To investigate the reinforcement of Bis-GMA/TEGDMA dental resins (without conventional glass filler) and the corresponding composites (with conventional glass filler)containing vari ed mass fractions of halloysite nanotubes (HNTs).
Three dispersion methods were studied to separate the silanized halloysite as individual HNTs and to uniformly distribute them into dental matrices. Photopolymerization induced volumetric shrinkage was measured by using a mercury dilatometer. Real time near infrared spectroscopy was adopted to study the degree of vinyl double bond conversion and the photopolymerization rate. Mechanical properties of the composites were tested by a universal mechanical testing machine. Analysis of Variance (ANOVA) was used for the statistical analysis of the acquired data. Morphologies of halloysite/HNTs and representative fracture surfaces of the reinforced dental resins/composites were examined by SEM and TEM.
Impregnation of small mass fractions (e.g., 1% and 2.5%) of the silanized HNTs in Bis-GMA/TEGDMA dental resins/composites improved mechanical properties significantly; however; large mass fractions (e.g., 5%) of impregnation did not further improve the mechanical properties. The impregnation of HNTs into dental resins/composites could result in two opposite effects: the reinforcing effect due to the highly separated and uniformly distributed HNTs, and the weakening effect due to the formation of HNT agglomerates/particles.
Uniform distribution of a small amount of well-separated silanized HNTs into Bis-GMA/TEGDMA dental resins/composites could result in substantial improvements on mechanical properties.
Dental composites; Bis-GMA; TEGDMA; Halloysite nanotubes
Clinical epidemiological studies suggested a link between fetal growth conditions and later coronary heart disease (CHD) in adult life. However, no such studies have been conducted in a Chinese population.
We investigated the association between various birth characteristics and CHD occurrence in a Chinese cohort.
Retrospective cohort study.
Peking Union Medical College Hospital, Beijing, China.
A total of 2,033 subjects who were born at Peking Union Medical College Hospital between 1921 and 1954.
Neonatal birth-weight, placental weight, length from crown to heel, head circumference, and biparietal and occipitofrontal diameters were routinely recorded at the time of birth. All participants were followed up between May 2002 and April 2004 for the occurrence of CHD.
CHD was identified in 135 patients. The occurrence of CHD was inversely related to birth sizes, such as birth-weight, head circumference, placental weight (P < 0.05), but was not significantly related to birth length or ponderal index (birth-weight/birth length3). After multivariable logistic regression, the ratio of birth-weight to birth length was an independent predictor of CHD along with two other variables: obesity and age.
This was a single-center retrospective study.
In China low birth size or birth disproportion, which is suggestive of fetal growth retardation, has an effect on CHD occurrence during adulthood. This suggests that environmental factors operate in both the prenatal and postnatal periods with regard to the development of CHD.
Birth size; coronary artery disease; fetal growth retardation; risk factors
MicroRNAs (miRNAs) are endogenous small non-coding RNAs which play a critical role in gene regulation in plants. Pinelliapedatisecta is one of the most important herbs in traditional Chinese medicine, but there are no microRNAs of Pinelliapedatisecta were deposited in miRBase and the research of the related miRNA biological functions is still insufficient. To detect Pinelliapedatisecta miRNAs and discover their expression difference with Pinelliaternata, we carried out a microarray profiling. A total of 101 miRNAs belonging to 22 miRNA families were detected both in Pinelliapedatisecta and Pinelliaternata respectively, among them 21 miRNAs showed their differentially expression. GO (gene ontology) term enrichment analysis of the target genes of differential expression miRNAs reveal that these miRNAs mainly affect the reproduction, transcription factor activity and plant developmental process. To elucidate the target function of miRNAs, we constructed a degradome library from Pinellia pedatisecta leaf. The result showed that a total of 18 transcript were identified as targets of miRNAs and further analysis indicated that miR156 and miR529 may function together to repress SPL14.
