Circadian Rhythms Correlated in DNA Methylation and Gene Expression Identified in Human Blood and Implicated in Psychiatric Disorders.

Circadian rhythms modulate the biology of many human tissues and are driven by a nearly 24-h transcriptional feedback loop. Dynamic DNA methylation may play a role in driving 24-h rhythms of gene expression in the human brain. However, little is known about the degree of circadian regulation between the DNA methylation and the gene expression in the peripheral tissues, including human blood. We hypothesized that 24-h rhythms of DNA methylation play a role in driving 24-h RNA expression in human blood. To test this hypothesis, we analyzed DNA methylation levels and RNA expression in blood samples collected from eight healthy males at six-time points over 24 h. We assessed 442,703 genome-wide CpG sites in methylation and 12,364 genes in expression for 24-h rhythmicity using the cosine model. Our analysis revealed significant rhythmic patterns in 6345 CpG sites and 21 genes. Next, we investigated the relationship between methylation and expression using powerful circadian signals. We found a modest negative correlation (ρ = -0.83, p = 0.06) between the expression of gene TXNDC5 and the methylation at the nearby CpG site (cg19116172). We also observed that circadian CpGs significantly overlapped with genetic risk loci of schizophrenia and autism spectrum disorders. Notably, one gene, TXNDC5, showed a significant correlation between circadian methylation and expression and has been reported to be association with neuropsychiatric diseases.

Atrophic gastritis rather than Helicobacter pylori infection can be an independent risk factor of colorectal polyps: a retrospective study in China.

BACKGROUND: Colonoscopy is considered the most effective screening method for colorectal polyps. However, the longevity and complexity of the procedure makes it less desirable to screen for colorectal polyps in the general population. Therefore, it is essential to identify other independent risk factors. In this study, we explored the link between Hp infection, atrophic gastritis, and colorectal polyps to identify a new potential risk factors of colorectal polyps. METHODS: In this study, atrophic gastritis and intestinal polyps were diagnosed by endoscopy and pathology. All the 792 patients in this retrospective study were divided into sub-groups based on the presence of colorectal polyps. The correlation between polyps and atrophic gastritis was analyzed using the chi-square test and Kruskal-Wallis test. The receiver operating characteristic (ROC) curve was used to compare the predictive value for colorectal polyps between Hp infection and atrophic gastritis. Binary logistic regression was utilized to identify independent risk factors for colorectal polyps. RESULTS: Patients with colorectal polyps were primarily male with advanced age, and the number of patients with colorectal polyps had a higher association with smoking, alcohol drinking, and Hp infection than the control group. A positive correlation between the number of colorectal polyps and the severity of atrophic gastritis was observed. ROC analysis showed that atrophic gastritis was a better risk factors for colorectal polyps. Multivariate analysis identified atrophic gastritis as an independent risk factor for colorectal polyps (OR 2.294; 95% CI 1.597-3.296). CONCLUSIONS: Atrophic gastritis confirmed could be an independent risk factors for colorectal polyps.

Joint polarization detection and degradation mechanisms for underwater image enhancement.

Light absorption and scattering exist in the underwater environment, which can lead to blurring, reduced brightness, and color distortion in underwater images. Polarized images have the advantages of eliminating underwater scattering interference, enhancing contrast, and detecting material information of the object in underwater detection. In this paper, from the perspective of polarization imaging, different concentrations (0.15 g/ml, 0.30 g/ml, and 0.50 g/ml), different wave bands (red, green, and blue), different materials (copper, wood, high-density PVC, aluminum, cloth, foam, cloth sheet, low-density PVC, rubber, and porcelain tile), and different depths (10 cm, 20 cm, 30 cm, and 40 cm) are set up in a chamber for the experimental environment. By combining the degradation mechanism of underwater images and the analysis of polarization detection results, it is proved that the degree of polarization images have greater advantages than degree of linear polarization images, degree of circular polarization images, S1, S2, and S3 images, and visible images underwater. Finally, a fusion algorithm of underwater visible images and polarization images based on compressed sensing is proposed to enhance underwater degraded images. To improve the quality of fused images, we introduce orthogonal matching pursuit (OMP) in the high-frequency part to improve image sparsity and consistency detection in the low-frequency part to improve the image mutation phenomenon. The fusion results show that the peak SNR values of the fusion result maps using OMP in this paper are improved by 32.19% and 22.14% on average over those using backpropagation and subspace pursuit methods. With different materials and concentrations, the underwater image enhancement algorithm proposed in this paper improves information entropy, average gradient, and standard deviation by 7.76%, 18.12%, and 40.8%, respectively, on average over previous algorithms. The image NIQE value shows that the image quality obtained by this paper's algorithm is improved by about 69.26% over the original S0 image.

