 mg/mL, 0.125 mg/mL and 0.06 mg/mL could significantly inhibit SDHCEC early apoptosis induced by 800 µM hydrogen peroxide, most remarkable at 0.25 mg/mL TMP, P<0.05.
Our results suggested that hydrogen peroxide can induce apoptosis related damage to SDHCEC. TMP can protect SDHCEC from the damage, and the protective effects may be associated with its anti-apoptosis mechanism.
PMCID: PMC4270986  PMID: 25540744
human corneal epithelial cell; cell viability; apoptosis; hydrogen peroxide
12.  Exogenous IFN-beta regulates the RANKL-c-Fos-IFN-beta signaling pathway in the collagen antibody-induced arthritis model 
Although a variety of drugs have been used to treat the symptoms of rheumatoid arthritis (RA), none of them are able to cure the disease. Interferon β (IFN-β) has pleiotropic effects on RA, but whether it can be used to treat RA remains globally controversial. Thus, in this study we tested the effects of IFN-β on RA patients and on collagen antibody-induced arthritis (CAIA) model mice.
The cytokine and auto-antibody expression profiles in the serum and synovial fluid (SF) from RA patients were assessed using enzyme-linked immunosorbent assay (ELISA) and compared with the results from osteoarthritis (OA) patients. Exogenous IFN-β was administered to RA patients and CAIA model mice, and the therapeutic effects were evaluated. Endogenous IFN-β expression in the joint bones of CAIA model mice was evaluated by quantitative real-time PCR (qRT-PCR). The effects of exogenous IFN-β on CAIA model mice were assessed using a clinical scoring system, hematoxylin eosin and safranin-O with fast green counterstain histology, molybdenum target X-ray, and tartrate-resistant acid phosphatase (TRAP) staining. The RANKL-RANK signaling pathway was analyzed using qRT-PCR. The RAW 264.7 cell line was differentiated into osteoclasts with RANKL stimulation and then treated with exogenous IFN-β.
The expression of inflammatory cytokines (IFN-γ, IL-17, MMP-3, and RANKL) and auto-antibodies (CII antibodies, RF-IgM, and anti-CCP/GPI) were significantly higher in RA compared with OA patients. After IFN-β intervention, some clinical symptoms in RA patients were partially alleviated, and the expression of IFN-γ, IL-17, MMP-3, and OPG) returned to normal levels. In the CAIA model, the expression of endogenous IFN-β in the joint bones was decreased. After IFN-β administration, the arthritis scores were decreased; synovial inflammation, cartilage, and bone destruction were clearly attenuated; and the expression of c-Fos and NFATc1 were reduced, while RANKL and TRAF6 expression was unchanged. In addition, exogenous IFN-β directly inhibited RANKL-induced osteoclastogenesis.
Exogenous IFN-β administration immunomodulates CAIA, may reduce joint inflammation and, perhaps more importantly, bone destruction by inhibiting the RANKL-c-Fos signaling pathway. Exogenous IFN-β intervention should be selectively used on RA patients because it may only be useful for RA patients with low endogenous IFN-β expression.
PMCID: PMC4273316  PMID: 25491303
Rheumatoid arthritis; Interferon-β; Collagen II antibody-induced arthritis; Receptor activator of nuclear factor κB ligand; c-Fos
13.  Association of XPC Gene Polymorphisms with Susceptibility to Prostate Cancer: Evidence from 3,936 Subjects 
Aim: Polymorphisms of xeroderma pigmentosum complementation group C (XPC) are thought to have significant effects on prostate cancer (PCa) risk. The aim of our study was to evaluate the impact of XPC gene polymorphisms on PCa risk by using a meta-analysis. Methods: Data were collected from the following electronic databases: PubMed, EMBASE, Elsevier Science Direct, Cochrane Library, and CNKI, with the last report up to April 30, 2013. Odds ratios with 95% confidence intervals were used to assess the strength of the association. Results: A total of five separate case–control studies (1966 cases and 1970 controls) were included in this meta-analysis. Meta-analysis was performed for the rs2228001 and PAT+/−polymorphisms. We did not detect a significant association between rs2228001 polymorphism and PCa (p>0.05). Similar results were found in stratification analyses by ethnicity and tumor stage. We detected a significant association of PAT+/−polymorphism with PCa (p<0.05). In stratification analysis, we did not detect a significant association of PAT+/−polymorphism with risk of bone metastasis in PCa patients (p>0.05). Conclusion: These analyses suggest that XPC gene PAT+/−polymorphism, but not rs2228001, likely contributes to susceptibility to PCa.