A recent trend in drug development is to identify drug combinations or multi-target agents that effectively modify multiple nodes of disease-associated networks. Such polypharmacological effects may reduce the risk of emerging drug resistance by means of attacking the disease networks through synergistic and synthetic lethal interactions. However, due to the exponentially increasing number of potential drug and target combinations, systematic approaches are needed for prioritizing the most potent multi-target alternatives on a global network level. We took a functional systems pharmacology approach toward the identification of selective target combinations for specific cancer cells by combining large-scale screening data on drug treatment efficacies and drug-target binding affinities. Our model-based prediction approach, named TIMMA, takes advantage of the polypharmacological effects of drugs and infers combinatorial drug efficacies through system-level target inhibition networks. Case studies in MCF-7 and MDA-MB-231 breast cancer and BxPC-3 pancreatic cancer cells demonstrated how the target inhibition modeling allows systematic exploration of functional interactions between drugs and their targets to maximally inhibit multiple survival pathways in a given cancer type. The TIMMA prediction results were experimentally validated by means of systematic siRNA-mediated silencing of the selected targets and their pairwise combinations, showing increased ability to identify not only such druggable kinase targets that are essential for cancer survival either individually or in combination, but also synergistic interactions indicative of non-additive drug efficacies. These system-level analyses were enabled by a novel model construction method utilizing maximization and minimization rules, as well as a model selection algorithm based on sequential forward floating search. Compared with an existing computational solution, TIMMA showed both enhanced prediction accuracies in cross validation as well as significant reduction in computation times. Such cost-effective computational-experimental design strategies have the potential to greatly speed-up the drug testing efforts by prioritizing those interventions and interactions warranting further study in individual cancer cases.
Selective inhibition of specific panels of multiple protein targets provides an unprecedented potential for improving therapeutic efficacy of anticancer agents. We introduce a computational systems pharmacology strategy, which uses the concept of target inhibition networks to predict effective multi-target combinations for treating specific cancer types. The strategy is based on integration of two complementary information sources, drug treatment efficacies and drug-target binding affinities, which are readily available in drug screening labs. Compared to the cancer sequencing efforts, which often result in a huge number of non-targetable genetic alterations, the target combinations from our strategy are druggable, by definition, hence enabling more straightforward translation toward clinically actionable treatment strategies. The model predictions were experimentally validated using siRNA-mediated target silencing screens in three case studies involving MDA-MB-231 and MCF-7 breast cancer and BxPC-3 pancreatic cancer cells. In more general terms, the cancer cell-specific target inhibition networks provided additional insights into the drugs' mechanisms of action, for instance, how the cancer cell survival pathways can be targeted by synergistic and synthetic lethal interactions through multi–target perturbations. These results demonstrate that the principles introduced here offer the possibilities to move toward more systematic prediction and evaluation of the most effective drug target combinations.
Salvia miltiorrhiza is one of the most important traditional Chinese medicinal plants because of its excellent performance in treating coronary heart disease. Phenolic acids mainly including caffeic acid, rosmarinic acid and salvianolic acid B are a group of active ingredients in S. miltiorrhiza. Abscisic acid (ABA), gibberellin (GA) and ethylene are three important phytohormones. In this study, effects of the three phytohormones and their interactions on phenolic production in S.
miltiorrhiza hairy roots were investigated. The results showed that ABA, GA and ethylene were all effective to induce production of phenolic acids and increase activities of PAL and TAT in S. miltiorrhiza hairy roots. Effects of phytohormones were reversed by their biosynthetic inhibitors. Antagonistic actions between the three phytohormones played important roles in the biosynthesis of phenolic acids. GA signaling is necessary for ABA and ethylene-induced phenolic production. Yet, ABA and ethylene signaling is probably not necessary for GA3-induced phenolic production. The complex interactions of phytohormones help us reveal regulation mechanism of secondary metabolism and scale-up production of active ingredients in plants.
