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1.  QiShenYiQi Pills, a compound in Chinese medicine, protects against pressure overload-induced cardiac hypertrophy through a multi-component and multi-target mode 
Scientific Reports  2015;5:11802.
The present study aimed to explore the holistic mechanism for the antihypertrophic effect of a compound in Chinese medicine, QiShenYiQi Pills (QSYQ) and the contributions of its components to the effect in rats with cardiac hypertrophy (CH). After induction of CH by ascending aortic stenosis, rats were treated with QSYQ, each identified active ingredient (astragaloside IV, 3, 4-dihydroxy-phenyl lactic acid or notoginsenoside R1) from its 3 major herb components or dalbergia odorifera, either alone or combinations, for 1 month. QSYQ markedly attenuated CH, as evidenced by echocardiography, morphology and biochemistry. Proteomic analysis and western blot showed that the majority of differentially expressed proteins in the heart of QSYQ-treated rats were associated with energy metabolism or oxidative stress. Each ingredient alone or their combinations exhibited similar effects as QSYQ but to a lesser extent and differently with astragaloside IV and notoginsenoside R1 being more effective for enhancing energy metabolism, 3, 4-dihydroxy-phenyl lactic acid more effective for counteracting oxidative stress while dalbergia odorifera having little effect on the variables evaluated. In conclusion, QSYQ exerts a more potent antihypertrophic effect than any of its ingredients or their combinations, due to the interaction of its active components through a multi-component and multi-target mode.
PMCID: PMC4488877  PMID: 26136154
2.  Relationship of Meeting Physical Activity Guidelines with Health-Related Utility 
Arthritis care & research  2014;66(7):1041-1047.
Health-related utility measures overall health status and quality of life and is commonly incorporated into cost-effectiveness analyses. This study investigates whether attainment of federal physical activity guidelines translates into better health-related utility in adults with or at risk for knee osteoarthritis (OA).
Cross-sectional data from 1908 adults with or at risk for knee OA participating in the accelerometer ancillary study of the Osteoarthritis Initiative (OAI) were assessed. Physical activity was measured using 7 days of accelerometer monitoring and was classified as 1) Meeting Guidelines (≥150 bouted moderate-to-vigorous [MV] minutes per week); 2) Insufficiently Active (≥1 MV bout[s] per week but below guidelines); or 3) Inactive (zero MV bouts per week). A Short Form 6D (SF6-D) health-related utility score was derived from patient-reported health status. Relationship of physical activity levels to median health-related utility adjusted for socioeconomic and health factors was tested using quantile regression.
Only 13% of participants met physical activity guidelines; 45% were inactive. Relative to the Inactive, median health-related utility scores were significantly greater for the Meeting Guidelines (0.063; confidence interval [CI] 0.055–0.071) and Insufficiently Active (0.059; CI 0.054–0.064) groups. These differences showed a statistically significant linear trend and strong cross-sectional relationship with physical activity level even after adjusting for socioeconomic and health factors.
We found a significant positive relationship between physical activity level and health-related utility. Interventions that encourage adults, including persons with knee OA, to increase physical activity even if recommended levels are not attained may improve their quality of life.
PMCID: PMC4051873  PMID: 24339324
3.  Resveratrol levels and all-cause mortality in older community-dwelling adults 
JAMA internal medicine  2014;174(7):1077-1084.
Resveratrol, a polyphenol found in grapes, red wine, chocolate, and certain berries and roots, is considered to have antioxidant, anti-inflammatory, and anti-cancer effects in humans and is related to longevity in some lower organisms.
To determine whether resveratrol levels achieved with diet are associated with inflammation, cancer, cardiovascular disease, and mortality in humans.
Prospective cohort study, the Invecchiare in Chianti (InCHIANTI) Study (“Aging in the Chianti Region”), 1998-2009.
Two villages in the Chianti area, Tuscany region of Italy.
Population-based sample of 783 community-dwelling men and women, ≥65 y
24-h urinary resveratrol metabolites
Main outcomes and measures
Primary outcome measure was all-cause mortality. Secondary outcomes were markers of inflammation (serum C-reactive protein [CRP], interleukin [IL]-6, IL-1β, and tumor necrosis factor [TNF]-α), and prevalent and incident cancer and cardiovascular disease
Mean (95% Confidence Interval) log total urinary resveratrol metabolite concentrations were 7.08 (6.69, 7.48) nmol/g creatinine. During nine years of follow-up, 268 (34.3%) of the participants died. From the lowest to the highest quartile of baseline total urinary resveratrol metabolites, the proportion of participants who died from all causes was 34.4, 31.6, 33.5, and 37.4%, respectively (P = 0.67). Participants in the lowest quartile had a hazards ratio for mortality of 0.80 (95% confidence interval 0.54, 1.17) when compared with those in the highest quartile of total urinary resveratrol in a multivariable Cox proportional hazards model that adjusted for potential confounders. Resveratrol levels were not significantly associated with serum CRP, IL-6, IL-1β, TNF-α, prevalent or incident cardiovascular disease or cancer. Conclusions: In older community-dwelling adults, total urinary resveratrol metabolite concentration was not associated with inflammatory markers, cardiovascular disease, or cancer, or predictive of all-cause mortality. Resveratrol levels achieved with a Western diet do not have a substantial influence on health status and mortality risk.