Magnetic resonance imaging thicknesses and apparent diffusion coefficient values of the endometrium and junction zone in women of reproductive age.

BACKGROUND: The endometrium and uterine junction zone often change throughout the menstrual cycle. Some pathological conditions may appear normal in uterine imaging, which will lead to missed diagnosis and misdiagnosis. PURPOSE: To evaluate the changes in the thickness and apparent diffusion coefficient (ADC) values of the endometrium and uterine junction zone throughout the menstrual cycle in magnetic resonance imaging (MRI) of women of reproductive age. MATERIAL AND METHODS: Data were collected from 40 healthy women of reproductive age with regular menstrual cycles from January 2017 to April 2018. They underwent four total MRI sessions during the menstrual, proliferation, and early and late secretive phases. The main MRI sequences were T2-weighted (T2W) volume isotropic turbo spin echo acquisition (VISTA) spectral attenuated inversion recovery (SPAIR) and diffusion-weighted imaging (b = 0, 600, 800, 1000 s/mm2), which were used to measure the thicknesses and ADC values of endometrium and uterine junction zone. RESULTS: First, the endometrium was thinnest during the menstrual phase and thickest in the late secretive phase. Second, the uterine junction zone was thinnest in the late secretive phase and thickest in the menstrual phase. Third, the ADC values of the endometrium were lowest in the menstrual phase and peaked in the early secretive phase. Finally, the ADC values of the uterine junction zone were lowest in the menstrual phase and peaked in the late secretive phase. CONCLUSION: The endometrium and uterine junction zone showed cyclic changes. Radiologists should consider these changes in the thickness and ADC values when analyzing MRI images of the uterus.

Assessment of potential ecological risk based on the vertical characteristics of potential toxic elements in sediments from a high-density cage culture reservoir in China.

The pollution of sediments around Lu Ban Island is a serious environmental issue that is threatening human health. The concentration of As, Cd, Cu, Cr, Hg, Ni, Pb, and Zn at 73 layer points were investigated, vertical distribution characteristics, correlation among potential toxic elements and potential ecological risks of sediments at different depth were analyzed. The following results were obtained, (1) the hypothesis that there was a linear relationship between concentration of potential toxic elements and the reciprocal of deep was reasonable. Based on hypothesis, the ultimate value of concentration by making depth go to infinity was regarded as the background concentration. The background concentration of As, Cd, Cu, Cr, Hg, Ni, Pb, and Zn are respectively 4.94 mg/kg, 0.20 mg/kg, 15.48 mg/kg, 58.41 mg/kg, 0.062 mg/kg, 26.96 mg/kg, 20.29 mg/kg, and 53.31 mg/kg. (2) But correlation between Ni and As was relatively weak, high degree of correlation among other potential toxic elements were found. Based on their correlation, eight potential toxic elements were classified into three groups. First group included Ni and Cr, mainly releasing by coal burning; Cu, Pb, Zn, Hg, and Cd were grouped together, possibly due to their shared source of fish cage culture; Arsenic with relatively weak correlation with other potential toxic elements was classified as a separate class, which was usually one important mineral resource associated with phosphate. (3) Potential ecological risk index (PERI) of sediment above - 0.40 m belonged to moderate risk, the PERI of sediment in - 0.10 m, - 0.20 m, and - 0.40 m were 289.06, 254.33, and 201.44, respectively. Sediment below - 0.40 m belonged to low risk with average PERI value 112.82, with no significant changes in PERI values. The order of contribution to PERI was Hg > Cd > As > Cu > Pb > Ni > Cr > Zn. (4) According to result of cluster analysis and potential ecological risk, the potential ecological risk of sediment above - 0.40 m mainly contributed by potential toxic elements of Cu, Cd, Hg, Pb, and Zn sharing source of fish cage culture.

