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BACKGROUND AND AIMS: Prior studies suggest a positive association between dietary AGEs and adverse health outcomes but have not well-characterized AGEs intake and its association with mortality in a general adult population in the United States. METHODS AND RESULTS: We included 5,474 adults with diabetes from the 2003 to 2018 National Health and Nutrition Examination Survey, a nationally representative sample of the non-institutionalized civilian population in the United States. Concordance to dietary guidelines (Healthy Eating Index 2015 [HEI-2015]) and intake of the AGE Nɛ-(carboxymethyl)lysine (CML) were estimated using an existing database and two 24-hour food recalls. Multivariable Cox regression evaluated the association between AGEs intake and all-cause mortality. A secondary analysis measured CML, Nɛ-(1-carboxyethyl)lysine (CEL), and Nδ-(5-hydro-5-methyl-4-imidazolon-2-yl)-ornithine (MGH1) from an alternative database. Higher AGEs intake was associated with lower concordance to dietary guidelines (Means and standard errors of HEI-2015 score, by quartiles of AGEs intake: Q1=55.2 ± 0.6, Q2=54.1 ± 0.5, Q3=52.1 ± 0.5, Q4=49.0 ± 0.5; p

T-SPOT®.TB (T-SPOT) is an interferon-gamma release assay (IGRA) used to detect infection with Mycobacterium tuberculosis based on the number of spot-forming T-cells; however, delays in sample processing have been shown to reduce the number of these spots that are detected following laboratory processing. Adding T-Cell Xtend (XT) into blood samples before processing reportedly extends the amount of time allowed between blood collection and processing up to 32 hours. In this study, paired blood samples from 306 adolescents and adults at high risk for latent tuberculosis (TB) infection (LTBI) or progression to TB disease were divided into three groups: 1) early processing (∼4.5 hours after collection) with and without XT, 2) delayed processing (∼24 hours after collection) with and without XT, and 3) early processing without XT and delayed processing with XT. The participants' paired samples were processed at a local laboratory and agreement of qualitative and quantitative results were assessed. The addition of XT did not consistently increase or decrease the number of spots. In groups 1, 2, and 3, samples processed with XT had 13% (10/77), 28.0% (30/107) and 24.6% (30/122), respectively, more spots while 33.8% (26/77), 26.2% (28/107), and 38.5% (47/122) had less spots compared with samples processed without XT. The findings suggest that XT does not reliably mitigate the loss of spot-forming T-cells in samples with processing delay.

T-SPOT.TB (T-SPOT) is an interferon gamma release assay (IGRA) used to detect infection with Mycobacterium tuberculosis based on the number of spot-forming T cells; however, delays in sample processing have been shown to reduce the number of these spots that are detected following laboratory processing. Adding T-Cell Xtend (XT) into blood samples before processing reportedly extends the amount of time allowed between blood collection and processing up to 32 h. In this study, paired blood samples from 306 adolescents and adults at high risk for latent tuberculosis (TB) infection (LTBI) or progression to TB disease were divided into three groups: (i) early processing (∼4.5 h after collection) with and without XT, (ii) delayed processing (∼24 h after collection) with and without XT, and (iii) early processing without XT and delayed processing with XT. The participants’ paired samples were processed at a local laboratory and agreement of qualitative and quantitative results was assessed. The addition of XT did not consistently increase or decrease the number of spots. In groups 1, 2, and 3, samples processed with XT had 13% (10/77), 28.0% (30/107), and 24.6% (30/122), respectively, more spots, while 33.8% (26/77), 26.2% (28/107), and 38.5% (47/122) had fewer spots than samples processed without XT. The findings suggest that XT does not reliably mitigate the loss of spot-forming T cells in samples with processing delay.

This study investigated the mechanisms underlying regulation of the serotonin system in the rat brain during exercise-induced chronic fatigue. High-performance liquid chromatography-mass spectrometry (HPLC-MS) was performed to measure serum tryptophan of the fatigued rat. HPLC was conducted to measure 5-hydroxytryptamine (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA) in the frontal cortex and hippocampus. In addition, 5-HT1A receptor and 5-HT transporter (5-HTT) mRNA expressions were measured at the same locations using real-time PCR. The results demonstrated a significant reduction in the serum tryptophan level in rats with exercise-induced chronic fatigue. Moreover, increased 5-HT and decreased 5-HIAA levels were detected in the frontal cortex and hippocampus, and these alterations were significant. Further, 5-HTT expression was significantly increased and 5-HT1A receptor expression was significantly decreased. These results indicate that the 5-HT system plays an important role in the development of exercise-induced chronic fatigue. The 5-HT levels in different parts of the brain increased simultaneously, especially at synapses, and these alterations were associated with changes in 5-HTT and 5-HT1A mRNA expressions.

