CEBS (Chemical Effects in Biological Systems) is an integrated public repository for toxicogenomics data, including the study design and timeline, clinical chemistry and histopathology findings and microarray and proteomics data. CEBS contains data derived from studies of chemicals and of genetic alterations, and is compatible with clinical and environmental studies. CEBS is designed to permit the user to query the data using the study conditions, the subject responses and then, having identified an appropriate set of subjects, to move to the microarray module of CEBS to carry out gene signature and pathway analysis. Scope of CEBS: CEBS currently holds 22 studies of rats, four studies of mice and one study of Caenorhabditis elegans. CEBS can also accommodate data from studies of human subjects. Toxicogenomics studies currently in CEBS comprise over 4000 microarray hybridizations, and 75 2D gel images annotated with protein identification performed by MALDI and MS/MS. CEBS contains raw microarray data collected in accordance with MIAME guidelines and provides tools for data selection, pre-processing and analysis resulting in annotated lists of genes of interest. Additionally, clinical chemistry and histopathology findings from over 1500 animals are included in CEBS. CEBS/BID: The BID (Biomedical Investigation Database) is another component of the CEBS system. BID is a relational database used to load and curate study data prior to export to CEBS, in addition to capturing and displaying novel data types such as PCR data, or additional fields of interest, including those defined by the HESI Toxicogenomics Committee (in preparation). BID has been shared with Health Canada and the US Environmental Protection Agency. CEBS is available at http://cebs.niehs.nih.gov. BID can be accessed via the user interface from https://dir-apps.niehs.nih.gov/arc/. Requests for a copy of BID and for depositing data into CEBS or BID are available at http://www.niehs.nih.gov/cebs-df/.

Recent studies demonstrated that metformin exerts anti-neoplastic effect in a spectrum of malignancies. However, the mechanism whereby metformin affects various cancers, including gastric cancer, is poorly elucidated. Considering apoptosis plays critical role in tumorigenesis, we, in the present study, investigated the in vitro apoptotic effect of metformin on human gastric cancer cell and the underlying mechanism. Three differently-differentiated gastric cancer cell lines, MKN-28, SGC-7901 and BGC-823, along with one noncancerous gastric cell line GES-1 were used. We found that metformin treatment selectively induces apoptosis in the 3 cancer cell lines, but not the noncancerous one, as confirmed by flow cytometry, Caspase-Glo assay and western blotting against PARP and cleaved caspase 3. Moreover, the apoptotic effect of metformin seems to correlate negatively with the differentiation degree of gastric cancer. Metformin-induced apoptosis may be partially mediated through inhibition of anti-apoptotic survivin. Additionally, AMPK and mTOR, 2 important regulatory molecules responsible for metformin action, were investigated for their possible involvements in metformin-induced apoptosis of gastric cancer cell. AMPK knockdown by siRNA restores metformin-inhibited survivin expression and partially abolishes metformin-induced apoptosis. Similarly, forced overexpression of mTOR downstream effector p70S6K1 relieves metformin-induced inhibition of survivin and partly attenuates metformin-induced apoptosis. More importantly, survivin overexpression alleviates metformin-induced apoptosis. Xenograft nude mouse experiment also confirmed that AMPK/mTOR-mediated decrease of suvivin is in vivo implicated in metformin-induced apoptosis. Taken together, these evidences suggest that AMPK/mTOR-mediated inhibition of survivin may partly contribute to metformin-induced apoptosis of gastric cancer cell.

High levels of inspired oxygen, hyperoxia, are frequently used in patients with acute respiratory failure. Hyperoxia can exacerbate acute respiratory failure, which has high mortality and no specific therapies. We identified a novel roles for PINK1 (PTEN-induced putative kinase 1), a mitochondrial protein, and the cytosolic innate immune protein, NLRP3, in the lung and endothelium. We generated double knockouts (PINK1−/−/NLRP3−/−) as well as cell-targeted PINK1 silencing and lung-targeted overexpression constructs to specifically show that PINK1 mediates cytoprotection in wild type (WT) and NLRP3−/− mice. The ability to resist hyperoxia is proportional to PINK1 expression – PINK1−/− mice were the most susceptible, WT mice, which induced PINK1 after hyperoxia, had intermediate susceptibility and NLRP3−/− mice, which had high basal and hyperoxia-induced PINK1, were the least susceptible. Genetic deletion of PINK1 or PINK1 silencing in the lung endothelium increased susceptibility to hyperoxia via alterations in autophagy/mitophagy, proteasome activation, apoptosis and oxidant generation.

BackgroundThe associations of sarcopenia with adverse health status have highlighted the importance of sarcopenia research and intervention. This study was designed to analyze the characteristics of aging-related differences in appendicular skeletal muscle mass (ASM), handgrip strength (HS), gait speed (GS) and their associated factors in older Chinese, in order to generate guidance for sarcopenia intervention in this population.MethodsPopulation-based cross-sectional study. The criteria proposed by Asian Working Group for Sarcopenia were used to define low ASM, HS, and GS. The time required for five repeated chair stands (RCS) was also measured to evaluate physical performance. The differences of continuous variables were compared using one-way ANOVA tests and the Pearson correlation was used to analyze the relationship of each measurement adjusted by gender and age. Stepwise logistic regression was used to determine associated factors of low HS and low physical performance.ResultsThe data were analyzed in a total of 218 younger adults (aged 20–59, 76 males, 142 females) and 461 older adults (≥60 year, 207 males and 254 females). There were significant differences among age groups for HS, GS, and RCS while females were found to have significantly lower HS and GS values. ASM was significantly correlated with HS but not with other measures. Correlations among HS and GS, RCS were influenced by age differences. In the older group, unstructured daily routine (OR = 2.77) was associated with the risk of low GS, while physical exercise (OR = 0.27), and engaging in hobbies (OR = 0.11) were associated with faster GS. Co-morbidity (OR = 1.99) was associated with the risk of reduced performance of RCS, while engaging in hobbies was associated with faster RCS performance (OR = 0.35).ConclusionsMuscle strength and physical performance varied with aging in older Chinese. Measures of GS, HS, and RCS provide a readily available and effective method for assessing the risk of functional mobility decline. Maintaining a healthy life style and physical activity throughout life is beneficial for older people to improve their physical performance, especially in the early stages of aging.