Translation, cross-cultural adaptation, validity and reliability of the Brazilian Portuguese version of Activity Scale for Kids questionnaire.

BACKGROUND: The Activity Scale for Kids (ASK) assesses the physical disability of children (5 to 15 years old) with neurological, orthopaedic or rheumatic diseases. The objective of this study was to translate and cross-culturally adapt the ASK for Brazilian Portuguese and assess the validity and reliability of the instrument. METHODS: A total of 67 children and adolescents with musculoskeletal, neurological or rheumatic diseases participated in the study. We evaluated the comprehension of the pre-final version of the questionnaire in 24 participants and reliability and validity in the other 43 participants. The translation and adaptation of ASK to Brazilian Portuguese followed guidelines from previous studies. The validity of the Brazilian Portuguese version of the ASK was verified through Spearman's correlation with the Pediatric Quality of Life Inventory™ Version 4.0 (PedQL). Intraclass correlation coefficient verified inter- and intra-evaluator reliability, while internal consistency was assessed using Cronbach's alpha. Scores were used to assess the standard error of the mean and minimal detectable change. RESULTS: The Brazilian Portuguese version of the ASK presented excellent reliability, internal consistency, agreement and moderate correlation with PedsQL (0.522, P < 0.001) between ASK performance and PedsQL; 0.537, P < 0.001 between ASK capacity and PedsQL. CONCLUSION: The Brazilian Portuguese version of the ASK has good validity and reliability and may be used by professionals and researchers to assess the functioning of children and adolescents with disabilities.

Clinical Outcome of Primary Total Hip Arthroplasty in Patients with Morbid Obesity-Retrospective and Prospective Follow-Up Studies.

Background and objective: There is a general clinical concern on the negative impact of obesity on surgical complications and functional outcomes. We hypothesized that the patients with morbid obesity are exceptionally prone to a significantly increased risk for surgical and short-term complications after primary total hip arthroplasty (THA). We aimed to identify the range of Body Mass Index (BMI) values of patients with a significant risk for lower functional improvement after THA. Materials and methods: In Stage 1 of the study, we conducted a retrospective comparative analysis of the rate of complications and functional outcomes in patients treated by primary THA, with normal weight (BMI 19-25, N = 1205) vs. Class 1 (BMI 26-34, N = 450), Class 2 (BMI 35-39, N = 183), and Class 3 (BMI ≥ 40, N = 47) obese patients. After the statistical similarity rates of complications and 6- and 12-month functional outcomes (by Harris Hip and SF-36 scores) were revealed in Class 1 patients and patients with normal BMI, we conducted the Stage 2 prospective study, by the same comparison protocol, on the cohorts of Class 2 (N = 29) and Class 3 (N = 16) patients compared to the Class 1 patients (N = 37) as controls. Results: Stage 1: There was no difference in surgical complications and function on 6- and 12-month postoperative follow-up (physical and mental) between Class 1 and patients with normal BMI (p > 0.05). Surgical complications were significantly higher in Class 2 (p < 0.05) and Class 3 (p < 0.001) patients. Functional activity on the 12-month follow-up increased significantly in all study groups, but in the Class 3 patients, the functional parameters were significantly lower (0.001). The mental health status on the follow-up was similar in all study groups. Stage 2 study revealed similar to the retrospective study comparison of parameters, except for the significantly lower mental health scores in Class 2 and Class 3 patients (p < 0.05) and functional scores in Class 3 patients (p < 0.05). Conclusion: Although the functional ability increased in all patients, it was significantly lower in Class 3 patients (with morbid obesity). Therefore, the patients with Class 1 and Class 2 obesity should be conceptionally distinguished from Class 3 patients in the decision-making process for a primary THA because of the less favorable functional and mental health improvement in those with morbid obesity (Class 3).

BrainEXP: a database featuring with spatiotemporal expression variations and co-expression organizations in human brains.