PMCID: PMC4346286  PMID: 24819981
cancer; cardiovascular disease; inflammation; longevity; resveratrol; InCHIANTI
4.  Modified Leukocyte Filter Removes Tumor Cells from the Salvaged Blood 
PLoS ONE  2015;10(6):e0130864.
Intraoperative blood salvage, an effective blood conservation strategy, has not been applied in onco-surgery, because of potential malignant cell contamination. In this study we tested effectiveness of a modified leukocyte depletion filter (M-LDF) for removal of tumor cells.
Materials and Methods
The effects of M-LDF and regular LDF on removal of cells (HepG2 cell line) were compared. The safety of M-LDF was tested with blood (collected and washed during onco-surgery), the salvaged blood mixed with tumor cells from the solid tumor of the same patient, or mixed with HepG2 cells (n=30 in each protocol). Cancer cells were identified by flow cytometry, culture and bioassay with and without filtration.
M-LDF removed 5-log of HepG2 and nucleated cells, which was much higher than regular LDF, and cells were destroyed when they passed through M-LDF. Cytokeratin-positive cells in all samples were removed by M-LDF. Invasive growth adherent cells were found in most of unfiltered samples and 67% of the inoculated nude mice developed tumors in LDF-treated sample. Neither adherent cells nor nude mice developed tumors were found in M-LDF-treated samples.
Discussion and Conclusion
Since M-LDF can effectively remove and destroy cancer cells in the salvaged blood, it has great potential for clinical application.
PMCID: PMC4476620  PMID: 26098626
5.  Loss of the liver X receptor LXRα/β in peripheral sensory neurons modifies energy expenditure 
eLife  null;4:e06667.
Peripheral neural sensory mechanisms play a crucial role in metabolic regulation but less is known about the mechanisms underlying vagal sensing itself. Recently, we identified an enrichment of liver X receptor alpha and beta (LXRα/β) in the nodose ganglia of the vagus nerve. In this study, we show mice lacking LXRα/β in peripheral sensory neurons have increased energy expenditure and weight loss when fed a Western diet (WD). Our findings suggest that the ability to metabolize and sense cholesterol and/or fatty acids in peripheral neurons is an important requirement for physiological adaptations to WDs.
eLife digest
The vagus nerves run from the brainstem to the heart and the digestive system and help to control several processes including digestion and heart rate. Because of their role in regulating food intake, these nerves are attractive targets for scientists hoping to develop treatments for obesity.
There are two types of fat tissue found in mammals: white fat, which is used as an energy store and makes up most of the extra fat seen in obese individuals; and brown fat, which can generate body heat. The vagus nerves monitor fat and cholesterol levels in the body via receptor proteins that respond to messages sent from the fat tissues and the liver. Previous research unexpectedly found that mice genetically engineered to lack these receptor proteins—called LXRα and LXRβ—do not become obese even when fed a high-fat, high-cholesterol diet that would make normal mice gain excessive weight.
Mansuy-Aubert et al. have now investigated in more detail why mice without these receptor proteins are resistant to obesity. When fed a high-fat, high-cholesterol diet, mice that lacked the LXRα and LXRβ receptors in sensory neurons had higher cholesterol levels in their nerve cells than normal mice on the same diet. Mice lacking these receptors also burned more energy and gained less weight than normal mice.
Next, Mansuy-Aubert et al. examined fat tissue from both types of mice. This revealed that the heat-generating brown fat was more active in mice lacking the LXRα and LXRβ receptors. Some of the white fat in these mice had also become more like brown fat, allowing the mice to burn more energy and so gain less weight.
In many Western countries, many people also eat a diet that is high in fat and cholesterol. This raises the possibility that drugs that block the LXRα and LXRβ receptors in sensory neurons in humans could help to treat or prevent obesity, although further work will be needed to investigate this.
PMCID: PMC4467361  PMID: 26076474
nuclear receptors; sensory neurons; energy expenditure; mouse
6.  Levo-tetrahydropalmatine attenuates mouse blood-brain barrier injury induced by focal cerebral ischemia and reperfusion: Involvement of Src kinase 
Scientific Reports  2015;5:11155.
The restoration of blood flow following thrombolytic therapy causes ischemia and reperfusion (I/R) injury leading to blood-brain barrier (BBB) disruption and subsequent brain edema in patients of ischemic stroke. Levo-tetrahydropalmatine (l-THP) occurs in Corydalis genus and some other plants. However, whether l-THP exerts protective role on BBB disrpution following cerebral I/R remains unclear. Male C57BL/6N mice (23 to 28 g) were subjected to 90 min middle cerebral artery occlusion, followed by reperfusion for 24 h. l-THP (10, 20, 40 mg/kg) was administrated by gavage 60 min before ischemia. We found I/R evoked Evans blue extravasation, albumin leakage, brain water content increase, cerebral blood flow decrease, cerebral infarction and neurological deficits, all of which were attenuated by l-THP treatment. Meanwhile, l-THP inhibited tight junction (TJ) proteins down-expression, Src kinase phosphorylation, matrix metalloproteinases-2/9 (MMP-2/9) and caveolin-1 activation. In addition, surface plasmon resonance revealed binding of l-THP to Src kinase with high affinity. Then we found Src kinase inhibitor PP2 could attenuate Evans blue dye extravasation and inhibit the caveolin-1, MMP-9 activation, occludin down-expression after I/R, respectively. In conclusion, l-THP attenuated BBB injury and brain edema, which were correlated with inhibiting the Src kinase phosphorylation.