Protein arginylation mediated by arginyltransferase (ATE1) is essential for heart formation during embryogenesis, however its cell-autonomous role in cardiomyocytes and the differentiated heart muscle has never been investigated. To address this question, we generated cardiac muscle-specific Ate1 knockout mice, in which Ate1 deletion was driven by α-myosin heavy chain promoter (αMHC-Ate1 mouse). These mice were initially viable, but developed severe cardiac contractility defects, dilated cardiomyopathy, and thrombosis over time, resulting in high rates of lethality after 6 months of age. These symptoms were accompanied by severe ultrastructural defects in cardiac myofibrils, seen in the newborns and far preceding the onset of cardiomyopathy, suggesting that these defects were primary and likely underlay the development of the future heart defects. Several major sarcomeric proteins were arginylated in vivo. Moreover, Ate1 deletion in the hearts resulted in a significant reduction of active and passive myofibril forces, suggesting that arginylation is critical for both myofibril structural integrity and contractility. Thus, arginylation is essential for maintaining the heart function by regulation of the major myofibril proteins and myofibril forces, and its absence in the heart muscle leads to progressive heart failure through cardiomyocyte-specific defects.
arginylation; dilated cardyomyopathy; myofibrils
Osteopetrosis, a disorder of skeletal bone, can cause death during childhood. We previously described a new spontaneous autosomal recessive osteopetrosis mouse mutant, “new toothless” (ntl). In this study, we reported for the first time the identification, cloning and characterization of the coiled-coil domain-containing 154 (CCDC154), a novel gene whose deletion of ~5 kb sequence including exons 1–6 was completely linked to the ntl mutant. The CCDC154 was conserved between mouse and human and is wildly expressed in mouse tissues. The cellular localization of CCDC154 was in the early endosomes. Overexpression of CCDC154 inhibited cell proliferation of HEK293 cells by inducing G2/M arrest. CCDC154 also inhibited tumor cell growth, and the soft agar assay revealed a significant decrease of the colony size of Hela cells upon transfection of CCDC154. Our results indicate that CCDC154 is a novel osteopetrosis-related gene involved in cell cycle regulation and tumor suppression growth.
CCDC154; osteopetrosis; cellular localization; cell proliferation; G2/M arrest
Peptidylprolyl cis/trans isomerase NIMA-interacting 1 (PIN1) is involved in the process of tumorigenesis. The two single nucleotide polymorphisms (−677T>C, −842G>C) in the PIN1 promoter region have been suspected of being associated with cancer risk for years, but the conclusion is still inconclusive.
Eligible case-control studies were retrieved by searching databases and references of related reviews and studies. Genotype distribution data, adjusted odds ratios (ORs) and 95% confidence (CIs) intervals were extracted to calculate pooled ORs.
A total of 4619 cancer cases and 4661 controls were included in this meta-analysis. Overall, the PIN1 −667T>C polymorphism was not associated with cancer risk, while the −842C allele was significantly associated with reduced cancer risk (CC+GC vs. GG, OR = 0.725, 95% CI: 0.607–0.865; Pheterogeneity = 0.012 and GC vs. GG: OR = 0.721, 95% CI: 0.591–0.880; Pheterogeneity = 0.003). Results from genotype distribution data were in agreement with those calculated with adjusted ORs and 95% CIs. No publication bias was detected.
Results of this meta-analysis suggest that the PIN1 −842G>C polymorphism is associated with decreased cancer risk, but that the −667T>C polymorphism is not.
Hyperuricemia (HUA) is a potential risk factor for developing insulin resistance, hypertension, dyslipidemia and cardiovascular disease. Therefore, we studied the prevalence of HUA and associated risk factors in the population of two provinces in northern China.
Based on the research of Chinese Physiological Constant and Health Conditions conducted in 2008–2010, we enrolled 29,639 subjects in a randomized, stratified study in four sampling areas in Heilongjiang Province and the Inner Mongolia Autonomous Region. We collected 13,140 serum samples to determine biochemical indicators including uric acid(UA), glucose, blood lipids, liver function, and renal function, and finally a representative sample of 8439 aged 18 years and older was determined. We also defined and stratified HUA, hypertension, diabetes, obesity and lipid abnormalities according to international guidelines.
