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1.  Family functioning, marital quality and social support in Chinese patients with epilepsy 
The purpose of this study was to examine family functioning, marital quality, social support, and anxiety and depression in Chinese patients with Epilepsy (PWE) in comparison with healthy people.
This case–control study included 42 PWE and 42 healthy controls. Participants completed the Zung’s self-rating depression scale, the Zung’s self-rating anxiety scale, the Chinese version of family cohesion and flexibility evaluation scales, the Chinese version of the marital inventory ENRICH, and the Chinese versions of the social support rating scale and perceived social support scale.
PWE reported higher levels of anxiety and depression, and lower levels of family cohesion, marriage quality and social support compared with controls. Support within and outside the family was negatively associated with depression, however social support did not significantly predict depression in PWE. In patients, support within the family and emotional support predicted family cohesion and marriage quality. Instrumental support was negatively associated with anxiety in patients but positively associated with depression in healthy controls. Support within the family predicted family cohesion and marriage quality in both the control group and patient group, depression predicted family adaptation in both the control group and patient group, while support outside the family predicted marriage quality only in the patient group. Both emotional and instrumental support predicted family adaptation in the control group, and emotional support predicted family cohesion in patients.
PWE in China had higher levels of anxiety and depression, dissatisfaction with family functioning and marital life, and less social support compared with healthy controls. Emotional support within and outside families promoted family cohesion and marriage quality, depression decreased family adaptation, and instrumental support decreased anxiety of PWE. These findings suggest that enhancing family and emotional supports and decreasing depression could promote the family functioning and marital quality of PWE, and instrumental support may play a role in decreasing anxiety.
PMCID: PMC4320606  PMID: 25627321
Family function; Marital quality; Epilepsy; Social support; Depression; Anxiety
2.  Involvement of RhoA/ROCK1 signaling pathway in hyperglycemia-induced microvascular endothelial dysfunction in diabetic retinopathy 
Diabetic retinopathy (DR) is a well-known serious complication of diabetes mellitus (DM), and can eventually advance to end-stage blindness. In the early stage of DR, endothelial cell barrier disorganized primarily and tight junction (TJ) protein composition transformed subsequently. The small GTPase RhoA and its downstream effector Rho-associated coiled-coil containing protein kinase 1 (ROCK1) regulate a mass of cellular processes, including cell adherence, proliferation, permeability and apoptosis. Although RhoA inhibitors have provided substantial clinical benefit as hypertonicity therapeutics, their use is limited by complex microenvironment as DR. While ample evidence indicates that TJ can be influenced by the RhoA/ROCK1 signaling, the underlying mechanisms remain incompletely understood. Here, we have uncovered a significant signaling network involved in diabetic retinal microvascular endothelial dysfunction (RMVED). Our results indicated that the activation of RhoA/ROCK1 pathway due to high glucose played a key role in microvascular endothelial cell dysfunction (MVED) by way of directly inducing TJ proteins over-expression during DR. We demonstrated that inhibition of RhoA/ROCK1 may attenuate the hypertonicity of endothelial cell caused by high glucose microenvironment meanwhile. Besides, chemical and pharmacological inhibitors of RhoA/ROCK1 pathway may partly block inflammation due to DR. Simultaneously, the apoptosis aroused by high glucose was also prevented considerably by fasudil, a kind of pharmacological inhibitor of RhoA/ROCK1 pathway. These findings indicate that RhoA/ROCK1 signaling directly modulates MVED, suggesting a novel therapeutic target for DR.
PMCID: PMC4230108  PMID: 25400825
RhoA; ROCK1; tight junction; apoptosis; fasudil; endothelial dysfunction; diabetic retinopathy
3.  Health related quality of life in patients with chronic gastritis and peptic ulcer and factors with impact: a longitudinal study 
BMC Gastroenterology  2014;14:149.
The assessment of Health Related Quality of Life (HRQOL) has been applied as a significant outcome indicator for patients with chronic diseases. No HRQOL study, however, has looked at HRQOL in patients with chronic gastritis and peptic ulcers. This paper focuses on comparing HRQOL in patients with chronic gastritis and peptic ulcers and examining the factors that influence the HRQOL of such patients. Results can be used for making decisions in clinical trials as well as aiding individual management and preventive care of these diseases.
The Chinese version of the SF-36 (CSF-36) was administered twice to 244 patients with chronic gastritis and peptic ulcers. Mean scores across the two disease groups were compared using t-tests, change over time was analyzed with paired samples t-tests, and factors predicting HRQOL were investigated using the univariate general linear model.
The mean domain scores of patients with chronic gastritis were lower than those for patients with peptic ulcers, with the exception of physical functioning. Both groups had lower HRQOL compared with population norms. Mean domain scores increased after treatment in both groups. HRQOL in patients with these two chronic diseases differed by age, education level, marriage, income, and gender, but their explanatory power was relatively low.
Quality of life of patients with chronic gastritis was lower than that of patients with peptic ulcers, which was lower than population norms. Quality of life in both patients groups was associated with socio-demographic risk factors.
PMCID: PMC4236548  PMID: 25141760
Chronic digestive disease; Health-related quality of life; SF-36; Influence factors; Standardized response mean
4.  A Catheter-Based Acoustic Interrogation Device for Monitoring Motility Dynamics of the Lower Esophageal Sphincter 
Sensors (Basel, Switzerland)  2014;14(8):14700-14711.