PMCID: PMC4461916  PMID: 26059793
7.  Novel immunological and nutritional-based prognostic index for gastric cancer 
AIM: To assess the prognostic significance of immunological and nutritional-based indices, including the prognostic nutritional index (PNI), neutrophil-lymphocyte ratio (NLR), and platelet-lymphocyte ratio in gastric cancer.
METHODS: We retrospectively reviewed 632 gastric cancer patients who underwent gastrectomy between 1998 and 2008. Areas under the receiver operating characteristic curve were calculated to compare the predictive ability of the indices, together with estimating the sensitivity, specificity and agreement rate. Univariate and multivariate analyses were performed to identify risk factors for overall survival (OS). Propensity score analysis was performed to adjust variables to control for selection bias.
RESULTS: Each index could predict OS in gastric cancer patients in univariate analysis, but only PNI had independent prognostic significance in multivariate analysis before and after adjustment with propensity scoring (hazard ratio, 1.668; 95% confidence interval: 1.368-2.035). In subgroup analysis, a low PNI predicted a significantly shorter OS in patients with stage II-III disease (P = 0.019, P < 0.001), T3-T4 tumors (P < 0.001), or lymph node metastasis (P < 0.001). Canton score, a combination of PNI, NLR, and platelet, was a better indicator for OS than PNI, with the largest area under the curve for 12-, 36-, 60-mo OS and overall OS (P = 0.022, P = 0.030, P < 0.001, and P = 0.024, respectively). The maximum sensitivity, specificity, and agreement rate of Canton score for predicting prognosis were 84.6%, 34.9%, and 70.1%, respectively.
CONCLUSION: PNI is an independent prognostic factor for OS in gastric cancer. Canton score can be a novel preoperative prognostic index in gastric cancer.
PMCID: PMC4438031  PMID: 26019461
Gastric cancer; Prognostic nutritional index; Canton score; Prognosis; Neutrophil-lymphocyte ratio; Platelet-lymphocyte ratio
8.  Upregulation of microRNA-23a regulates proliferation and apoptosis by targeting APAF-1 in laryngeal carcinoma 
Oncology Letters  2015;10(1):410-416.
MicroRNA-23a (miR-23a) is a potential biomarker for laryngeal cancer. Apoptotic protease activating factor 1 (APAF-1) was recently demonstrated to be a target of miR-23a. However, whether miR-23a exerts its effects via APAF-1 in laryngeal cancer, remains unknown. In the present study, miR-23a expression was detected by reverse transcription-quantitative polymerase chain reaction (RT-qPCR). APAF-1 mRNA and protein expression levels were assayed by RT-qPCR and western blotting, respectively. Binding of miR-23a to APAF-1 was monitored by a luciferase reporter assay. Gain-of-function and loss-of-function studies were performed in order to investigate the roles of miR-23a and APAF-1 in Hep2 cell proliferation and apoptosis. miR-23a and APAF-1 were found to be significantly upregulated and downregulated, respectively, in laryngeal cancer tissues, and there was a significant negative correlation between APAF-1 and miR-23a expression. The results of the luciferase reporter assay demonstrated that miR-23a bound directly to the APAF-1 mRNA 3′-untranslated region. Ectopic expression of miR-23a and knockdown of APAF-1 significantly promoted cell proliferation and colony formation, and inhibited early apoptosis in Hep2 cells. In conclusion, miR-23a acts as an oncogenic regulator in laryngeal carcinoma by directly targeting APAF-1, and may be a useful biomarker in the diagnosis and treatment of laryngeal carcinoma.
PMCID: PMC4487154  PMID: 26171041
laryngeal squamous cell carcinoma; microRNA-23a; apoptotic protease activating factor 1; proliferation; apoptosis
9.  Inhibition of Ovarian Epithelial Carcinoma Tumorigenesis and Progression by microRNA 106b Mediated through the RhoC Pathway 
PLoS ONE  2015;10(5):e0125714.