PMCID: PMC3865621  PMID: 24093803
14.  Nifedipine Promotes the Proliferation and Migration of Breast Cancer Cells 
PLoS ONE  2014;9(12):e113649.
Nifedipine is widely used as a calcium channel blocker (CCB) to treat angina and hypertension,but it is controversial with respect the risk of stimulation of cancers. In this study, we demonstrated that nifedipine promoted the proliferation and migration of breast cancer cells both invivo and invitro. However, verapamil, another calcium channel blocker, didn’t exert the similar effects. Nifedipine and high concentration KCl failed to alter the [Ca2+]i in MDA-MB-231 cells, suggesting that such nifedipine effect was not related with calcium channel. Moreover, nifedipine decreased miRNA-524-5p, resulting in the up-regulation of brain protein I3 (BRI3). Erk pathway was consequently activated and led to the proliferation and migration of breast cancer cells. Silencing BRI3 reversed the promoting effect of nifedipine on the breast cancer. In a summary, nifedipine stimulated the proliferation and migration of breast cancer cells via the axis of miRNA-524-5p-BRI3–Erk pathway independently of its calcium channel-blocking activity. Our findings highlight that nifedipine but not verapamil is conducive for breast cancer growth and metastasis, urging that the caution should be taken in clinic to prescribe nifedipine to women who suffering both hypertension and breast cancer, and hypertension with a tendency in breast cancers.
PMCID: PMC4249963  PMID: 25436889
15.  Lasiodiplodia sp. ME4-2, an endophytic fungus from the floral parts of Viscum coloratum, produces indole-3-carboxylic acid and other aromatic metabolites 
BMC Microbiology  2014;14:297.
Studies on endophytes, a relatively under-explored group of microorganisms, are currently popular amongst biologists and natural product researchers. A fungal strain (ME4-2) was isolated from flower samples of mistletoe (Viscum coloratum) during a screening program for endophytes. As limited information on floral endophytes is available, the aim of the present study is to characterise fungal endophytes using their secondary metabolites.
ME4-2 grew well in both natural and basic synthetic media but produced no conidia. Sequence analysis of its internal transcribed spacer rDNA demonstrated that ME4-2 forms a distinct branch within the genus Lasiodiplodia and is closely related to L. pseudotheobromae. This floral endophyte was thus identified as Lasiodiplodia sp. based on its molecular biological characteristics. Five aromatic compounds, including cyclo-(Trp-Ala), indole-3-carboxylic acid (ICA), indole-3-carbaldehyde, mellein and 2-phenylethanol, were found in the culture. The structures of these compounds were determined using spectroscopic methods combined with gas chromatography. To the best of our knowledge, our work is the first to report isolation of these aromatic metabolites from a floral endophyte. Interestingly, ICA, a major secondary metabolite produced by ME4-2, seemed to be biosynthesized via an unusual pathway. Furthermore, our results indicate that the fungus ME4-2 is a potent producer of 2-phenylethanol, which is a common component of floral essential oils.
This study introduces a fungal strain producing several important aromatic metabolites with pharmaceutical or food applications and suggests that endophytic fungi isolated from plant flowers are promising natural sources of aromatic compounds.