This paper presents novel minimally-invasive, catheter-based acoustic interrogation device for monitoring motility dynamics of the lower esophageal sphincter (LES). A micro-oscillator actively emitting sound wave at 16 kHz is located at one side of the LES, and a miniature microphone is located at the other side of the sphincter to capture the sound generated from the oscillator. Thus, the dynamics of the opening and closing of the LES can be quantitatively assessed. In this paper, experiments are conducted utilizing an LES motility dynamics simulator. The sound strength is captured by the microphone and is correlated to the level of LES opening and closing controlled by the simulator. Measurements from the simulator model show statistically significant (p < 0.05) Pearson correlation coefficients (0.905 on the average in quiet environment and 0.736 on the average in noisy environment, D.O.F. = 9). Measuring the level of LES opening and closing has the potential to become a valuable diagnostic technique for understanding LES dysfunction and the disorders associated with it.
PMCID: PMC4178998  PMID: 25120160
lower esophageal sphincter (LES); oscillator; microphone; acoustic catheter
5.  Urinary 6-sulfatoxymelatonin level in diabetic retinopathy patients with type 2 diabetes 
Melatonin is a powerful antioxidant. Decreased melatonin excretion has been reported to be associated with several oxidative stress-related diseases. The urinary metabolite of melatonin, 6-sulfatoxymelatonin (aMT6s), has proved to be a very reliable index of melatonin production. The present study aims to evaluate the level of urinary aMT6s in patients with type 2 diabetes mellitus and diabetic retinopathy. Urine samples were collected from 10 patients with diabetes and no diabetic retinopathy (NDR), 19 patients with nonproliferative diabetic retinopathy (NPDR), 38 patients with proliferative diabetic retinopathy (PDR), and 16 subjects without diabetes mellitus, who served as controls. The level of aMT6s in specimens was assayed by a commercial aMT6s ELISA kit, creatinine levels were also measured for each sample to get urinary aMT6s/creatinine ratio. Creatinine-adjusted urinary aMT6s values were compared among four groups. The urinary aMT6s (mean ± SD) levels were 9.95 ± 2.42, 9.90 ± 2.28, 8.40 ± 1.84 and 5.58 ± 1.33 ng/mg creatinine in the controls and in patients with NDR, NPDR, or PDR, respectively. The urinary aMT6s level of the PDR group was significantly lower than that of the control, NDR and DR groups. No significant difference was found among the control, NDR and DR groups. After adjustment for various factors (age, smoking, cancer, and coronary heart disease) that may influence the aMT6s level, the odds-ratio of urinary aMT6s comparing PDR patients to controls was 0.246 (95% confidence interval = 0.108-0.558, P = 0.001). Therefore, the urinary aMT6s level is significantly decreased in diabetic patients with PDR but not in diabetic patients without PDR, which indicates that decreased urinary aMT6s level may be associated with the pathogenesis of PDR.
PMCID: PMC4129050  PMID: 25120815
6-sulfatoxymelatonin; melatonin; diabetic retinopathy
6.  Epigenetic inactivation of mir-34b/c in addition to mir-34a and DAPK1 in chronic lymphocytic leukemia 
TP53 mutation/deletion is uncommon in chronic lymphocytic leukemia (CLL). We postulated that components of TP53-centered tumor suppressor network, miR-34b/c, in addition to DAPK1 and miR-34a might be inactivated by DNA hypermethylation. Moreover, we tested if miR-34b/c methylation might correlate with miR-203 or miR-124-1 methylation in CLL.
miR-34b/c, miR-34a and DAPK1 methylation was studied in 11 normal controls, 7 CLL cell lines, and 78 diagnostic CLL samples by methylation-specific polymerase chain reaction. MEC-1 cells were treated with 5-Aza-2’-deoxycytidine for reversal of methylation-associated miRNA silencing. Tumor suppressor properties of miR-34b were demonstrated by over-expression of precursor miR-34b in MEC-1 cells.
miR-34b/c promoter was unmethylated in normal controls, but completely methylated in 4 CLL cell lines. miR-34b/c expression was inversely correlated with miR-34b/c methylation. Different MSP statuses of miR-34b/c, including complete methylation and complete unmethylation, were verified by quantitative bisulfite pyrosequencing. 5-Aza-2’-deoxycytidine treatment resulted in promoter demethylation and miR-34b re-expression in MEC1 cells. Moreover, over-expression of miR-34b resulted in inhibition of cellular proliferation and increased cell death. In primary CLL samples, miR-34a, miR-34b/c and DAPK1 methylation was detected in 2.6%, 17.9% and 34.6% of patients at diagnosis respectively. Furthermore, 39.7%, 3.8% and 2.6% patients had methylation of one, two or all three genes respectively. Overall, 46.2% patients had methylation of at least one of these three genes. Besides, miR-34b/c methylation was associated with methylation of miR-34a (P = 0.03) and miR-203 (P = 0.012) in CLL.
Taken together, miR-34b/c is a tumor suppressor miRNA frequently methylated, and hence silenced in CLL. Together with DAPK1 methylation, miR-34b/c methylation is implicated in the disruption of the TP53-centered tumor suppressor network. Moreover, the association of miRNA methylation warrants further study.