Summary: Gene expression changes over the lifespan and varies among different tissues or cell types. Gene co-expression also changes by sex, age, different tissues or cell types. However, gene expression under the normal state and gene co-expression in the human brain has not been fully defined and quantified. Here we present a database named Brain EXPression Database (BrainEXP) which provides spatiotemporal expression of individual genes and co-expression in normal human brains. BrainEXP consists of 4567 samples from 2863 healthy individuals gathered from existing public databases and our own data, in either microarray or RNA-Seq library types. We mainly provide two analysis results based on the large dataset: (i) basic gene expression across specific brain regions, age ranges and sexes; (ii) co-expression analysis from different platforms. Availability and implementation: http://www.brainexp.org/. Supplementary information: Supplementary data are available at Bioinformatics online.

Seawater Immersion Aggravates Early Mitochondrial Dysfunction and Increases Neuronal Apoptosis After Traumatic Brain Injury.

Traumatic brain injury (TBI) is a major cause of death and disability in naval warfare. Due to the unique physiochemical properties of seawater, immersion in it exacerbates TBI and induces severe neural damage and complications. However, the characteristics and underlying mechanisms of seawater-immersed TBI remain unclear. Mitochondrial dysfunction is a major cause of TBI-associated brain damage because it leads to oxidative stress, decrease in energy production, and apoptosis. Thus, the present study aimed to further elucidate the current understanding of the pathology of seawater-immersed TBI, particularly the role of mitochondrial dysfunction, using a well-defined rat model of fluid percussion injury and a stretch injury model comprising cultured neurons. The biochemical and pathological markers of brain-related and neuronal injuries were evaluated. Histological analysis suggested that seawater immersion enhanced brain tissue injury and induced a significant increase in apoptosis in rats with TBI. Additionally, lactate dehydrogenase release occurred earlier and at higher levels in stretched neurons at 24 h after seawater immersion, which was consistent with more severe morphological changes and enhanced apoptosis. Furthermore, seawater immersion induced more rapid decreases in mitochondrial membrane potential, adenosine triphosphate (ATP) content, and H+-ATPase activity in the cortices of TBI rats. In addition, the immunochemical results revealed that seawater immersion further attenuated mitochondrial function in neurons exposed to stretch injury. The increases in neuronal damage and apoptosis triggered by seawater immersion were positively correlated with mitochondrial dysfunction in both in vivo and in vitro models. Thus, the present findings strengthen the current understanding of seawater-immersed TBI. Moreover, because seawater immersion aggravates mitochondrial dysfunction and contributes to post-traumatic neuronal cell death, it is important to consider mitochondria as a therapeutic target for seawater-immersed TBI.

Correction to: A complex mechanism for HDGF-mediated cell growth, migration, invasion, and TMZ chemosensitivity in glioma.

In the original publication, there are errors in Fig. 3D and Fig. 5C and are corrected as follows.

Mast cell activation, TLR4-NF-κB/TNF-α pathway variation in rats' intestinal ischemia-reperfusion injury and Tongxinluo's therapeutic effect.

This study was designed to investigate mast cell activation and related TLR4-NF-κB/TNF-α pathway variation in 3 and 7 days' rats intestinal I/R injury, and TXL's intervention effect. Rat intestine I/R injury was carried out using superior mesenteric artery occlusion model with 30 min ischemia followed 3 or 7 days' reperfusion. Rats were administered TXL ultrafine power of 0.4, 0.8 and 1.6g/kg/d respectively for 3 or 7 days after modeling. Mast cell activation was determined by immunofluorescent double staining. TLR4, ANGPTL4 and microRNA126 were determined by RT-PCR. PECAM-1, NF-κB p65, TNF-α and VE-Cadherin were determined by immunohistochemical staining. Intestine I/R induced massively mast cell activation and overexpressed TLR4, NF-κB, TNF-α, PECAM-1, miR126 in 3 and 7 days. VE-cadherin and ANGPTL4 expression was reduced. TXL treatment attenuated mast cell activation and inhibited TLR4, NF-κB, TNF-α, PECAM-1 over-expression in 3 and 7 days, protected VE-cadherin and ANGPTL4 protein. Inflammation boomed in rats' intestine I/R injury for 3 and 7 days, characterized by mast cell and related TLR4-NF-κB/TNF-α pathway activation, accompanied with endothelial barrier dysfunction and enhanced vascular permeability. TXL treatment attenuated inflammation, protected endothelial barrier function. TXL treat intestine I/R injury, according with "Treat different diseases with the same method" in TCM theory.

Highly stretchable hybrid silica/polymer optical fiber sensors for large-strain and high-temperature application.