PMCID: PMC4255639  PMID: 25433389
Lasiodiplodia sp; Floral endophytes; Mistletoe; Aromatic compounds
Beta adrenergic receptor (β-AR) subtypes act through diverse signaling cascades to modulate cardiac function and remodeling. Previous in vitro studies suggest that β1-AR signaling is cardiotoxic whereas β2-AR signaling is cardioprotective, and may be the case during ischemia/reperfusion in vivo. The objective of this study was to assess whether β2-ARs also played a cardioprotective role in the pathogenesis of non-ischemic forms of cardiomyopathy.
Methods and Results
To dissect the role of β1 vs β2-ARs in modulating MLP (Muscle LIM Protein) cardiomyopathy, we crossbred MLP−/− with β1−/− or β2−/− mice. Deletion of the β2-AR improved survival, cardiac function, exercise capacity and myocyte shortening; in contrast haploinsufficency of the β1-AR reduced survival. Pathologic changes in Ca2+ handling were reversed in the absence of β2-ARs: peak Ca2+ and SR Ca2+ were decreased in MLP−/− and β1+/− /MLP−/− but restored in β2−/−MLP−/−. These changes were associated with reversal of alterations in troponin I and phospholamban phosphorylation. Gi inhibition increased peak and baseline Ca2+, recapitulating changes observed in the β2−/−/MLP−/−. The L-type Ca2+ blocker verapamil significantly decreased cardiac function in β2−/−MLP−/− vs WT. We next tested if the protective effects of β2-AR ablation were unique to the MLP model using TAC-induced heart failure. Similar to MLP, β2−/− mice demonstrated delayed progression of heart failure with restoration of myocyte shortening and peak Ca2+ and Ca2+ release.
Deletion of β2-ARs prevents the development of MLP−/− cardiomyopathy via positive modulation of Ca2+ due to removal of inhibitory Gi signaling and increased phosphorylation of troponin I and phospholamban. Similar effects were seen after TAC. Unlike previous models where β2-ARs were found to be cardioprotective, in these two models, β2-AR signaling appears to be deleterious, potentially through negative regulation of Ca2+ dynamics.
PMCID: PMC3791213  PMID: 23920331
Adrenergic receptors; cardiomyopathy; excitation-contraction coupling; signal transduction
17.  PIGD: a database for intronless genes in the Poaceae 
BMC Genomics  2014;15(1):832.
Intronless genes are a feature of prokaryotes; however, they are widespread and unequally distributed among eukaryotes and represent an important resource to study the evolution of gene architecture. Although many databases on exons and introns exist, there is currently no cohesive database that collects intronless genes in plants into a single database.
In this study, we present the Poaceae Intronless Genes Database (PIGD), a user-friendly web interface to explore information on intronless genes from different plants. Five Poaceae species, Sorghum bicolor, Zea mays, Setaria italica, Panicum virgatum and Brachypodium distachyon, are included in the current release of PIGD. Gene annotations and sequence data were collected and integrated from different databases. The primary focus of this study was to provide gene descriptions and gene product records. In addition, functional annotations, subcellular localization prediction and taxonomic distribution are reported. PIGD allows users to readily browse, search and download data. BLAST and comparative analyses are also provided through this online database, which is available at
PIGD provides a solid platform for the collection, integration and analysis of intronless genes in the Poaceae. As such, this database will be useful for subsequent bio-computational analysis in comparative genomics and evolutionary studies.
PMCID: PMC4195894  PMID: 25270086
Poaceae; Intronless Genes; Database
18.  Increased expression of miR-222 is associated with poor prognosis in bladder cancer 
MicroRNA-222 (miR-222) has been shown to play a potential oncogenic role in bladder cancer. The aim of this study was to evaluate the expression of miR-222 in bladder cancer and its potential relevance to clinicopathological characteristics and patient survival.
Surgical specimens of cancer tissue and adjacent normal tissue were obtained from 97 patients with bladder cancer. The relative expression levels of miR-222 in the cancer and the normal adjacent tissue were measured by quantitative reverse-transcriptase PCR. We analyzed their correlation with clinicopathological parameters and prognostic value.