Epithelial ovarian cancer (EOC) is the most lethal of the gynecological malignancies. Exploring the molecular mechanisms and major factors of invasion and metastasis could have great significance for the treatment and prognosis of EOC. Studies have demonstrated that microRNA 106b (miR-106b) may be a promising therapeutic target for inhibiting breast cancer bone metastasis, but the role of miR-106b in EOC is largely unknown. In this work, miRNA-106b expression was quantified in various ovarian tissues and tumors. Ovarian carcinoma cell lines were transfected with miR-106b, after which, cell phenotype and expression of relevant molecules was assayed. Dual-luciferase reporter assays and xenograft mouse models were also used to investigate miR-106b and its target gene. MiR-106b mRNA expression was found to be significantly higher in normal ovarian tissues and benign tumors than in ovarian carcinomas and borderline tumors (p < 0.01), and was negatively associated with differentiation (Well vs. Por & Mod) and the International Federation of Gynecology and Obstetrics (FIGO) staging (stage I/II vs. stage III/IV) in ovarian carcinoma (p < 0.05). MiR-106b transfection reduced cell proliferation; promoted G1 or S arrest and apoptosis (p < 0.05); suppressed cell migration and invasion (p < 0.05); reduced Ras homolog gene family member C (RhoC), P70 ribosomal S6 kinase (P70S6K), Bcl-xL, Matrix metallopeptidase 2 (MMP2), MMP9 mRNA and protein expression; and induced p53 expression (p < 0.05). Dual-luciferase reporter assays indicated that miR-106b directly targets RhoC by binding its 3’UTR. MiR-106b transfection also suppressed tumor development and RhoC expression in vivo in xenograft mouse models. This is the first demonstration that miR-106b may inhibit tumorigenesis and progression of EOC by targeting RhoC. The involvement of miR-106b-mediated RhoC downregulation in EOC aggression may give extended insights into molecular mechanisms underlying cancer aggression. Approaches aimed at overexpressing miR-106b may serve as promising therapeutic strategies for treating EOC patients.
PMCID: PMC4416747  PMID: 25933027
10.  Terminal Supraparticle Assemblies from Similarly Charged Protein Molecules and Nanoparticles 
Nature communications  2014;5:3593.
Self-assembly of proteins and inorganic nanoparticles into terminal assemblies makes possible a large family of uniformly sized hybrid colloids. These particles can be compared in terms of utility, versatility and multifunctionality to other known types of terminal assemblies. They are simple to make and offer theoretical tools for designing their structure and function. To demonstrate such assemblies, we combine cadmium telluride nanoparticles with cytochrome C protein and observe spontaneous formation of spherical supraparticles with a narrow size distribution. Such self-limiting behaviour originates from the competition between electrostatic repulsion and non-covalent attractive interactions. Experimental variation of supraparticle diameters for several assembly conditions matches predictions obtained in simulations. Similar to micelles, supraparticles can incorporate other biological components as exemplified by incorporation of nitrate reductase. Tight packing of nanoscale components enables effective charge and exciton transport in supraparticles as demonstrated by enzymatic nitrate reduction initiated by light absorption in the nanoparticle.
PMCID: PMC4405188  PMID: 24845400
11.  PPARγ in Vagal Neurons Regulates High-Fat Diet Induced Thermogenesis 
Cell metabolism  2014;19(4):722-730.
The vagus nerve innervates visceral organs and have long been suspected to play a role in surveying peripheral metabolic status and relaying it to the CNS. However, it remains unknown whether vagal sensory neurons can directly interact with dietary-derived nutrients and whether altered nutrient sensing by the vagus nerve would impair long-term energy balance. In this study, we systematically profiled nuclear receptor expression in vagal sensory neurons and found PPARγ expression is negatively regulated by high-fat-diet feeding (HFD). We demonstrate PPARγ in vagal neurons regulates HFD-induced thermogenesis that involves active re-programing of white adipocyte cell fate. Moreover, we show that PPARγ regulates the expression of a set of neuronal genes that are important for synaptic transmission. Altogether, our findings provide insights into how vagal afferents survey metabolic information from peripheral tissues and demonstrated that PPARγ-dependent lipid sensing in vagal sensory neurons is important for the maintenance of energy homeostasis.
PMCID: PMC4046333  PMID: 24703703
nuclear receptor; dietary-derived lipids; vagal afferents; nutrient sensing; energy homeostasis
12.  Serum Carboxymethyl-lysine, an Advanced Glycation End Product, and Age-Related Macular Degeneration: the Age Gene/Environment Susceptibility-Reykjavik Study 
JAMA ophthalmology  2014;132(4):464-470.
Advanced glycation end products have been implicated in the pathogenesis of age-related macular degeneration (AMD).
To investigate the relationship between serum carboxymethyl-lysine (CML), a major circulating advanced glycation end product, and AMD in older adults.
Cross-sectional study.
Population-based sample of older adults in the Age Gene/Environment Susceptibility-Reykjavik Study.
4907 adults, aged ≥66 years
Serum CML and risk factors for AMD.
Main Outcome Measures
Early or late AMD, assessed through fundus images taken through dilated pupils using a 45-degree digital camera and grading for drusen size, type, area, increased retinal pigment, retinal pigment epithelial depigmentation, neovascular lesions, and geographic atrophy using the modified Wisconsin Age-Related Maculopathy Grading System.
Of the 4907 participants, 1025 (20.9%) had early AMD and 276 (5.6%) had late AMD. Mean (standard deviation [SD]) serum CML concentrations among adults with no AMD, early AMD, and late AMD (exudative AMD and pure geographic atrophy) were 3.0 (0.9), 3.1 (1.0), and 3.1 (0.9) μmol/L, respectively (P = 0.07). Log serum CML (per 1 log SD) was not associated with any AMD (early and late AMD) (Odds Ratio [O.R.] 0.97, 95% Confidence Interval [C.I.] 0.90, 1.04, P = 0.44) or with late AMD (O.R. = 0.94, 95% C.I. 0.82, 1.08, P = 0.36) in respective multivariable logistic regression models adjusting for age, sex, body mass index, smoking, and renal function.