The large-range and high-sensitivity strain measurement in high-temperature ambiance is a great challenge in engineering applications. Because of the frangibility of the glass material, the traditional optical fiber strain sensors cannot endure a limit strain of 1%. To break through the limit, we propose a hybrid silica/polymer optical fiber sensor. It can endure extraordinarily large strain. The maximum strain of 35% is confirmed by experiments. To achieve high sensitivity and detect a small change in strain, a phase tracking method is used. The sensitivity of the sensor is 28 pm/µÎµ which is 28 times larger than that of the traditional FBG sensors. In addition, because of the excellent high-temperature endurance of polyimide (PI) and adhesive, the sensor can survive in the high temperature up to 220 °C. The proposed hybrid silica/polymer optical fiber sensor has potentials to monitor deformation in plastic products, structure health in composite materials, and even strain in biomaterials.

TRAIL Mediated Signaling in Breast Cancer: Awakening Guardian Angel to Induce Apoptosis and Overcome Drug Resistance.

Sequencing technologies have allowed us to characterize highly heterogeneous molecular landscape of breast cancer with unprecedented details. Tremendous breakthroughs have been made in unraveling contributory role of signaling pathways in breast cancer development and progression. It is becoming progressively more understandable that deregulation of spatio-temporally controlled pathways underlie development of resistance against different drugs. TRAIL mediated signaling has attracted considerable appreciation because of its characteristically unique ability to target cancer cells while leaving normal cells intact. Discovery of TRAIL was considered as a paradigm shift in molecular oncology because of its conspicuous ability to selectively target cancer cells. There was an exponential growth in the number of high-quality reports which highlighted cancer targeting ability of TRAIL and scientists worked on the development of TRAIL-based therapeutics and death receptor targeting agonistic antibodies to treat cancer. However, later studies challenged simplistic view related to tumor targeting ability of TRAIL. Detailed mechanistic insights revealed that overexpression of anti-apoptotic proteins, inactivation of pro-apoptotic proteins and downregulation of death receptors were instrumental in impairing apoptosis in cancer cells. Therefore researchers started to give attention to identification of methodologies and strategies to overcome the stumbling blocks associated with TRAIL-based therapeutics. Subsequent studies gave us a clear picture of signaling cascade of TRAIL and how deregulation of different proteins abrogated apoptosis. In this chapter we have attempted to provide an overview of the TRAIL induced signaling, list of proteins frequently deregulated and modern approaches to strategically restore apoptosis in TRAIL-resistant breast cancers.

Effect of Plantar Flexor Muscle Strengthening on the Gait of Children With Idiopathic Toe Walking: A Study Protocol.

PURPOSE: To evaluate the effect of plantar flexor strengthening associated with conventional physical therapy treatment in participants with idiopathic toe walking. METHODS: Thirty participants, of both sexes diagnosed with idiopathic toe walking, aged 5 and 11 years, will be recruited and randomized into 2 groups: the control group, who will undergo gait training, triceps surae muscle stretching, anterior tibial muscle strengthening, and motor sensory training, and the intervention group, who will undergo the same training as the control group and, additionally, triceps surae muscle strengthening. The intervention will be performed twice a week for 8 weeks. The participants will undergo a 3-dimensional gait kinematic analysis, passive amplitude of dorsiflexion movement, isometric dynamometry of the anterior tibial and triceps surae muscles, motor coordination, quality of life, and perception of the parents regarding the equinus gait at baseline and at the end of treatment. Quality of life will be reevaluated during a 24-week follow-up.

Fine-particulate matter (PM2.5), a risk factor for rat gestational diabetes with altered blood glucose and pancreatic GLUT2 expression.