The risk of developing neurodegenerative disorders such as Alzheimer's disease (AD) increases dramatically with age. Understanding the underlying mechanisms of brain aging is crucial for developing preventative and/or therapeutic approaches for age-associated neurological diseases. Recently, it has been suggested that epigenetic factors, such as histone modifications, maybe be involved in brain aging and age-related neurodegenerations. In this study, we investigated 14 histone modifications in brains of a cohort of young (3 months), old (22 months), and old age-matched dietary restricted (DR) and rapamycin treated BALB/c mice. Results showed that 7 out of all measured histone markers were changed drastically with age. Intriguingly, histone methylations in brain tissues, including H3K27me3, H3R2me2, H3K79me3 and H4K20me2 tend to disappear with age but can be partially restored by both DR and rapamycin treatment. However, both DR and rapamycin treatment also have a significant impact on several other histone modifications such as H3K27ac, H4K16ac, H4R3me2, and H3K56ac, which do not change as animal ages. This study provides the first evidence that a broad spectrum of histone modifications may be involved in brain aging. Besides, this study suggests that both DR and rapamycin may slow aging process in mouse brain via these underlying epigenetic mechanisms.

Reverse transcription quantitative-polymerase chain reaction (RT-qPCR) is a routine method for gene expression analysis, and reliable results depend on proper normalization by stable reference genes. Caloric restriction (CR) is a robust lifestyle intervention to slow aging and delay onset of age-associated diseases via inducing global changes in gene expression. Reliable normalization of RT-qPCR data becomes crucial in CR studies. In this study, the expression stability of 12 candidate reference genes were evaluated in inguinal white adipose tissue (iWAT), skeletal muscle (Sk.M) and liver of CR mice by using three algorithms, geNorm, NormFinder, and Bestkeeper. Our results showed β2m, Ppia and Hmbs as the most stable genes in iWAT, Sk.M and liver, respectively. Moreover, two reference genes were sufficient to normalize RT-qPCR data in each tissue and the suitable pair of reference genes was β2m-Hprt in iWAT, Ppia-Gusb in Sk.M and Hmbs-β2m in liver. By contrast, the least stable gene in iWAT or Sk.M was Gapdh, and in liver was Pgk1. Furthermore, the expression of Leptin and Ppar-γ were profiled in these tissues to validate the selected reference genes. Our data provided a basis for gene expression analysis in future CR studies.

The Chemical Effects in Biological Systems database (CEBS) is a comprehensive and unique toxicology resource that compiles individual and summary animal data from the National Toxicology Program (NTP) testing program and other depositors into a single electronic repository. CEBS has undergone significant updates in recent years and currently contains over 11 000 test articles (exposure agents) and over 8000 studies including all available NTP carcinogenicity, short-term toxicity and genetic toxicity studies. Study data provided to CEBS are manually curated, accessioned and subject to quality assurance review prior to release to ensure high quality. The CEBS database has two main components: data collection and data delivery. To accommodate the breadth of data produced by NTP, the CEBS data collection component is an integrated relational design that allows the flexibility to capture any type of electronic data (to date). The data delivery component of the database comprises a series of dedicated user interface tables containing pre-processed data that support each component of the user interface. The user interface has been updated to include a series of nine Guided Search tools that allow access to NTP summary and conclusion data and larger non-NTP datasets. The CEBS database can be accessed online at http://www.niehs.nih.gov/research/resources/databases/cebs/.

Sirtuin 1 (Sirt1) has a range of molecular functions and has emerged as an important protein in aging and metabolic regulations. Studies have reported a correlation between disturbance of Sirt1 activity and the onset of aging‑ or obesity‑associated diseases, including diabetes, cardiovascular disease and neurodegenerative disorders. However, a systematic investigation to examine the changes of Sirt1 expression in a wide range of ages and to what degree it changes has yet to be performed. To assess the effects of aging on the changes of Sirt1 expression, an in vivo model of aging, senescence-accelerated mouse prone 8 (SAM‑P8) and a control counterpart strain, senescence-accelerated mouse resistant 1 (SAM‑R1) was used. The mRNA and protein expression levels of Sirt1 were detected in four different tissues, including brain, liver, skeletal muscle and white adipose tissue, in both strains at different ages (1-, 4-, 8- and 12-month old). Therefore, different life stages, including young age prior to maturation, adult, middle age and old age were examined. The results identified that Sirt1 expression declined with age at the transcriptional and translational levels in the brain, liver, skeletal muscle and white adipose tissue in SAM-P8 and SAM‑R1. The Sirt1 expression level was lower in SAM-P8 than in SAM‑R1, particularly at old age. Among the four tissues, it was most significantly reduced in the brain.