The expression level of miR-222 was significantly higher in tumor tissues than in corresponding non-cancerous tissues (5.46 ± 1.45 versus 1.92 ± 0.65, P < 0.0001), and a high expression of miR-222 was found to be significantly associated with tumor grade (P = 0.003) and tumor stage (P = 0.005). The miR-222 expression level was classified as high or low in relation to the median value (cutoff value = 5.15). Kaplan-Meier analysis showed that patients with higher levels of miR-222 had significantly poorer survival than those with lower expression of this miRNA in patients, with a 5-year overall survival of 29.53% and 52.75%, respectively (P = 0.0034). In the multivariate Cox proportional hazards analysis, which included miR-222 level, tumor grade, tumor stage, and tumor number, high miR-222 expression was independently associated with poor survival (P < 0.001; hazard ratio 6.17; 95% CI 2.33 to 10.39).
miR-222 overexpression is involved in the poor prognosis of bladder cancer and can be used as a biomarker for selection of cases requiring special attention.
PMCID: PMC4132207  PMID: 25078265
Bladder cancer; microRNA-222; Prognosis
19.  Comparison of continuous subcutaneous insulin infusion and insulin glargine-based multiple daily insulin aspart injections with preferential adjustment of basal insulin in patients with type 2 diabetes 
The purpose of this study was to evaluate and compare multiple daily injection (MDI) therapy of bolus insulin aspart and basal insulin glargine with continuous subcutaneous insulin infusion (CSII) with aspart in patients with type 2 diabetes mellitus (T2DM). It was assessed whether MDI was capable of controlling glycemic index with a higher efficacy than CSII by preferential adjustment of basal insulin with a lower total daily insulin dosage in T2DM. Two hundred patients with T2DM were enrolled in the study and randomly assigned to CSII (n=100) and MDI (n=100; aspart immediately prior to each meal and glargine at bedtime) groups for 12 weeks of therapy. During the last week of each treatment period, the subjects wore a continuous glucose monitoring system for 2–3 days. The dosage of basal insulin was preferentially adjusted to control prior-meal blood glucose levels, and the characteristics of insulin dosage were analyzed. No statistically significant differences were observed between the two groups in hemoglobin A1c (HbA1c), which dropped from 10–11% prior to therapy to 7–7.5% after 12 weeks. After 12 weeks, good glycemic level control was achieved in all patients in the MDI and CSII groups. A statistically significant difference in the dose of insulin between the CSII and MDI groups was observed (P<0.001). In conclusion, no significant differences were found between the two therapies in the incidence of hypoglycemia and HbA1c for the 12 weeks. The basal insulin dosage was significantly decreased in the MDI group compared with that in the CSII group, but the CSII group was superior to MDI group in decreasing fasting blood glucose and shortening the time required for hypoglycemia to meet the targeted level.
PMCID: PMC4151650  PMID: 25187822
type 2 diabetes; insulin aspart; glargine insulin; hypoglycemia
20.  Dystrophin and Utrophin “Double Knockout” Dystrophic Mice Exhibit a Spectrum of Degenerative Musculoskeletal Abnormalities 
Duchenne muscular dystrophy (DMD) is a degenerative muscle disorder characterized by the lack of dystrophin expression at the sarcolemma of muscle fibers. In addition, DMD patients acquire osteopenia, fragility fractures, and scoliosis indicating that a deficiency in skeletal homeostasis coexists but little is known about the effects of DMD on bone and other connective tissues within the musculoskeletal system. Recent evidence has emerged implicating adult stem cell dysfunction in DMD myopathogenesis. Given the common mesenchymal origin of muscle and bone, we sought to investigate bone and other musculoskeletal tissues in a DMD mouse model. Here, we report that dystrophin–utrophin double knockout (dko) mice exhibit a spectrum of degenerative changes, outside skeletal muscle, in bone, articular cartilage, and intervertebral discs, in addition to reduced lifespan, muscle degeneration, spinal deformity, and cardiomyopathy previously reported. We also report these mice to have a reduced capacity for bone healing and exhibit spontaneous heterotopic ossification in the hind limb muscles. Therefore, we propose the dko mouse as a model for premature musculoskeletal aging and posit that a similar phenomenon may occur in patients with DMD.