Heat shock response, mediated by heat shock proteins, is a highly conserved physiological process in multicellular organisms for reestablishment of cellular homeostasis. Expression of heat shock factors and subsequent heat shock protein plays a role in protection against proteotoxicity in invertebrate and vertebrate models. Proteotoxicity due to beta-amyloid peptide (Abeta) oligomerization has been linked to the pathogenesis of Alzheimer's disease. Previously, we demonstrated that progressive paralysis induced by expression of human Abeta(1-42) in transgenic Caenorhabditis elegans was alleviated by Abeta oligomer inhibitors Ginkgo biloba extract and its constituents [Wu, Y., Wu, Z., Butko, P., Christen, Y., Lambert, M.P., Klein, W.L., Link, C.D., Luo, Y., 2006. Amyloid-beta-induced pathological behaviors are suppressed by Ginkgo biloba extract EGb 761 and ginkgolides in transgenic Caenorhabditis elegans. J. Neurosci. 26(50): 13102-13113]. In this study, we apply a protective heat shock to the transgenic C. elegans and demonstrate: (1) a delay in paralysis, (2) increased expression of small heat shock protein HSP16.2, and (3) significant reduction of Abeta oligomers in a heat shock time-dependent manner. These results suggest that transient heat shock lessens Abeta toxicity by diminishing Abeta oligomerization, which provides a link between up regulation of endogenous chaperone proteins and protection against Abeta proteotoxicity in vivo.

Standardized Ginkgo biloba extract EGb 761 exhibits beneficial effects to patients with Alzheimer's disease (AD). It was previously demonstrated that EGb 761 inhibits amyloid beta (Abeta) oligomerization in vitro, protects neuronal cells against Abeta toxicity, and improves cognitive defects in a mouse model of AD (Tg 2576). In this study, the neurogenic potential of EGb 761 and its effect on cAMP response element binding protein (CREB) were examined in a double transgenic mouse model (TgAPP/PS1). EGb 761 significantly increases cell proliferation in the hippocampus of both young (6 months) and old (22 months) TgAPP/PS1 mice, and the total number of neuronal precursor cells in vitro in a dose-dependent manner. Furthermore, Abeta oligomers inhibit phosphorylation of CREB and cell proliferation in the hippocampus of TgAPP/PS1 mice. Administration of EGb 761 reduces Abeta oligomers and restores CREB phosphorylation in the hippocampus of these mice. The present findings suggest that 1) enhanced neurogenesis by EGb 761 may be mediated by activation of CREB, 2) stimulation of neurogenesis by EGb 761 may contribute to its beneficial effects in AD patients and improved cognitive functions in the mouse model of AD, and 3) EGb 761 has therapeutic potential for the prevention and improved treatment of AD.

Tumor‐initiating stem cells (also referred to as cancer stem cells, CSCs) are a subpopulation of cancer cells that play unique roles in tumor propagation, therapeutic resistance and tumor recurrence. It is increasingly important to understand how molecular signaling regulates the self‐renewal and differentiation of CSCs. Basic helix‐loop‐helix (bHLH) transcription factors are critical for the differentiation of normal stem cells, yet their roles in neoplastic stem cells are not well understood. In glioblastoma neurosphere cultures that contain cancer stem cells (GBM‐CSCs), the bHLH family member inhibitors of DNA binding protein 2 and 4 (Id2 and Id4) were found to be upregulated during the differentiation of GBM‐CSCs in response to histone deacetylase inhibitors. In this study, we examined the functions of Id2 and Id4 in GBM neurosphere cells and identified Id proteins as efficient differentiation regulators of GBM‐CSCs. Overexpression of Id2 and Id4 promoted the lineage‐specific differentiation of GBM neurosphere cells as evidenced by the induction of neuronal/astroglial differentiation markers Tuj1 and GFAP and the inhibition of the oligodendroglial marker GalC. Id protein overexpression also reduced both stem cell marker expression and neurosphere formation potential, a biological marker of cancer cell “stemness.” We further showed that Id2 and Id4 regulated GBM neurosphere differentiation through downregulating of another bHLH family member, the oligodendroglial lineage‐associated transcription factors (Olig) 1 and 2. Our results provide evidence for distinct functions of Id proteins in neoplastic stem cells, which supports Id proteins and their downstream targets as potential candidates for differentiation therapy in CSCs. (Cancer Sci 2012; 103: 1028–1037)