Recent studies have shown an intriguing association between air pollution and diabetic risk. This study was to investigate the impact of fine particulate matter (PM2.5) on glucose consequences and pancreas glucose transporter2 (GLUT2) expression in a gestational diabetes mellitus (GDM) rat model. GDM rats were exposed to a low PM2.5 dose during pregnancy. After exposure, interleukin-6 (IL-6) and blood routine tests (BRT) were detected. Pancreas underwent pathologic examination. The levels of pancreatic homogenate glutathione peroxidase (GSH-Px), methane dicarboxylic aldehyde (MDA) and GLUT2 were detected. There were lower maternal body weight gain and fetal weight in the PM2.5 group. Exposure to PM2.5 caused increased absorbed blastocyst number, higher blood mono-nuclear cells (PBMC), platelets and IL-6 levels. The postprandial blood glucose (PBG) was elevated at most time points after exposure. The pancreas of PM2.5 exposed rats revealed periductal inflammation under pathological examination. The pancreatic GSH-Px significantly reduced and MDA increased in exposed group. The pancreatic GLUT2 expression was decreased after PM2.5 exposure. Our study provides direct evidence that PM2.5 exposure can result in pancreatic pathological changes and glycemic consequences in GDM rats. The oxidative response and inflammation are involved in PM2.5 increased risk of pancreatic impairment and glycemic consequences.

Fine particulate matter (PM2.5), a risk factor of rat gestational diabetes with altered blood glucose and pancreatic GLUT2 expression.

Recent studies have shown an association between air pollution and diabetic risk. This study was to investigate the impact of fine particulate matter (PM2.5) on glucose consequences and pancreas glucose transporter 2 (GLUT2) expression and its related mechanisms in a gestational diabetes mellitus (GDM) rat model. GDM rats were exposed to a low PM2.5 dose while the controls received saline. Interleukin-6 (IL-6) and blood routine tests (BRT) were detected for analyzing coagulation and inflammation. Pancreas tissues underwent pathologic examination, the levels of homogenate glutathione peroxidase (GSH-Px), and methane dicarboxylic aldehyde (MDA) were detected for oxidative stress estimation, and the degree of GLUT2 expression of pancreas was analyzed. There were lower maternal body weight gain and fetal weight in the PM2.5 group. Exposure to PM2.5 caused increased absorbed blastocyst number and postprandial blood glucose (PBG) blood mono-nuclear cells (PBMC), platelets, and IL-6 levels. The pancreas of PM2.5 exposed rats revealed inflammation under pathological examination. The pancreatic GSH-Px significantly reduced and MDA increased and GLUT2 protein expression decreased after exposure. Our study provides direct evidence that PM2.5 exposure can result in glycemic consequences in GDM rats. The oxidative response and inflammation are involved in PM2.5 increased risk of adverse maternal and fetal consequences.

Resting energy expenditure in obese women: comparison between measured and estimated values.

Assessing energy requirements is a fundamental activity in clinical dietetic practice. The aim of this study was to investigate which resting energy expenditure (REE) predictive equations are the best alternatives to indirect calorimetry before and after an interdisciplinary therapy in Brazilian obese women. In all, twelve equations based on weight, height, sex, age, fat-free mass and fat mass were tested. REE was measured by indirect calorimetry. The interdisciplinary therapy consisted of nutritional, physical exercise, psychological and physiotherapy support during the course of 1 year. The average differences between measured and predicted REE, as well as the accuracy at the ±10 % level, were evaluated. Statistical analysis included paired t tests, intraclass correlation coefficients and Bland-Altman plots. Validation was based on forty obese women (BMI 30-39·9 kg/m2). Our major findings demonstrated a wide variation in the accuracy of REE predictive equations before and after weight loss in non-morbid, obese women. The equations reported by Harris-Benedict and FAO/WHO/United Nations University (UNU) were the only ones that did not show significant differences compared with indirect calorimetry and presented a bias <5 %. The Harris-Benedict equation provided 40 and 47·5 % accurate predictions before and after therapy, respectively. The FAO equation provided 35 and 47·5 % accurate predictions. However, the Bland-Altman analysis did not show good agreement between these equations and indirect calorimetry. Therefore, the Harris-Benedict and FAO/WHO/UNU equations should be used with caution for obese women. The need to critically re-assess REE data and generate regional and more homogeneous REE databases for the target population is reinforced.

Alpha-enolase as a potential cancer prognostic marker promotes cell growth, migration, and invasion in glioma.