PMCID: PMC4108902  PMID: 23097179
muscular dystrophy; osteopenia; bone healing; ectopic calcification; proteoglycans
21.  Glucosamine Supplementation Demonstrates a Negative Effect On Intervertebral Disc Matrix in an Animal Model of Disc Degeneration 
Spine  2013;38(12):984-990.
Study Design
Laboratory based controlled in vivo study
To determine the in vivo effects of oral glucosamine sulfate on intervertebral disc degeneration
Summary of Background Data
Although glucosamine has demonstrated beneficial effect in articular cartilage, clinical benefit is uncertain. A CDC report from 2009 reported that many patients are using glucosamine supplementation for low back pain (LBP), without significant evidence to support its use. Because disc degeneration is a major contributor of LBP, we explored the effects of glucosamine on disc matrix homeostasis in an animal model of disc degeneration.
Eighteen skeletally mature New Zealand White rabbits were divided into four groups: control, annular puncture, glucosamine, and annular puncture+glucosamine. Glucosamine treated rabbits received daily oral supplementation with 107mg/day (weight based equivalent to human 1500mg/day). Annular puncture surgery involved puncturing the annulus fibrosus (AF) of 3 lumbar discs with a 16G needle to induce degeneration. Serial MRIs were obtained at 0, 4, 8, 12, and 20 weeks. Discs were harvested at 20 weeks for determination of glycosaminoglycan(GAG) content, relative gene expression measured by RT-PCR, and histological analyses.
The MRI index and NP area of injured discs of glucosamine treated animals with annular puncture was found to be lower than that of degenerated discs from rabbits not supplemented with glucosamine. Consistent with this, decreased glycosaminoglycan was demonstrated in glucosamine fed animals, as determined by both histological and GAG content. Gene expression was consistent with a detrimental effect on matrix.
These data demonstrate that the net effect on matrix in an animal model in vivo, as measured by gene expression, MRI, histology, and total proteoglycan is anti-anabolic. This raises concern over this commonly used supplement, and future research is needed to establish the clinical relevance of these findings.
PMCID: PMC3672267  PMID: 23324939
intervertebral disc; glucosamine; degeneration; matrix; annular puncture; glycosaminoglycan
22.  Proteomic analysis of immature rat pups brain in response to hypoxia and ischemia challenge 
Hypoxia and ischemia significantly affects perinatal brain development, even worse in preterm infants. However, the details of the mechanism leading to permanent brain damage after hypoxia-ischemia attack have not been fully elucidated. Proteomics could provide insight into the potential mechanism and help to promote the clinical treatment. In this study, quantitative analysis was performed 24 hours after hypoxia-ischemia using liquid-chromatography mass spectrometry coupled to label-free analysis. Compared to control, 193 proteins were present only in hypoxic-ischemic group. In addition, 34 proteins were more than 2 folds up-regulated and 14 proteins were more than 2 folds down-regulated in hypoxia-ischemia group. Gene Ontology database showed that the majority of differentially expressed proteins comprised mitochondrial proteins et al. Molecular function analysis revealed that the majority of proteins were involved in ion binding et al. Biological process analysis showed that the majority of proteins were involved in response to organic substance et al. STRING 9.0 software analysis were used to explore the complex interactions existed among the proteins. Western blot were used to verify the fold changes of some proteins-microtubule-associated protein 2 and microtubule-associated protein tau. This novel study performed a full-scale screening of the proteomics research in hypoxic-ischemic brain damage of immature rat.