There were significant differences in the UA levels between different genders and regions. The total prevalence of HUA is 13.7%. Men had a higher prevalence of HUA than women (21% vs. 7.9%; P < 0.0001). As age increased, HUA prevalence decreased in men but rose in women. The suburbs of big cities had the highest HUA prevalence (18.7%), and in high-prevalence areas the proportion of women with HUA also increased. A stepwise logistic regression model was used to filter out twelve HUA risk factors, including age, gender, residence, hypercholesterolemia, hypertriglyceridemia, impaired fasting glucose, hypertension, obesity, abdominal obesity, CKD, drinking and sleeping. After adjusting for these factors, the odds ratio of HUA was 1.92 times higher in men than in women. Compared with agricultural and pastoral areas, the odds ratio of having HUA was 2.14 for participants in the suburbs of big cities and 1.57 in the center of big cities.
The prevalence of HUA is high in northern China. The differences in HUA prevalence by geographic region suggested that unbalanced economic development and health education, therefore HUA prevention measures should be strengthened to improve quality of life and reduce health care costs.
Prevalence; Hyperuricemia; Risk factors
Malignant glioma is the most common type of primary brain tumor in adults, characterized by rapid tumor growth and infiltration of tumor cells throughout the brain. Alterations in the activity of the 26S proteasome have been associated with malignant glioma cells, although the specific defects have not been identified. Recently, microRNA-326 (miR-326) was shown to play an important role in glioblastoma and breast cancer, but the underlying molecular mechanisms remain unclear. In the present study, the human Nin one binding protein (NOB1) was identified as a direct target of miR-326 and a potential oncogene in human glioma. Similar to NOB1 silencing by shRNA, overexpression of miR-326 in human glioma cell lines (A172 and U373) caused cell cycle arrest at the G1 phase, delayed cell proliferation and enhanced apoptosis. MiR-326 inhibited colony formation in soft agar and decreased growth of a xenograft tumor model, suggesting that miR-326 and NOB1 are required for tumorigenesis in vitro and in vivo. Furthermore, these processes were shown to involve the MAPK pathway. NOB1 overexpression in human glioma samples was detected by Affymetrix array analysis, and NOB1 mRNA and protein levels were shown to be increased in high-grade glioma compared to low-grade glioma and normal brain tissue. Furthermore, high levels of NOB1 were associated with unfavorable prognosis of glioma patients. Taken together, these results indicate that miR-326 and NOB1 may play an important role in the development of glioma.
FOXO1 is at a convergence point of receptor tyrosine kinase (RTK) signaling, which is one of the three core pathways implicated in glioblastoma. It was recently shown that FOXO1 can effectively induce glioma cell death and inhibit tumor growth through cell cycle arrest and apoptosis. We therefore evaluated FOXO1 and pFOXO1 protein expression in 181 primary astrocytoma samples and 16 normal brain samples. Astrocytoma samples expressed higher cytoplasmic FOXO1 and pFOXO1 than normal brain samples. Nuclear pFOXO1 level was significantly higher than nuclear FOXO1 in astrocytomas. High cytoplasmic FOXO1 expression was associated with older onset age (P = 0.001) and higher WHO grade (P = 0.001). The trend was also observed between cytoplasmic pFOXO1 expression and WHO grade although not significant. Univariate survival analysis showed that both high cytoplasmic FOXO1 and pFOXO1 expression indicated a significantly shorter median overall survival and progression-free survival. Multivariate survival analysis revealed cytoplasmic FOXO1 expression, cytoplasmic pFOXO1 expression, WHO grade, gender, extent of resection and radiotherapy to be independent prognostic factors for overall survival and progression-free survival. Thus, our data suggested that cytoplasmic FOXO1 and pFOXO1 expression may serve as valuable prognostic variables in astrocytomas and may have significant implications for the development and application of targeted therapy.
Two major challenges in proteomics are the large number of proteins and their broad dynamic range within the cell. We exploited the abundance-dependent Michaelis-Menten kinetics of trypsin digestion to selectively digest and deplete abundant proteins with a method we call DigDeAPr. We validated the depletion mechanism with known yeast protein abundances and observed greater than 3-fold improvement in low abundance human protein identification and quantitation metrics. This methodology should be broadly applicable to many organisms, proteases, and proteomic pipelines.