PMCID: PMC3941938  PMID: 24559316
MicroRNA; TP53 network; Tumor suppressor; DNA methylation; Chronic lymphocytic leukemia
7.  Epigenetic inactivation of miR-9 family microRNAs in chronic lymphocytic leukemia - implications on constitutive activation of NFκB pathway 
Molecular Cancer  2013;12:173.
The miR-9 family microRNAs have been identified as a tumor suppressor miRNA in cancers. We postulated that miR-9-1, miR-9-2 and miR-9-3 might be inactivated by DNA hypermethylation in chronic lymphocytic leukemia (CLL).
Methylation of miR-9-1, miR-9-2 and miR-9-3 was studied in eight normal controls including normal bone marrow, buffy coat, and CD19-sorted peripheral blood B-cells from healthy individuals, seven CLL cell lines, and seventy-eight diagnostic CLL samples by methylation-specific polymerase chain reaction.
The promoters of miR-9-3 and miR-9-1 were both unmethylated in normal controls, but methylated in five (71.4%) and one of seven CLL cell lines respectively. However, miR-9-2 promoter was methylated in normal controls including CD19 + ve B-cells, hence suggestive of a tissue-specific but not tumor-specific methylation, and thus not further studied. Different MSP statuses of miR-9-3, including complete methylation, partial methylation, and complete unmethylation, were verified by quantitative bisulfite methylation analysis. 5-Aza-2′-deoxycytidine treatment resulted in miR-9-3 promoter demethylation and re-expression of pri-miR-9-3 in I83-E95 and WAC3CD5+ cells, which were homozygously methylated for miR-9-3. Moreover, overexpression of miR-9 led to suppressed cell proliferation and enhanced apoptosis together with downregulation of NFκB1 in I83-E95 cells, supporting a tumor suppressor role of miR-9-3 in CLL. In primary CLL samples, miR-9-3 was detected in 17% and miR-9-1 methylation in none of the patients at diagnosis. Moreover, miR-9-3 methylation was associated with advanced Rai stage (≥ stage 2) (P = 0.04).
Of the miR-9 family, miR-9-3 is a tumor suppressor miRNA relatively frequently methylated, and hence silenced in CLL; whereas miR-9-1 methylation is rare in CLL. The role of miR-9-3 methylation in the constitutive activation of NFκB signaling pathway in CLL warrants further study.
PMCID: PMC3877874  PMID: 24373626
microRNA; miR-9-3; Tumor suppressor; DNA methylation; NFκB; Chronic lymphocytic leukemia
8.  Belief in Divine Control, Coping, and Race/Ethnicity among Older Women with Breast Cancer 
Belief in divine control is often assumed to be fatalistic. However, the assumption has rarely been investigated in racial/ethnic minorities.
This study aims to examine the association between belief in divine control and coping and how the association was moderated by ethnicity/acculturation in a multi-ethnic sample of breast cancer patients.
Latina, African American, and non-Hispanic White older women with newly diagnosed breast cancer (N=257) from a population-based survey completed the scale of Belief in Divine Control and the Brief COPE.
Belief in divine control was positively related to approach coping (i.e., positive reframing, active coping, and planning) in all ethnic groups. Belief in divine control was positively related to acceptance and negatively related to avoidance coping (i.e., denial and behavioral disengagement) among low-acculturated Latinas.
Negative presumptions about fatalistic implications of belief in divine control should be critically reappraised, especially when such skepticism is applied to racial/ethnic minority patients.
PMCID: PMC3873338  PMID: 22529040
Religiosity and belief in divine control; Coping; Cancer fatalism; Race/ethnicity; Acculturation; Aged
9.  Norisoboldine Suppresses VEGF-Induced Endothelial Cell Migration via the cAMP-PKA-NF-κB/Notch1 Pathway 
PLoS ONE  2013;8(12):e81220.
The migration of endothelial cells has been regarded as a potential target for the treatment of angiogenesis-related diseases. Previously, we demonstrated that norisoboldine (NOR), an alkaloid compound isolated from Radix Linderae, can significantly suppress synovial angiogenesis by selectively inhibiting endothelial cell migration. In this study, we evaluated the importance of various pathways in VEGF-induced endothelial cell migration using specific inhibitor. VEGF-induced endothelial cell migration and sprouting were significantly inhibited by H-89 (an inhibitor of protein kinase A (PKA)) but not by inhibitors of other pathways. NOR markedly suppressed VEGF-induced intracytoplasmic cAMP production and PKA activation and thereby down-regulated the activation of downstream components of the PKA pathway, including enzymes (src, VASP and eNOS) and the transcription factor NF-κB. Moreover, the transcription activation potential of NF-κB, which is related to IκBα phosphorylation and the disruption of the p65/IκBα complex, was reduced by NOR. Meanwhile, NOR selectively inhibited the expression of p-p65 (ser276) but not p-p65 (ser536) or PKAc, indicating that PKAc participates in the regulation of NF-κB by NOR. Co-immunoprecipitation and immunofluorescence assays confirmed that NOR inhibited the formation of the PKAc/p65 complex and thereby decreased p65 (ser276) phosphorylation to prevent p65 binding to DNA. Docking models indicated that the affinity of NOR for PKA was higher than that of the original PKA ligand. Moreover, the fact that H-89 improved Notch1 activation, but DAPT (an inhibitor of Notch) failed to affect PKA activation, suggested that PKA may act on upstream of Notch1. In conclusion, the inhibitory effects of NOR on endothelial cell migration can be attributed to its modulation of the PKA pathway, especially on the processes of p65/IκBα complex disruption and PKAc/p65 complex formation. These results suggest that NOR inhibit VEGF-induced endothelial cell migration via a cAMP-PKA-NF-κB/Notch1 signaling pathway.