Higher serum CML had no significant cross-sectional association with prevalent AMD in this large population-based cohort of older adults in Iceland.
PMCID: PMC4169215  PMID: 24481410
advanced glycation end products; age-related macular degeneration; aging; Iceland
13.  The role of autophagy induced by tumor microenvironment in different cells and stages of cancer 
Cell & Bioscience  2015;5:14.
Development of a tumor is a very complex process, and invasion and metastasis of malignant tumors are hallmarks and are difficult problems to overcome. The tumor microenvironment plays an important role in controlling tumor fate and autophagy induced by the tumor microenvironment is attracting more and more attention. Autophagy can be induced by several stressors in the tumor microenvironment and autophagy modifies the tumor microenvironment, too. Autophagy has dual roles in tumor growth. In this review, we discussed the interaction between autophagy and the tumor microenvironment and the paradoxical roles of autophagy on tumor growth at different stages of tumor development.
PMCID: PMC4384293  PMID: 25844158
Autophagy; Tumor microenvironment; Tumorigenesis
14.  Endotrophin triggers adipose tissue fibrosis and metabolic dysfunction 
Nature communications  2014;5:3485.
We recently identified endotrophin as an adipokine with potent tumour-promoting effects. However, the direct effects of local accumulation of endotrophin in adipose tissue have not yet been studied. Here we use a doxycycline-inducible adipocyte-specific endotrophin overexpression model to demonstrate that endotrophin plays a pivotal role in shaping a metabolically unfavourable microenvironment in adipose tissue during consumption of a high-fat diet (HFD). Endotrophin serves as a powerful co-stimulator of pathologically relevant pathways within the ‘unhealthy’ adipose tissue milieu, triggering fibrosis and inflammation and ultimately leading to enhanced insulin resistance. We further demonstrate that blocking endotrophin with a neutralizing antibody ameliorates metabolically adverse effects and effectively reverses metabolic dysfunction induced during HFD exposure. Collectively, our findings demonstrate that endotrophin exerts a major influence in adipose tissue, eventually resulting in systemic elevation of pro-inflammatory cytokines and insulin resistance, and the results establish endotrophin as a potential target in the context of metabolism and cancer.
PMCID: PMC4076823  PMID: 24647224
15.  How long do the Hong Kong Chinese expect their URTI to last? – Effects on antibiotic use 
Recent literature shows that there is a large mismatch between the US patients’ expected duration of acute cough illness and the actual duration. It has been suggested that this discrepancy may lead to antibiotic misuse. Currently, there is limited relevant information for the Chinese. This study aims to investigate the duration that Hong Kong Chinese expect their upper respiratory tract infection (URTI) to last and its possible association with antibiotic use.
A cross-sectional telephone questionnaire survey with 2,471 adult respondents was conducted in Hong Kong between November and December of 2010. The expected URTI duration of the respondents and their antibiotic use behaviors were analyzed. Multivariable logistic regression analysis was used to adjust for the effects of demographic factors including age, gender, education and income.
Excluding 80 uncertain responses, 544 (23.1%) respondents expected their URTI to last for 1–3 days in general, 613 (25.5%) for 4–6 days, 1168 (48.6%) for 1–2 weeks, and 66 (2.7%) for > 2 weeks. The mean of expected duration was 7.4 (SD:4.2) days. Respondents expecting 1–3 days duration were least likely to ask for and be treated with antibiotics. The proportion of respondents being treated with antibiotics for the last URTI increased from 10% for the 1–3 days group to 23% for the > 2 weeks group (χ2 = 19.086, P < 0.001). The effect of expected duration remained significant (P = 0.0188) after adjusting for the effects of demographic factors.
The Hong Kong Chinese expect their URTI to last for about 7 days on average. Different from the notion that underestimation of the actual duration would lead to antibiotic misuse, this study shows that patients expecting a longer duration have a doubled chance to be treated with antibiotics.
PMCID: PMC4372325  PMID: 25886759
Antibiotic use; Chinese; General practice; Expected URTI duration
16.  Study of parasitic resistance effects in nanowire and nanoribbon biosensors 
In this work, we investigate sensor design approaches for eliminating the effects of parasitic resistance in nanowire and nanoribbon biosensors. Measurements of pH with polysilicon nanoribbon biosensors are used to demonstrate a reduction in sensitivity as the sensor length is reduced. The sensitivity (normalised conductance change) is reduced from 11% to 5.5% for a pH change from 9 to 3 as the sensing window length is reduced from 51 to 11 μm. These results are interpreted using a simple empirical model, which is also used to demonstrate how the sensitivity degradation can be alleviated by a suitable choice of sensor window length. Furthermore, a differential sensor design is proposed that eliminates the detrimental effects of parasitic resistance. Measurements on the differential sensor give a sensitivity of 15%, which is in good agreement with the predicted maximum sensitivity obtained from modeling.