Nasopharyngeal carcinoma (NPC) is an Epstein-Barr virus–associated malignancy that is most common in East Asia, Africa, and Alaska. Radiotherapy is the main treatment option; unfortunately, disease response to concurrent radiotherapy and chemotherapy varies among patients with NPC, and in many cases, NPC becomes resistant to radiotherapy. Our previous studies indicated that Jab1/CSN5 was overexpressed and plays a role in the pathogenesis and radiotherapy resistance in NPC. Therefore, it is important to seek for innovative therapeutics targeting Jab1/CSN5 for NPC. In this study, we explored the antitumor effect of a curcumin analogue T83 in NPC, and found T83 exhibits antitumor activity and induces radiosensitivity through inactivation of Jab1 in NPC.
NPC cell viability and proliferation were detected by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and colony formation assays. Cell cycle distribution was detected with use of flow cytometry. Apoptosis was examined by using the Annexin V/propidium iodide staining assay and cleavage poly(ADP-ribose polymerase (PARP) and cleavage caspase-3 expression. Jab1 expression was examined by Western blotting.
A growth inhibitory effect was observed with T83 treatment in a dose- and time-dependent manner. T83 significantly induced G2/M arrest and apoptosis in NPC. In addition, T83 inhibited Jab1 expression and sensitized NPC cells to radiotherapy.
Our data indicate that T83 exhibits potent inhibitory activity in NPC cells and induces radiotherapy sensitivity. Thus, T83 has translational potential as a chemopreventive or therapeutic agent for NPC.
Nasopharyngeal carcinoma; Tumorigenesis; Epstein-Barr virus–associated malignancy; Jab1/CSN5; Curcumin
Herein we report the characterization and optimization of single-step inline enrichment of phosphopeptides directly from small amounts of whole cell and tissue lysates (100 – 500 μg) using a hydroxyapatite (HAP) microcolumn and Multidimensional Protein Identification Technology (MudPIT). In comparison to a triplicate HILIC-IMAC phosphopeptide enrichment study, ~80% of the phosphopeptides identified using HAP-MudPIT were unique. Similarly, analysis of the consensus phosphorylation motifs between the two enrichment methods illustrates the complementarity of calcium-and iron-based enrichment methods and the higher sensitivity and selectivity of HAP-MudPIT for acidic motifs. We demonstrate how the identification of more multiply phosphorylated peptides from HAP-MudPIT can be used to quantify phosphorylation cooperativity. Through optimization of HAP-MudPIT on a whole cell lysate we routinely achieved identification and quantification of ca. 1000 phosphopeptides from a ~1 hr enrichment and 12 hr MudPIT analysis on small quantities of material. Finally, we applied this optimized method to identify phosphorylation sites from a mass-limited mouse brain region, the amygdala (200 – 500 μg), identifying up to 4000 phosphopeptides per run.
Hydroxyapatite; MudPIT; phosphopeptide enrichment; whole cell lysate; mouse amygdala; phosphorylation cooperativity
Hepatic glucose production (HGP) is crucial for glucose homeostasis, but the underlying mechanisms have not been fully elucidated. Here we show that a calcium-sensing enzyme, CaMKII, is activated in a calcium- and IP3R-dependent manner by cAMP and glucagon in primary HCs and by glucagon and fasting in vivo. Genetic deficiency or inhibition of CaMKII blocks nuclear translocation of FoxO1 by affecting its phosphorylation, impairs fasting- and glucagon/cAMP-induced glycogenolysis and gluconeogenesis, and lowers blood glucose levels, while constitutively active CaMKII has the opposite effects. Importantly, the suppressive effect of CaMKII deficiency on glucose metabolism is abrogated by transduction with constitutively nuclear FoxO1, indicating that the effect of CaMKII deficiency requires nuclear exclusion of FoxO1. This same pathway is also involved in excessive HGP in the setting of obesity. These results reveal a calcium-mediated signaling pathway involved in FoxO1 nuclear localization and hepatic glucose homeostasis.