PMCID: PMC3857208  PMID: 24349042
Cancer  2012;118(21):5366-5373.
Although large numbers of cancer survivors exist in every community, including minority communities, there is a significant gap in knowledge about best practices for these patients.
Community Networks Programs (CNPs) funded by the National Cancer Institute’s Center to Reduce Cancer Health Disparities, have developed and tested unique services for these communities. These programs have utilized community based participatory research techniques under a framework of diffusion of innovation and communications theory.
This article describes some specifically tailored interventions that may be useful to a wide range of providers working with the underserved
Enhancing life after cancer can be achieved in underserved communities by supplementing local resources.
PMCID: PMC3381933  PMID: 22434384
community networks; cancer; quality of life; health disparities; palliative care; comprehensive cancer care; spirituality
11.  Fenofibrate Attenuated Glucose-Induced Mesangial Cells Proliferation and Extracellular Matrix Synthesis via PI3K/AKT and ERK1/2 
PLoS ONE  2013;8(10):e76836.
Excess mesangial extracellular matrix (ECM) and mesangial cell proliferation is the major pathologic feature of diabetic nephropathy (DN). Fenofibrate, a PPARα agonist, has been shown to attenuate extracellular matrix formation in diabetic nephropathy. However, the mechanisms underlying this effect remain to be elucidated. In this study, the effect of fenofibrate on high-glucose induced cell proliferation and extracellular matrix exertion and its mechanisms were investigated in cultured rat mesangial cells by the methylthiazoletetrazolium (MTT) assay, flow cytometry and western blot. The results showed that treatment of mesangial cells (MCs) with fenofibrate repressed high-glucose induced up-regulation of extracellular matrix Collagen-IV, and inhibited entry of cell cycle into the S phase. This G1 arrest and ECM inhibition was caused by the reduction of phosphorylation and activation of extracellular signal-regulated kinase 1/2 (ERK1/2) and AKT. On the contrary, PPARα siRNA accelerated high glucose-induced cell cycle progression by ERK1/2 and AKT activation. Taken together, fenofibrate ameliorated glucose-induced mesangial cell proliferation and matrix production via its inhibition of PI3K/AKT and ERK1/2 signaling pathways. Such mechanisms may contribute to the favorable effects of treatment using fenofibrate in diabetic nephropathy.
PMCID: PMC3793917  PMID: 24130796
12.  Antagonism of Betulinic Acid on LPS-Mediated Inhibition of ABCA1 and Cholesterol Efflux through Inhibiting Nuclear Factor-kappaB Signaling Pathway and miR-33 Expression 
PLoS ONE  2013;8(9):e74782.
ATP-binding cassette transporter A1 (ABCA1) is critical in exporting cholesterol from macrophages and plays a protective role in the development of atherosclerosis. The purpose of this study was to investigate the effects of betulinic acid (BA), a pentacyclic triterpenoid, on ABCA1 expression and cholesterol efflux, and to further determine the underlying mechanism. BA promoted ABCA1 expression and cholesterol efflux, decreased cellular cholesterol and cholesterol ester content in LPS-treated macrophages. Furthermore, we found that BA promoted ABCA1 expression via down-regulation of miR-33s. The inhibition of LPS-induced NF-κB activation further decreased miR-33s expression and enhanced ABCA1 expression and cholesterol efflux when compared with BA only treatment. In addition, BA suppressed IκB phosphorylation, p65 phosphorylation and nuclear translocation, and the transcription of NF-κB-dependent related gene. Moreover, BA reduced atherosclerotic lesion size, miR-33s levels and NF-κB activation, and promoted ABCA1 expression in apoE−/− mice. Taken together, these results reveal a novel mechanism for the BA-mediated ABCA1 expression, which may provide new insights for developing strategies for modulating vascular inflammation and atherosclerosis.
PMCID: PMC3783495  PMID: 24086374
13.  Multi-Ethnic Differences in Responses to Laboratory Pain Stimuli among Children 
A growing body of literature suggests ethnic differences in experimental pain. However, these studies largely focus on adults and the comparison between Caucasians and African-Americans. The primary aim of this study is to determine ethnic differences in laboratory induced pain in a multi-ethnic child sample.
Participants were 214 healthy children (mean age = 12.7, SD= 3.0 yrs). Ninety-eight Caucasian, 58 Hispanic, 34 African-American, and 24 Asian children were exposed to four trials of pressure and radiant heat pain stimuli. Pain responses were assessed with self-report measures (i.e., pain intensity and unpleasantness) and behavioral observation (i.e., pain tolerance).
Asians demonstrated more pain sensitivity than Caucasians, who evidenced more pain sensitivity than African-Americans and Hispanics. The results hold even after controlling for age, sex, SES, and experimenter’s ethnicity. Asians also showed higher anticipatory anxiety compared with other ethnic groups. Anticipatory anxiety accounted for some ethnic differences in pain between Asians, Hispanics, and African Americans.