PMCID: PMC4385057  PMID: 25852375
Biosensor; Nanowire; Nanoribbon; Parasitic resistance; Differential biosensor; pH sensor
17.  RhoC is a major target of microRNA-93-5P in epithelial ovarian carcinoma tumorigenesis and progression 
Molecular Cancer  2015;14(1):31.
An increasing amount of evidence has revealed that microRNAs regulate various biological processes, including cell differentiation, cell proliferation, apoptosis, drug resistance, and fat metabolism. Studies have shown that miR-93’s targetome in cancer has not been fully defined. Moreover, the role of miR-93 in epithelial ovarian carcinoma (EOC) remains largely unknown.
MIR-93 mRNA expression in normal ovarian tissue, benign tumors, borderline tumors, primary ovarian carcinomas, and metastatic omentum was quantified. The ovarian carcinoma cell lines OVCAR3, SKOV3/DDP, and HO8910-PM were transfected with miR-93-5P, after which cell phenotype and expression of relevant molecules were assayed. Dual-luciferase reporter assay and a xenograft mouse model were used to examine miR-93 and its target gene RHOC (Ras homolog gene family member C).
MIR-93 mRNA expression was significantly lower in ovarian carcinomas and borderline tumors than in normal ovarian tissues (p < 0.05), and was lower in metastatic omentum than in relative primary ovarian carcinomas (p < 0.05). MIR-93 mRNA expression was also negatively associated with differentiation (well vs. poor and moderate) and International Federation of Gynecology and Obstetrics staging (FIGO stage I/II vs. stage III/IV) in ovarian carcinoma (p < 0.05), besides, miR-93 was higher expressed in mucinous adenocarcinoma than the other types (p < 0.05). MiR-93-5P overexpression reduced proliferation (p < 0.05); promoted G1 or S arrest and apoptosis (p < 0.05); suppressed migration and invasion (p < 0.05); and reduced RhoC, P70S6 kinase, Bcl-xL, matrix metalloproteinase 9 (MMP9) mRNA or protein expression; conversely, it induced P53 and cleaved PARP expression (p < 0.05). Dual-luciferase reporter assay indicated that miR-93 directly targeted RhoC by binding its 3′ untranslated region. MiR-93-5P transfection also suppressed tumor development and RhoC expression (determined by immunohistochemistry) in vivo in the xenograft mouse model (p < 0.05).
This is the first demonstration that miR-93-5P may inhibit EOC tumorigenesis and progression by targeting RhoC. These findings indicate that miR-93-5P is a potential suppressor of ovarian cellular proliferation. The involvement of miR-93-5P–mediated RhoC downregulation in inhibiting EOC aggressiveness may provide extended insight into the molecular mechanisms underlying cancer aggressiveness.
PMCID: PMC4328068  PMID: 25649143
MiR-93-5P; RhoC; Ovarian epithelial carcinoma; Tumorigenesis and progression
18.  Klotho in the cerebrospinal fluid of adults with and without Alzheimer's disease 
Neuroscience letters  2013;558:37-40.
The aging-suppressor gene klotho encodes a single-pass transmembrane protein that is predominantly secreted by the choroid plexus of the brain and in the kidney. Klotho-deficient mice develop multiple aging phenotypes, including impaired cognition. Klotho concentrations have not been described in the CSF of humans. We measured klotho in the CSF of 20 older adults with Alzheimer's disease and in 20 older and 20 younger adults with normal cognition. In 10 adults, aged 38-87 years, CSF klotho measurements were made at baseline and every 6 hours up to 18-30 hours later. Mean (95% Confidence Interval [C.I.]) CSF klotho in men versus women were 899 (814, 983) and 716 (632, 801) pg/mL, respectively (P = 0.002). Mean (95% C.I.) CSF klotho in older adults with and without Alzheimer's disease were 664 (603, 725) and 776 (705, 828) pg/mL, respectively (P = 0.02), adjusting for sex. Mean (95% C.I.) klotho in older versus younger adults were 766 (658, 874) and 992 (884, 1100) pg/mL, respectively (P = 0.005), adjusting for sex. In the longitudinal study of CSF klotho, no significant circadian fluctuations were found in CSF klotho levels. This study suggests that CSF klotho concentrations are lower in females compared with males, in Alzheimer's disease, and in older versus younger adults.
PMCID: PMC4037850  PMID: 24211693
Aging; Alzheimer's Disease; Brain; Cerebrospinal Fluid; Klotho
19.  Decreased expression of GRIM-19 by DNA hypermethylation promotes aerobic glycolysis and cell proliferation in head and neck squamous cell carcinoma 
Oncotarget  2014;6(1):101-115.