The protein-protein interaction (PPI) networks are dynamically organized as modules, and are typically described by hub dichotomy: ‘party' hubs act as intramodule hubs and are coexpressed with their partners, yet ‘date' hubs act as coordinators among modules and are incoherently expressed with their partners. However, there remains skepticism about the existence of hub dichotomy. Since different algorithms and data sets were used in previous studies to test the model of hub classification, the conclusions may be largely influenced by the potential inherent biases. In this study, we evaluated two data sets of yeast interactome, and systematically investigated the behavior of hubs from multiple perspectives including co-expression patterns, topological roles and functional classifications. Our results revealed consistency between the two data sets, confirming the presence of hub dichotomy. Furthermore, we analyzed a human interactome data set, and demonstrated that the modular architecture of the PPI networks was more complicated than hub dichotomy.
BGIN is an alternatively spliced Rac1-GAP comprising a unique C-terminal poly-ubiquitin–binding module. Poly-Ub/BGIN interactions enhance BGIN distribution to membranes to limit Rac1 activity and downstream effector function in tissue culture cells and with proteotoxic stress such as neurodegenerative APP proteotoxicity.
Spatial control of RhoGTPase-inactivating GAP components remains largely enigmatic. We describe a brain-specific RhoGAP splice variant, BARGIN (BGIN), which comprises a combination of BAR, GAP, and partial CIN phosphatase domains spliced from adjacent SH3BP1 and CIN gene loci. Excision of BGIN exon 2 results in recoding of a 42–amino acid N-terminal stretch. The partial CIN domain is a poly-ubiquitin (poly-Ub)–binding module that facilitates BGIN distribution to membranous and detergent-insoluble fractions. Poly-Ub/BGIN interactions support BGIN-mediated inactivation of a membranous Rac1 population, which consequently inactivates membrane-localized Rac1 effector systems such as reactive oxygen species (ROS) generation by the Nox1 complex. Given that Ub aggregate pathology and proteotoxicity are central themes in various neurodegenerative disorders, we investigated whether BGIN/Rac1 signaling could be involved in neurodegenerative proteotoxicity. BGIN/Ub interactions are observed through colocalization in tangle aggregates in the Alzheimer’s disease (AD) brain. Moreover, enhanced BGIN membrane distribution correlates with reduced Rac1 activity in AD brain tissue. Finally, BGIN contributes to Rac1 inhibition and ROS generation in an amyloid precursor protein (APP) proteotoxicity model. These results suggest that BGIN/poly-Ub interactions enhance BGIN membrane distribution and relay poly-Ub signals to enact Rac1 inactivation, and attenuation of Rac1 signaling is partially dependent on BGIN in a proteotoxic APP context.
The Search Engine Processor (SEPro) is a tool for filtering, organizing, sharing, and displaying peptide spectrum matches. It employs a novel three-tier Bayesian approach that uses layers of spectrum, peptide, and protein logic to lead the data to converge to a single list of reliable protein identifications. SEPro is integrated into the PatternLab for proteomics environment, where an arsenal of tools for analyzing shotgun proteomic data is provided. By using the semi-labeled decoy approach for benchmarking, we show that SEPro significantly outperforms a commercially available competitor.
quality; filtering; semi-labeled decoy approach; sharing; shotgun proteomics
Researchers have identified an association between baseline γ-glutamyltransferase (GGT) and prehypertension. However, data from China are limited. A cross-sectional study was performed among 2,205 subjects from Heilongjiang Province in China. Multiple logistic regression analyses revealed a significant association between baseline GGT and prehypertension [1.59, 95% confidence interval (CI), 1.18–2.16], comparing quartile 4 to quartile 1. Subgroup analyses showed a stronger association between GGT and prehypertension in Koreans; men, current alcohol drinkers and subjects with pre-diabetes. Receiver operating characteristics (ROC) analysis demonstrated that when GGT was higher than 20 U/l, the risk of developing prehypertension increased. Serum GGT is used as a biochemical liver test, but our findings suggest that baseline values may also predict prehypertension in Chinese.