By examining response to laboratory pain stimuli in children representing multiple ethnicities, an understudied sample, the study reveals unique findings compared to the existing literature. These findings have implications for clinicians who manage acute pain in children from diverse ethnic backgrounds. Future investigations should examine mechanisms that account for ethnic differences in pain during various developmental stages.
PMCID: PMC3742024  PMID: 23668844
ethnicity; laboratory pain; children; health disparity; anticipatory anxiety
14.  Over-production of nitric oxide by oxidative stress-induced activation of the TGF-β1/PI3K/Akt pathway in mesangial cells cultured in high glucose 
Acta Pharmacologica Sinica  2013;34(4):507-514.
To investigate whether NO over-production in rat mesangial cells cultured in high glucose (HG) is related to activation of the TGF-β1/PI3K/Akt pathway.
Rat mesangial cells line (HBZY-1) was exposed to HG (24.44 mmol/L) or H2O2 (10 μmol/L) for 16 h. NO release was quantified using the Griess assay. The TGF-β1 level was measured using ELISA. The protein expression of p-Akt, t-Akt, Bim, and iNOS was examined by Western blotting. The mRNA levels of TGF-β1 and Bim were measured using RT-PCR. The cell proliferation rate was estimated using a BrdU incorporation assay.
Treatment of the cells with HG, H2O2, or TGF-β1 (5 ng/mL) significantly increased the NO level that was substantially inhibited by co-treatment with the NADPH oxidase inhibitor diphenylene iodonium (DPI), TGF-β1 inhibitor SB431542, or PI3K inhibitor LY294002. Both HG and H2O2 significantly increased the protein and mRNA levels of TGF-β1 in the cells, and HG-induced increases of TGF-β1 protein and mRNA were blocked by co-treatment with DPI. Furthermore, the treatment with HG or H2O2 significantly increased the expression of phosphorylated Akt and iNOS and cell proliferation rate, which was blocked by co-treatment with DPI, SB431542, or LY294002. Moreover, the treatment with HG or H2O2 significantly inhibited Bim protein and mRNA expression, which was reversed by co-treatment with DPI, SB431542, or LY294002.
The results demonstrate that high glucose causes oxidative stress and NO over-production in rat mesangial cells in vitro via decreasing Bim and increasing iNOS, which are at least partially mediated by the TGF-β1/PI3K/Akt pathway.
PMCID: PMC4002794  PMID: 23524565
mesangial cells; high glucose; oxidative stress; NO; iNOS; Bim; TGF-β1; PI3K/Akt pathway
15.  Electrochemiluminescence energy transfer-promoted ultrasensitive immunoassay using near-infrared-emitting CdSeTe/CdS/ZnS quantum dots and gold nanorods 
Scientific Reports  2013;3:1529.
The marriage of energy transfer with electrochemiluminescence has produced a new technology named electrochemiluminescence energy transfer (ECL-ET), which can realize effective and sensitive detection of biomolecules. To obtain optimal ECL-ET efficiency, perfect energy overlapped donor/acceptor pair is of great importance. Herein, we present a sensitive ECL-ET based immunosensor for the detection of tumor markers, using energy tunable CdSeTe/CdS/ZnS double shell quantum dots (QDs) and gold nanorods (GNRs) as the donor and acceptor, respectively. Firstly a facile microwave-assisted strategy for the synthesis of green- to near-infrared-emitting CdSeTe/CdS/ZnS QDs with time- and component-tunable photoluminescence was proposed. And, on the basis of the adjustable optical properties of both CdSeTe/CdS/ZnS QDs and GNRs, excellent overlap between donor emission and acceptor absorption can be obtained to ensure effective ECL-ET quenching, thus improving the sensing sensitivity. This method represents a novel approach for versatile detection of biomolecules at low concentrations.
PMCID: PMC3607123  PMID: 23524874
16.  Norisoboldine Suppresses Osteoclast Differentiation through Preventing the Accumulation of TRAF6-TAK1 Complexes and Activation of MAPKs/NF-κB/c-Fos/NFATc1 Pathways 
PLoS ONE  2013;8(3):e59171.
Norisoboldine (NOR) is the main alkaloid constituent in the dry root of Lindera aggregata (Sims) Kosterm. (L. strychnifolia Vill.). As reported previously, orally administered NOR displayed a robust inhibition of joint bone destruction present in both mouse collagen-induced arthritis and rat adjuvant-induced arthritis with lower efficacious doses than that required for ameliorating systemic inflammation. This attracted us to assess the effects of NOR on differentiation and function of osteoclasts, primary effector cells for inflammatory bone destruction, to get insight into its anti-rheumatoid arthritis mechanisms.