To identify novel tumor suppressor genes that are down-regulated by promoter hypermethylation in head and neck squamous cell carcinoma (HNSCC), genome-wide methylation profiling was performed using a methylated DNA immunoprecipitation (MeDIP) array in HNSCC and normal mucosa tissue samples. Promoter hypermethylation of the candidate gene, gene associated with retinoid-interferon induced mortality-19 (GRIM-19), was confirmed in HNSCC cell lines. Multivariate regression analysis determined that GRIM-19 hypermethylation was an independent significant factor for HNSCC diagnosis (OR:125.562; P < 0.001). HNSCC patients with lower ratio of GRIM-19/ACTB hypermethylation had increased overall and disease free survival. Furthermore, the optimal cutoff provided 90% sensitivity and 77% specificity of GRIM-19 hypermethylation as a diagnostic marker for HNSCC. Ectopic expression of GRIM-19 in HNSCC cells led to increased oxygen consumption, reduced glycolysis and decreased cell proliferation. HNSCC cells ectopically expressing GRIM-19 displayed increased p53 activity as well as decreased Stat3 and HIF-1α activities. Moreover, GRIM-19 knockdown not only resulted in decreased oxygen consumption and increased aerobic glycolysis but also promoted cell proliferation and tumorigenic capacity in HNSCC cells. Our data indicate that decreased GRIM-19 expression due to promoter hypermethylation may be important in head and neck carcinogenesis by promoting cell proliferation and regulating metabolic activity.
PMCID: PMC4381581  PMID: 25575809
GRIM-19; methylation; HNSCC; proliferation; metabolism
20.  Curcumin inhibits proliferation of gastric cancer cells by impairing ATP-sensitive potassium channel opening 
This study was aimed to investigate whether ATP-sensitive potassium channel (KATP) is involved in curcumin’s anti-proliferative effects against gastric cancer.
In an in vitro study, gastric cancer cell line SGC-7901 was treated with curcumin at serial concentrations and co-administrated with the KATP opener, diazoxide. The effect of curcumin and diazoxide on proliferation were assessed by MTT assay. Mitochondrial membrane potential (MMP) was studied by flow cytometry detection of rhodamine 123 staining. Apoptosis was evaluated by flow cytometry detection of Annexin V propidium iodide double staining. In an in vivo study, SGC-7901 cells were planted into nude mice as xenografts. Animals were treated with curcumin co-administered with diazoxide. Tumor volume and tumor weight were observed.
Curcumin incubation significantly induced loss of MMP in SGC-7901 cells in a dose- dependent manner (P < 0.05); the cell apoptotic rate also dramatically increased after curcumin incubation in a dose-dependent manner (P < 0.05). After co-administration with diazoxide, however, we found that both the MMP-loss-inducing and the apoptosis-inducing effects of curcumin in SGC-7901 cells were significantly impaired (all P < 0.05). As a result, the proliferation of SGC-7901 cells was maintained by diazoxide treatment.
Impaired mitoKATP opening causes MMP loss, and is involved in curcumin-induced apoptosis in gastric cancer.
PMCID: PMC4395964  PMID: 25523120
apoptosis; curcumin; gastric cancer; KATP
21.  High levels of SIRT1 expression enhance tumorigenesis and associate with a poor prognosis of colorectal carcinoma patients 
Scientific Reports  2014;4:7481.
SIRT1, a NAD+ dependent class III deacetylase, takes part in many important biological processes. Previous studies show that SIRT1 is overexpressed in some cancers and plays an essential role in tumorigenesis. However, the association between SIRT1 and colorectal cancer (CRC) is still unclear. We found that many CRC specimens had strong SIRT1 expression, which had an obvious correlation with poor prognosis of CRC patients. Meanwhile, SIRT1 expression had a co-localization with CD133, a current universal marker to characterize colorectal cancer stem cells (CSCs). In vitro studies also revealed that SIRT1 was overexpressed in colorectal CSC-like cells. Moreover, SIRT1 deficiency decreased percentage of CD133+ cells, attenuated the abilities of colony and sphere formation, and inhibited tumorigenicity in vivo in CRC cells. Further study demonstrated that the expressions of several stemness-associated genes, including Oct4, Nanog, Cripto, Tert and Lin28, were reduced by SIRT1 knockdown in CRC cells. Taken together, our findings suggest that SIRT1 plays a crucial role in keeping the characteristics of CSCs cells. SIRT1 is a potential independent prognostic factor of CRC patients after tumor resection with curative intent, and will contribute to providing a promising new approach to target at CSCs in CRC treatment.
PMCID: PMC4265776  PMID: 25500546
22.  Beclin 2 Functions in Autophagy, Degradation of G Protein-Coupled Receptors, and Metabolism 
Cell  2013;154(5):1085-1099.
The molecular mechanism of autophagy and its relationship to other lysosomal degradation pathways remain incompletely understood. Here, we identified a previously uncharacterized mammalian-specific protein, Beclin 2, which like Beclin 1, functions in autophagy and interacts with class III PI3K complex components and Bcl-2. However, Beclin 2, but not Beclin 1, functions in an additional lysosomal degradation pathway. Beclin 2 is required for ligand-induced endolysosomal degradation of several G protein-coupled receptors (GPCRs) through its interaction with GASP1. Beclin 2 homozygous knockout mice have decreased embryonic viability, and heterozygous knockout mice have defective autophagy, increased levels of brain cannabinoid 1 receptor, elevated food intake, and obesity and insulin resistance. Our findings identify Beclin 2 as a novel converging regulator of autophagy and GPCR turnover, and highlight the functional and mechanistic diversity of Beclin family members in autophagy, endolysosomal trafficking and metabolism.