The nematode Caenorhabditis elegans has in recent years been proven to be a powerful in vivo model for testing antimicrobial compounds. We report here that the alkaloid compound Harmane (2-methyl-β-carboline) increases the lifespan of nematodes infected with a human pathogen, the Shiga toxin-producing Escherichia coli O157:H7 strain EDL933 and several other bacterial pathogens. This was shown to be unrelated to the weak antibiotic effect of Harmane. Using GFP-expressing E. coli EDL933, we showed that Harmane does not lower the colonization burden in the nematodes. We also found that the expression of the putative immune effector gene F35E12.5 was up-regulated in response to Harmane treatment. This indicates that Harmane stimulates the innate immune response of the nematode; thereby increasing its lifespan during bacterial infection. Expression of F35E12.5 is predominantly regulated through the p38 MAPK pathway; however, intriguingly the lifespan extension resulting from Harmane was higher in p38 MAPK-deficient nematodes. This indicates that Harmane has a complex effect on the innate immune system of C. elegans. Harmane could therefore be a useful tool in the further research into C. elegans immunity. Since the innate immunity of C. elegans has a high degree of evolutionary conservation, drugs such as Harmane could also be possible alternatives to classic antibiotics. The C. elegans model could prove to be useful for selection and development of such drugs.
Abnormal serum lipid profiles are associated with the risk of some cancers, but the direction and magnitude of the association with renal cell carcinoma is unclear. We explore the relationship between serum lipids and renal cell carcinoma via a matched case-control study. A 1∶2-matched case-control study design was applied, where one renal cell carcinoma patient was matched to two non-renal-cell-carcinoma residents with respect to age (±0 year) and gender. Cases (n = 248) were inpatients with a primary diagnosis of renal cell carcinoma, confirmed by pathology after operations. Controls were sampled from a community survey database matched on age and gender with cases, 2 controls for each case. Stratified Cox proportional hazard regression analysis was used to obtain hazard ratios and corresponding 95% confidence intervals of lipids level and dyslipidemia for the risk of renal cell carcinoma. Elevated serum cholesterol (p<0.001), LDL cholesterol (p<0.001), and HDL cholesterol (p = 0.003) are associated with decreased hazard of renal cell carcinoma, adjusting for obesity, smoke, hypertension and diabetes. However, risk caused by hTG showed no statistical significance (p = 0.263). This study indicates that abnormal lipid profile influences the risk of renal cell carcinoma.
Metabolomics helps to identify links between environmental exposures and intermediate biomarkers of disturbed pathways. We previously reported variations in phosphatidylcholines in male smokers compared with non-smokers in a cross-sectional pilot study with a small sample size, but knowledge of the reversibility of smoking effects on metabolite profiles is limited. Here, we extend our metabolomics study with a large prospective study including female smokers and quitters.
Using targeted metabolomics approach, we quantified 140 metabolite concentrations for 1,241 fasting serum samples in the population-based Cooperative Health Research in the Region of Augsburg (KORA) human cohort at two time points: baseline survey conducted between 1999 and 2001 and follow-up after seven years. Metabolite profiles were compared among groups of current smokers, former smokers and never smokers, and were further assessed for their reversibility after smoking cessation. Changes in metabolite concentrations from baseline to the follow-up were investigated in a longitudinal analysis comparing current smokers, never smokers and smoking quitters, who were current smokers at baseline but former smokers by the time of follow-up. In addition, we constructed protein-metabolite networks with smoking-related genes and metabolites.
We identified 21 smoking-related metabolites in the baseline investigation (18 in men and six in women, with three overlaps) enriched in amino acid and lipid pathways, which were significantly different between current smokers and never smokers. Moreover, 19 out of the 21 metabolites were found to be reversible in former smokers. In the follow-up study, 13 reversible metabolites in men were measured, of which 10 were confirmed to be reversible in male quitters. Protein-metabolite networks are proposed to explain the consistent reversibility of smoking effects on metabolites.