Both RAW264.7 cells and mouse bone marrow-derived macrophages (BMMs) were stimulated with RANKL (100 ng/mL) to establish osteoclast differentiation models. ELISA, RT-PCR, gelatin zymography, western blotting, immunoprecipitation and EMSA were used to reveal related signalling pathways. NOR (10 and 30 µM), without significant cytotoxicity, showed significant reduction of the number of osteoclasts and the resorption pit areas, and it targeted osteoclast differentiation at the early stage. In conjunction with the anti-resorption effect of NOR, mRNA levels of cathepsin K and MMP-9 were decreased, and the activity of MMP-9 was attenuated. Furthermore, our mechanistic studies indicated that NOR obviously suppressed the ubiquitination of TRAF6, the accumulation of TRAF6-TAK1 complexes and the activation of ERK and p38 MAPK, and reduced the nuclear translocation of NF-κB-p65 and DNA-binding activity of NF-κB. However, NOR had little effect on expressions of TRAF6 or the phosphorylation and degradation of IκBα. Moreover, NOR markedly inhibited expressions of transcription factor NFATc1, but not c-Fos. Intriguingly, the subsequent nuclear translocations of c-Fos and NFATc1 were substantially down-regulated. Hence, we demonstrated for the first time that preventing the differentiation and function of osteoclasts at the early stage was an important anti-bone destruction mechanism of NOR, which might be attributed to inhibition of ubiquitination of TRAF6, the accumulation of TRAF6-TAK1 complexes and the activation of MAPKs/NF-κB/c-Fos/NFATc1 pathways.
PMCID: PMC3594163  PMID: 23536866
17.  A Pilot Study of Expressive Writing Intervention among Chinese Speaking Breast Cancer Survivors 
Little attention has been focused on Asian American breast cancer survivor's psychological needs. No outcome based psychosocial interventions have been reported to target at this population. Expressive writing interventions have been previously shown to improve health outcomes among non-Hispanic white breast cancer populations. This pilot study aimed to test the cultural sensitivity, feasibility, and potential health benefits of an expressive writing intervention among Chinese-speaking breast cancer survivors.
Participants (N=19) were asked to write about their deepest thoughts and feelings, their coping efforts, and positive thoughts and feelings regarding their experience with breast cancer each week for three weeks. Health outcomes were assessed at baseline, three, and six months after the intervention. A Community-Based Participatory Research Approach (CBPR) is used.
Expressive writing was associated with medium and large effect sizes (ηp2= 0.066~0.208) in improving multiple health outcomes (quality of life, fatigue, posttraumatic stress, intrusive thoughts, and positive affect) at follow-ups. Participants perceived the study to be valuable. The study yielded high compliance and completion rates.
Expressive writing is associated with long-term improvement of health outcomes among Chinese breast cancer survivors and has the potential to be utilized as a support strategy for minority cancer survivors. In addition, CBPR is valuable in improving feasibility and cultural sensitivity of the intervention in understudied populations. Future studies employing randomized controlled trial designs are warranted.
PMCID: PMC3587113  PMID: 22229930
Expressive Writing; Asian/Chinese Breast Cancer Survivors; Community Based Participatory Research (CBPR); Psychosocial Intervention; Quality of Life
18.  Blood Translation Elongation Factor-1δ Is a Novel Marker for Cadmium Exposure 
Translation elongation factor-1δ (TEF-1δ) has been identified as a novel cadmium-responsive proto-oncogene. However, it is still unclear whether TEF-1δ could be a potential biomarker of cadmium exposure. Rats were treated with CdCl2 at different concentrations (high dose 1.225, mid-dose 0.612 and low dose 0.306 mg/kg body weight, respectively) for 14 weeks, and the cadmium levels, weight coefficients, serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), blood urea nitrogen (BUN), serum creatinine (SCR), 24-h urine protein (24hPro), urinary creatinine (Cr) and pathological features were determined. The TEF-1δ expression in white blood cells and multiple organs were examined by reverse transcription polymerase chain reaction (PCR) and were also confirmed with fluorescence quantitative PCR. A cadmium dose-dependent increase (p < 0.05) of cadmium levels in blood, urine, liver, kidney, heart and lung, and the weight coefficients was observed. The liver and renal function indictors including AST, ALT, SCR, BUN and 24hPro, were elevated in a cadmium dose-dependent manner (p < 0.05). Significant pathological changes in liver, kidney, heart and lung were indicated. The TEF-1δ expression was up-regulated in both blood and organs (p < 0.05). Moreover, the expression level of blood TEF-1δ was positively correlated to TEF-1δ expression level, cadmium level and toxicity in the organs (p < 0.01). This study indicates that blood TEF-1δ is a novel valuable biomarker for cadmium exposure and its organ toxicity.
PMCID: PMC3634498  PMID: 23459232
cadmium; translation elongation factor-1δ; biomarker; toxicity
19.  Norisoboldine alleviates joint destruction in rats with adjuvant-induced arthritis by reducing RANKL, IL-6, PGE2, and MMP-13 expression 
Acta Pharmacologica Sinica  2013;34(3):403-413.
To explore the effects of norisoboldine (NOR), a major isoquinoline alkaloid in Radix Linderae, on joint destruction in rats with adjuvant-induced arthritis (AIA) and its underlying mechanisms.
AIA was induced in adult male SD rats by intradermal injection of Mycobacterium butyricum in Freund's complete adjuvant at the base of the right hind paw and tail. From d 14 after immunization, the rats were orally given NOR (7.5, 15, or 30 mg/kg) or dexamethasone (0.5 mg/kg) daily for 10 consecutive days. Joint destruction was evaluated with radiological scanning and H&E staining. Fibroblast-like synoviocytes (FLS) were prepared from fresh synovial tissues in the AIA rats. The expression of related proteins and mRNAs were detected by ELISA, Western blotting and RT-PCR.