PMCID: PMC4152027  PMID: 25197337
Hypoxia; ischemia; preterm; proteomics
23.  Mitochondrial-derived reactive oxygen species (ROS) play a causal role in aging-related intervertebral disc degeneration 
Oxidative damage is a well-established driver of aging. Evidence of oxidative stress exists in aged and degenerated discs, but it is unclear how it affects disc metabolism. In this study, we first determined whether oxidative stress negatively impacts disc matrix metabolism using disc organotypic and cell cultures. Mouse disc organotypic culture grown at atmospheric oxygen (20% O2) exhibited perturbed disc matrix homeostasis, including reduced proteoglycan synthesis and enhanced expression of matrix metalloproteinases, compared to discs grown at low oxygen levels (5% O2). Human disc cells grown at 20% O2 showed increased levels of mitochondrial-derived superoxide anions and perturbed matrix homeostasis. Treatment of disc cells with the mitochondria-targeted reactive oxygen species (ROS) scavenger XJB-5-131 blunted the adverse effects caused by 20% O2. Importantly, we demonstrated that treatment of accelerated aging Ercc1−/Δmice, previously established to be a useful in vivo model to study age-related intervertebral disc degeneration (IDD), also resulted in improved disc total glycosaminoglycan content and proteoglycan synthesis. This demonstrates that mitochondrial-derived ROS contributes to age-associated IDD in Ercc1−/Δmice. Collectively, these data provide strong experimental evidence that mitochondrial-derived ROS play a causal role in driving changes linked to aging-related IDD and a potentially important role for radical scavengers in preventing IDD.
PMCID: PMC3668354  PMID: 23389888
Aging; oxidative stress; reactive oxygen species (ROS); intervertebral discs; radical scavenger; nitroxide; matrix proteoglycan
24.  Clinical trial of thalidomide combined with radiotherapy in patients with esophageal cancer 
AIM: To investigate the short-term efficacy and tolerability of radiotherapy plus thalidomide in patients with esophageal cancer (EC).
METHODS: Serum samples from 86 EC patients were collected before, during, and after radiotherapy, and the vascular endothelial growth factor (VEGF) level was examined by ELISA. According to the change in serum VEGF level during radiotherapy, the patients were divided into two groups: in the drug group, VEGF level was increased or remained unchanged, and thalidomide was administered up to the end of radiotherapy; in the non-drug group, VEGF level was decreased and radiotherapy was given alone. Thirty healthy volunteers served as controls. The efficacy and safety of radiotherapy plus thalidomide therapy were investigated.
RESULTS: The 86 EC patients had a significantly higher level of VEGF compared with the 30 healthy controls before radiotherapy (P < 0.01), and the VEGF level was significantly correlated with primary tumor size, lymph node metastasis, histopathologic type, and clinical stage (P < 0.01). Of 83 evaluable cases, VEGF level was significantly decreased after radiotherapy in 32 patients in the drug group (P < 0.05), with an effective rate of 71.88%. The incidence of dizziness and/or burnout in the drug group and non-drug group was 62.50% and 15.69%, respectively (P = 0.000), and the incidence of somnolence was 12.50% and 0%, respectively (P = 0.019). No significant differences were observed.
CONCLUSION: Thalidomide can down-regulate serum VEGF level in EC patients, and combined with radiotherapy may improve treatment outcome. Thalidomide was well tolerated by EC patients.
PMCID: PMC4009547  PMID: 24803825
Thalidomide; Radiotherapy; Esophageal cancer; Vascular endothelial growth factor
25.  Emerging role of Interleukin-22 in autoimmune diseases 
Interleukin-22 (IL-22) is an IL-10 family cytokine member that was recently discovered to be mainly produced by Th17 cells. Previous studies have indicated the importance of IL-22 in host defense against Gram-negative bacterial organisms (in gut and lung). Recently, there is emerging evidence that IL-22 is involved in the development and pathogenesis of several autoimmune diseases, such as systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), multiple sclerosis (MS), Sjögren’s syndrome (SS) and psoriasis. Therapeutics targeting IL-22 therefore may have promise for treating various autoimmune diseases. In this review, we discuss the recent progression of the involvement of IL-22 in the development and pathogenesis of autoimmune diseases, as well as its clinical implications and therapeutic potential.
PMCID: PMC4003867  PMID: 22906768
IL-22; Th17; Th22; autoimmune; therapeutic

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