PMCID: PMC4231430  PMID: 23954414
23.  Hepatocyte Toll-like Receptor 4 Regulates Obesity-Induced Inflammation and Insulin Resistance 
Nature communications  2014;5:3878.
Chronic low-grade inflammation is a hallmark of obesity and thought to contribute to the development of obesity-related insulin resistance. Toll-like receptor 4 (Tlr4) is a key mediator of pro-inflammatory responses. Mice lacking Tlr4s are protected from diet-induced insulin resistance and inflammation; however which Tlr4 expressing cells mediate this effect is unknown. Here we show that mice deficient in hepatocyte Tlr4 (Tlr4LKO) exhibit improved glucose tolerance, enhanced insulin sensitivity, and ameliorated hepatic steatosis despite the development of obesity after a high fat diet (HFD) challenge. Furthermore, Tlr4LKO mice have reduced macrophage content in white adipose tissue, as well as decreased tissue and circulating inflammatory markers. In contrast, the loss of Tlr4 activity in myeloid cells has little effect on insulin sensitivity. Collectively, these data indicate that the activation of Tlr4 on hepatocytes contributes to obesity-associated inflammation and insulin resistance, and suggest that targeting hepatocyte Tlr4 might be a useful therapeutic strategy for the treatment of type 2 diabetes.
PMCID: PMC4080408  PMID: 24815961
24.  Up-regulation of hexokinase1 in the right ventricle of monocrotaline induced pulmonary hypertension 
Respiratory Research  2014;15(1):119.
Pulmonary arterial hypertension (PAH) is a proliferative arteriopathy associated with a glycolytic shift during heart metabolism. An increase in glycolytic metabolism can be detected in the right ventricle during PAH. Expression levels of glycolysis genes in the right ventricle during glycolysis that occur in monocrotaline (MCT)-induced pulmonary hypertension (PH) remain unknown.
PH was induced by a single subcutaneous injection of MCT (50 mg/kg) into rats, eventually causing right heart failure. Concurrently, a control group was injected with normal saline. The MCT-PH rats were randomly divided into three groups according to MCT treatment: MCT-2 week, 3 week, and 4 week groups (MCT-2w, 3w, 4w). At the end of the study, hemodynamics and right ventricular hypertrophy were compared among experimental groups. Expression of key glycolytic candidate genes was screened in the right ventricle.
We observed an increase in mean pulmonary arterial pressure, right ventricular systolic pressure and right ventricular hypertrophy index three weeks following MCT injection. Alterations in the morphology and structure of right ventricular myocardial cells, as well as the pulmonary vasculature were observed. Expression of hexokinase 1 (HK1) mRNA began to increase in the right ventricle of the MCT-3w group and MCT-4w group, while the expression of lactate dehydrogenase A (LDHA) was elevated in the right ventricle of the MCT-4w group. Hexokinase 2(HK2), pyruvate dehydrogenase complex α1 (PDHα1), and LDHA mRNA expression showed no changes in the right ventricle. HK1 mRNA expression was further confirmed by HK1 protein expression and immunohistochemical analyses. All findings underlie the glycolytic phenotype in the right ventricle.
There was an increase in the protein and mRNA expression of hexokinase-1 (HK1) three and four weeks after the injection of monocrotaline in the right ventricle, intervention of HK1 may be amenable to therapeutic intervention.
PMCID: PMC4198683  PMID: 25287584
Pulmonary hypertension; Right heart failure; Glycolysis; Hexokinase 1
25.  Prevalence and risk factors of abnormal left ventricular geometrical patterns in untreated hypertensive patients 
The various prevalence of LVH and abnormal LV geometry have been reported in different populations. So far, only a few reports are available on the prevalence of LV geometric patterns in a large Chinese untreated hypertensive population.
A total of 9,286 subjects (5167 men and 4119 women) completed the survey and 1641 untreated hypertensive patients (1044 males and 597 females) enrolled in the present study. The LV geometry was classified into four patterns: normal; abnormal,defined as concentric remodeling;concentric or eccentric hypertrophy based on the values of left ventricular mass index (LVMI) and relative wall thickness (RWT). Logistic regression model was applied to determine the odds ratio (OR) and 95% confidence intervals (CI) of the risk factors of left ventricular hypertrophy.
The prevalence of LVH was 20.2% in untreated hypertensive patients, much higher in women (30.8%) than in men (14.2%) (P < 0.01). The prevalence of LV geometrical patterns was 34.9%, 11.1%, 9.1% for concentric remodeling, concentric and eccentric hypertrophy,respectively. After adjustment by using Logistic regression model, the risk factors for LVH and abnormal LV geometry were age, female, systolic blood pressure, and body mass index. And low high density lipoprotein maybe a positive factor.
The prevalence of LVH and abnormal LV geometric patterns was higher in women than in men and increased with age. It is crucial to improve the awareness rate of hypertension and control the risk factors of CV complications in untreated hypertensive population.
PMCID: PMC4192326  PMID: 25280487
Left ventricular hypertrophy; Left ventricular geometry; Risk factors; Untreated hypertension

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