BACKGROUND: The success of using glycolytic inhibitors for cancer treatment relies on better understanding the roles of each frequently deregulated glycolytic genes in cancer. This report analyzed the involvement of a key glycolytic enzyme, alpha-enolase (ENO1), in tumor progression and prognosis of human glioma. METHODS: ENO1 expression levels were examined in glioma tissues and normal brain (NB) tissues. The molecular mechanisms of ENO1 expression and its effects on cell growth, migration and invasion were also explored by 3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyl tetrazolium bromide (MTT) assay, Transwell chamber assay, Boyden chamber assay, Western blot and in vivo tumorigenesis in nude mice. RESULTS: ENO1 mRNA and protein levels were upregulated in glioma tissues compared to NB. In addition, increased ENO1 was associated disease progression in glioma samples. Knocking down ENO1 expression not only significantly decreased cell proliferation, but also markedly inhibited cell migration and invasion as well as in vivo tumorigenesis. Mechanistic analyses revealed that Cyclin D1, Cyclin E1, pRb, and NF-κB were downregulated after stable ENO1 knockdown in glioma U251 and U87 cells. Conversely, knockdown of ENO1 resulted in restoration of E-cadherin expression and suppression of mesenchymal cell markers, such as Vimentin, Snail, N-Cadherin, ß-Catenin and Slug. Furthermore, ENO1 suppression inactivated PI3K/Akt pathway regulating the cell growth and epithelial-mesenchymal transition (EMT) progression. CONCLUSION: Overexpression of ENO1 is associated with glioma progression. Knockdown of ENO1 expression led to suppressed cell growth, migration and invasion progression by inactivating the PI3K/Akt pathway in glioma cells.

Quercetin enhances apoptotic effect of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) in ovarian cancer cells through reactive oxygen species (ROS) mediated CCAAT enhancer-binding protein homologous protein (CHOP)-death receptor 5 pathway.

Although tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) has shown efficacy in a phase 2 clinical trial, development of resistance to TRAIL by tumor cells is a major roadblock. We investigated whether quercetin, a flavonoid, can sensitize human ovarian cancer cells to TRAIL. Results indicate that quercetin sensitized cancer cells to TRAIL. The quercetin induced expression of death receptor DR5 but did not affect expression of DR4 in cancer cells. The induction of DR5 was mediated through activation of JNK and through upregulation of a transcription factor CCAAT enhancer-binding protein homologous protein (CHOP); as silencing of these signaling molecules abrogated the effect of quercetin. Upregulation of DR5 was mediated through the generation of reactive oxygen species (ROS), as ROS scavengers reduced the effect of quercetin on JNK activation, CHOP upregulation, DR induction, TRAIL sensitization, downregulated the expression of cell survival proteins and upregulated the proapoptotic proteins. Furthermore, quercetin enhances TRAIL mediated inhibition of tumor growth of human SKOV-3 xenograft was associated with induction of apoptosis, activation of caspase-3, CHOP and DR5. Overall, our data suggest that quercetin enhances apoptotic death of ovarian cancer cells to TRAIL through upregulation of CHOP-induced DR5 expression following ROS mediated endoplasmic reticulum-stress.

A complex mechanism for HDGF-mediated cell growth, migration, invasion, and TMZ chemosensitivity in glioma.

HDGF is overexpressed in gliomas as compared to normal brain. We therefore analyzed the molecular mechanisms of HDGF action in gliomas. HDGF was downregulated in normal brain tissue as compared to glioma specimens at both the mRNA and the protein levels. In glioma samples, increased HDGF expression was associated with disease progression. Knocking down HDGF expression not only significantly decreased cellular proliferation, migration, invasion, and tumorigenesis, but also markedly enhanced TMZ-induced cytotoxicity and apoptosis in glioma cells. Mechanistic analyses revealed that CCND1, c-myc, and TGF-ß were downregulated after stable HDGF knockdown in the U251 and U87 glioma cells. HDGF knockdown restored E-cadherin expression and suppressed mesenchymal cell markers such as vimentin, ß-catenin, and N-cadherin. The expression of cleaved caspase-3 increased, while Bcl-2 decreased in each cell line following treatment with shHDGF and TMZ, as compared to TMZ alone. Furthermore, RNAi-based knockdown study revealed that HDGF is probably involved in the activation of both the PI3K/Akt and the TGF-ß signaling pathways. Together, our data suggested that HDGF regulates glioma cell growth, apoptosis and epithelial-mesenchymal transition (EMT) probably through the Akt and the TGF-ß signaling pathways. These results provide evidence that targeting HDGF or its downstream targets may lead to novel therapies for gliomas.