In AIA rats, NOR (15 and 30 mg/kg) significantly decreased the swelling of paws and arthritis index scores, and elevated the mean body weight. NOR (30 mg/kg) prevented both the infiltration of inflammatory cells and destruction of bone and cartilage in joints. However, NOR (15 mg/kg) only suppressed the destruction of bone and cartilage, but did not obviously ameliorate synovial inflammation. NOR (15 and 30 mg/kg) significantly decreased the serum levels of receptor activator of nuclear factor κB ligand (RANKL), IL-6, PGE2, and MMP-13, but not the osteoprotegerin and MMP-1 levels. The mRNA levels of RANKL, IL-6, COX-2, and MMP-13 in synovium were also suppressed. Dexamethasone produced similar effects in AIA rats as NOR did, but without elevating the mean body weight. In the cultured FLS, treatment with NOR (10 and 30 mmol/L) significantly decreased the secretion of RANKL, IL-6, PGE2, and MMP-13 proteins. Furthermore, the treatment selectively prevented the activation of MAPKs, AKT and transcription factor AP-1 component c-Jun, but not the recruitment of TRAF6 or the activation of JAK2/STAT3. Treatment of the cultured FLS with the specific inhibitors of p38, ERK, AKT, and AP-1 significantly decreased the secretion of RANKL, IL-6, PGE2, and MMP-13 proteins.
NOR can alleviate joint destruction in AIA rats by reducing RANKL, IL-6, PGE2, and MMP-13 expression via the p38/ERK/AKT/AP-1 pathway.
PMCID: PMC4002497  PMID: 23396374
norisoboldine; dexamethasone; rheumatoid arthritis; adjuvant-induced arthritis; joint destruction; fibroblast-like synoviocyte; receptor activator of nuclear factor κB ligand; IL-6; PGE2; MMP-13; COX-2; p38/ERK/AKT/AP-1 pathway
20.  Relationship Between Resting Blood Pressure and Laboratory-Induced Pain Among Healthy Children 
Gender Medicine  2011;8(6):388-398.
Adult studies have demonstrated that increased resting blood pressure (BP) levels correlate with decreased pain sensitivity. However, few studies have examined the relationship between BP and experimental pain sensitivity among children.
This study investigated the association between resting BP levels and experimental pain tolerance, intensity, and unpleasantness in healthy children. We also explored whether these BP–pain relationships were age and gender dependent.
Participants underwent separate 4-trial blocks of cutaneous pressure and thermal pain stimuli, and 1 trial of a cold pain stimulus in counterbalanced order.
A total of 235 healthy children (49.6% female; mean age 12.7 [2.9] years; age range 8–18 years) participated. The study revealed specific gender-based BP–pain relationships. Girls with higher resting systolic BP levels were found to have lower thermal intensity ratings than girls with lower resting systolic BP levels; this relationship was stronger among adolescent girls than among younger girls. Among young girls (8–11 years), those with higher resting diastolic BP (DBP) levels were found to have lower cold intensity and unpleasantness as well as lower thermal intensity ratings than did young girls with lower resting DBP levels; these DBP–pain response relationships were not seen among adolescent girls.
Age, rather than resting BP, was predictive of laboratory pain ratings in boys. The findings suggest that the relationship between BP and experimental pain is age and gender dependent. These aspects of cardiovascular relationships to pain in males and females need further attention to understand their clinical importance.
PMCID: PMC3319441  PMID: 22035675
blood pressure; children; gender differences; laboratory pain
21.  Depression partially mediates the relationship between alexithymia and somatization in a sample of healthy children 
Journal of health psychology  2011;16(8):1177-1186.
A link between alexithymia and somatization has been widely established, yet little is known about different factors that may influence this relationship. Evidence supporting the idea of psychopathology as a mediator has been presented but not widely tested, particularly in children. The present study examined depressive symptoms as a mediator of alexithymia and somatization in a sample of healthy children in order to better understand the alexithymia-somatization link from a developmental perspective. Results indicated that depression significantly partially mediated this relationship, at least for two facets of alexithymia (difficulty identifying and describing feelings). Possible mechanisms, implications, and directions for future research are discussed.
PMCID: PMC3132307  PMID: 21464112
youth; depression; emotions; health psychology; mediator
22.  Pain in Long-Term Adult Survivors of Childhood Cancers and Their Siblings: A Report from the Childhood Cancer Survivor Study 
Pain  2011;152(11):2616-2624.
Little is known about pain among long-term adult survivors of childhood cancers. The study investigated pain prevalence in this population compared with sibling controls and examined pain-related risk factors. Three self-reported pain outcomes including pain conditions, prescription analgesics used, and pain attributed to cancer and treatment were assessed among 10,397 cancer survivors and 3,034 sibling controls from the Childhood Cancer Survivor Study (CCSS). Pain conditions (pain/abnormal sensation, migraines, and other headaches) were reported by 12.3%, 15.5%, and 20.5% of survivors respectively; 16.7% of survivors reported use of prescription analgesics, and 21% attributed pain to cancer and treatment. Risks of reporting pain conditions and using prescription analgesics were higher among survivors than siblings adjusting for sociodemographic factors. Younger age at diagnosis and a history of non-Hodgkin lymphoma, Wilms tumor, or neuroblastoma (compared to leukemia) were associated with greater risk of reporting pain conditions. A history of bone cancer or soft tissue sarcoma (compared to leukemia) was associated with greater risks of using prescription analgesics and cancer-related pain attribution. Non-brain directed scatter irradiation was associated with elevated risk for migraines and cancer-related pain attribution. Female gender and lower educational attainment were associated with increased reports of all three pain outcomes; minority status, unemployment, and being single were associated with greater risks for reporting pain conditions. These findings contribute to the understanding of pain and associated risk factors among adult survivors of childhood cancer and suggest areas of focus for pain intervention.