We showed that smoking-related changes in human serum metabolites are reversible after smoking cessation, consistent with the known cardiovascular risk reduction. The metabolites identified may serve as potential biomarkers to evaluate the status of smoking cessation and characterize smoking-related diseases.
metabolic network; metabolomics; molecular epidemiology; smoking; smoking cessation
Background and Objectives
Traumatic brain injury (TBI) affects millions worldwide and is without effective treatment. One area that is attracting growing interest is the use of transcranial low-level laser therapy (LLLT) to treat TBI. The fact that near-infrared light can penetrate into the brain would allow non-invasive treatment to be carried out with a low likelihood of treatment-related adverse events. LLLT may treat TBI by increasing respiration in the mitochondria, causing activation of transcription factors, reducing inflammatory mediators and oxidative stress, and inhibiting apoptosis.
Study Design/Materials and Methods
We tested LLLT in a mouse model of closed-head TBI produced by a controlled weight drop onto the skull. Mice received a single treatment with continuous-wave 665, 730, 810, or 980 nm lasers (36 J/cm2 delivered at 150 mW/cm2) 4-hour post-TBI and were followed up by neurological performance testing for 4 weeks.
Mice with moderate-to-severe TBI treated with 665 and 810 nm laser (but not with 730 or 980 nm) had a significant improvement in Neurological Severity Score that increased over the course of the follow-up compared to sham-treated controls. Morphometry of brain sections showed a reduction in small deficits in 665 and 810 nm laser treated mouse brains at 28 days.
The effectiveness of 810 nm agrees with previous publications, and together with the effectiveness of 660 nm and non-effectiveness of 730 and 980 nm can be explained by the absorption spectrum of cytochrome oxidase, the candidate mitochondrial chromophore in transcranial LLLT.
photobiomodulation; low-level laser therapy; traumatic brain injury; mouse model; Neurological Severity Score
Rab10 activation promotes GLUT4 storage vesicle recruitment to the plasma
membrane in response to insulin and coordinates with myosin-Va to mediate
Rab proteins are important regulators of insulin-stimulated GLUT4 translocation
to the plasma membrane (PM), but the precise steps in GLUT4 trafficking
modulated by particular Rab proteins remain unclear. Here, we systematically
investigate the involvement of Rab proteins in GLUT4 trafficking, focusing on
Rab proteins directly mediating GLUT4 storage vesicle (GSV) delivery to the PM.
Using dual-color total internal reflection fluorescence (TIRF) microscopy and an
insulin-responsive aminopeptidase (IRAP)-pHluorin fusion assay, we demonstrated
that Rab10 directly facilitated GSV translocation to and docking at the PM.
Rab14 mediated GLUT4 delivery to the PM via endosomal compartments containing
transferrin receptor (TfR), whereas Rab4A, Rab4B, and Rab8A recycled GLUT4
through the endosomal system. Myosin-Va associated with GSVs by interacting with
Rab10, positioning peripherally recruited GSVs for ultimate fusion. Thus,
multiple Rab proteins regulate the trafficking of GLUT4, with Rab10 coordinating
with myosin-Va to mediate the final steps of insulin-stimulated GSV
translocation to the PM.
Since accumulating evidence suggests the application of anesthetics may increase the risk of Alzheimer’s disease (AD), we investigated the cytotoxicity of inhaled general anesthesia in neurons and its underlying mechanism. Using primary cultured rat hippocampal neurons as the study model, here we show that isoflurane increases vulnerability to intracellular or extracellular amyloid β with or without serum deprivation. This isoflurane-induced effect is mediated by the downregulation of miR-214 level that lead to an elevated expression of Bax, a prominent target for miR-214. We conclude that isoflurane increases cell death in the presence of amyloid β by increasing Bax level through downregulating miR-214. Our data provide a new insight for inhaled anesthetics toxicity and indicate a possible mechanistic link between anesthetic application and neurodegenration in AD.