PMCID: PMC3304496  PMID: 21907493
Long-term adult survivors of childhood cancer; Self-reported pain; Pain attribution; Risk factors
23.  Sex Differences in the Association Between Cortisol Concentrations and Laboratory Pain Responses in Healthy Children 
Gender medicine  2009;6(Suppl 2):193-207.
Research in adult populations has highlighted sex differences in cortisol concentrations and laboratory pain responses, with men exhibiting higher cortisol concentrations and reduced pain responses compared with women. Yet, less is known about the relationship of cortisol concentrations to pain in children.
This study examined associations between sex, cortisol, and pain responses to laboratory pain tasks in children.
Salivary cortisol samples from subjects aged 8 to 18 years were obtained at baseline after entering the laboratory (SCb), after the completion of all pain tasks (SC1), and at the end of the session (SC2), 20 minutes later. Blood cortisol samples were also taken after completion of the pain tasks (BC1) and at the end of the session (BC2), 20 minutes later. Subjects completed 3 counterbalanced laboratory pain tasks: pressure, heat, and cold pressor tasks. Pain measures included pain tolerance, and self-reported pain intensity and unpleasantness for all 3 tasks.
The study included 235 healthy children and adolescents (119 boys, 116 girls; mean age, 12.7 years; range, 8–18 years; 109 [46.4%] were in early puberty; 94 [40.0%] white). Salivary and blood cortisol levels were highly correlated with each other. Salivary cortisol levels for the total sample and for boys and girls declined significantly from SCb to SC1 (P < 0.01), although there were no significant changes from SC1 to SC2. No significant sex differences in salivary or blood cortisol levels were evident at any assessment point. Separate examination of the cortisol–laboratory pain response relationships by sex (controlling for age and time of day) suggested different sex-specific patterns. Higher cortisol levels were associated with lower pain reactivity (ie, increased pressure tolerance) among boys compared with girls at SC1, SC2, and BC1 (SC1: r = 0.338, P = 0.003; SC2: r = 0.271, P = 0.020; and BC1: r = 0.261, P = 0.026). However, higher cortisol levels were related to higher pain response (ie, increased cold intensity [BC2: r = 0.229, P = 0.048] and unpleasantness [BC1: r = 0.237, P = 0.041]) in girls compared with boys.
These findings suggest important sex differences in cortisol–pain relationships in children and adolescents. Cortisol levels were positively associated with increased pain tolerance in boys and increased pain sensitivity in girls.
PMCID: PMC3486740  PMID: 19406369
pain; children; cortisol; sex differences
24.  Hepatitis B virus X protein suppresses caveolin-1 expression in hepatocellular carcinoma by regulating DNA methylation 
BMC Cancer  2012;12:353.
To understand the molecular mechanisms of caveolin-1 downregulation by hepatitis B virus X protein (HBx).
The DNA methylation status of the caveolin-1 promoter was examined by nested methylation-specific PCR of 33 hepatitis B virus (HBV)-infected hepatocellular carcinoma (HCC) samples. The SMMC-7721 hepatoma cell line was transfected with a recombinant HBx adenoviral vector, and the effects of HBx protein on caveolin-1 expression and promoter methylation were examined and confirmed by sequencing. A reporter gene containing the caveolin-1 promoter region was constructed, and the effects of HBx on the transcriptional activity of the promoter were also studied.
Methylation of the caveolin-1 promoter was detected in 84.8% (28/33) of HBV-infected HCC samples. Expression of caveolin-1 was significantly downregulated (P = 0.022), and multiple CpG sites in the promoter region of caveolin-1 were methylated in SMMC-7721 cells after HBx transfection. Transfected HBx significantly suppressed caveolin-1 promoter activity (P = 0.001).
HBx protein induces methylation of the caveolin-1 promoter region and suppresses its expression.
PMCID: PMC3522558  PMID: 22894556
Hepatitis B virus X protein; Hepatocellular carcinoma; Caveolin-1; Methylation
25.  Nano-embossing technology on ferroelectric thin film Pb(Zr0.3,Ti0.7)O3 for multi-bit storage application 
Nanoscale Research Letters  2011;6(1):474.
In this work, we apply nano-embossing technique to form a stagger structure in ferroelectric lead zirconate titanate [Pb(Zr0.3, Ti0.7)O3 (PZT)] films and investigate the ferroelectric and electrical characterizations of the embossed and un-embossed regions, respectively, of the same films by using piezoresponse force microscopy (PFM) and Radiant Technologies Precision Material Analyzer. Attributed to the different layer thickness of the patterned ferroelectric thin film, two distinctive coercive voltages have been obtained, thereby, allowing for a single ferroelectric memory cell to contain more than one bit of data.
PMCID: PMC3211987  PMID: 21794156

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