Previously we reported that the standardized Ginkgo biloba extract EGb 761 extended life span and increased stress resistance in Caenorhabditis elegans. In this study, pharmacological modulation of age-dependent muscle degeneration, or sarcopenia, was determined. Transgenic C. elegans strain (PD4251) expressing green fluorescent protein (GFP)-MYO-3, localized in body wall muscles and vulval muscle nuclei, were fed with EGb 761 or Wisconsin Ginseng, and muscle integrity was analyzed by quantification of GFP fluorescence. Both EGb 761 and Wisconsin Ginseng significantly delayed sarcopenia. Ginseng was more effective in worms of more advanced age, which is consistent with the ultrastructural changes observed by transmission electron microscopy. Furthermore, both agents ameliorated age-associated decline of locomotive behaviors including locomotion, body bend, and pharyngeal pumping. These results suggest that pharmacological extension of life span is a consequence of maintaining functional capacity of the tissue, and that C. elegans is a valid model system for testing therapeutic intervention for delaying the progress of sarcopenia.

Amyloid-β (Aβ) toxicity has been postulated to initiate synaptic loss and subsequent neuronal degeneration seen in Alzheimer's disease (AD). We previously demonstrated that the standardizedGinkgo bilobaextract EGb 761, commonly used to enhance memory and by AD patients for dementia, inhibits Aβ-induced apoptosis in neuroblastoma cells. In this study, we use EGb 761 and its single constituents to associate Aβ species with Aβ-induced pathological behaviors in a model organism,Caenorhabditis elegans.We report that EGb 761 and one of its components, ginkgolide A, alleviates Aβ-induced pathological behaviors, including paralysis, and reduces chemotaxis behavior and 5-HT hypersensitivity in a transgenicC. elegans. We also show that EGb 761 inhibits Aβ oligomerization and Aβ deposits in the worms. Moreover, reducing oxidative stress is not the mechanism by which EGb 761 and ginkgolide A suppress Aβ-induced paralysis because the antioxidantl-ascorbic acid reduced intracellular levels of hydrogen peroxide to the same extent as EGb 761, but was not nearly as effective in suppressing paralysis in the transgenicC. elegans. These findings suggest that (1) EGb 761 suppresses Aβ-related pathological behaviors, (2) the protection against Aβ toxicity by EGb 761 is mediated primarily by modulating Aβ oligomeric species, and (3) ginkgolide A has therapeutic potential for prevention and treatment of AD.

Background Epidemiological studies have associated estrogen replacement therapy with a lower risk of developing Alzheimer's disease, but a higher risk of developing breast cancer and certain cardiovascular disorders. The neuroprotective effect of estrogen prompted us to determine potential therapeutic impact of soy-derived estrogenic compounds. Transgenic C. elegans, that express human beta amyloid (Aβ), were fed with soy derived isoflavones genistein, daidzein and glycitein (100 μg/ml) and then examined for Aβ-induced paralysis and the levels of reactive oxygen species. Results Among the three compounds tested, only glycitein alleviated Aβ expression-induced paralysis in the transgenic C. elegans. This activity of glycitein correlated with a reduced level of hydrogen peroxide in the transgenic C. elegans. In vitro scavenging effects of glycitein on three types of reactive oxygen species confirmed its antioxidant properties. Furthermore, the transgenic C. elegans fed with glycitein exhibited reduced formation of β amyloid. Conclusion These findings suggest that a specific soy isoflavone glycitein may suppress Aβ toxicity through combined antioxidative activity and inhibition of Aβ deposition, thus may have therapeutic potential for prevention of Aβ associated neurodegenerative disorders.

assessed for mitochondrial respiratory activity and enzymatic activity in the presence and absence of toxic calcium exposure. Primary hippocampal rat neurons exposed to E2 or vehicle control were assessed for cytochrome c release and Bax translocation by immunocytochemistry and western blot analysis. Conclusions: E2-treated mitochondria displayed enhanced respiratory function coupled to increased expression and activity of the electron transport chain complex IV (cytochrome c oxidase). This enhancement of basal mitochondrial function was paralleled by the neuroprotective effects of E2, which were evidenced by an attenuation of the calcium-induced decline in mitochondrial respiratory function. Apoptosis during neurodegeneration is preceded by release of cytochrome c from the mitochondrial intermembrane space. This translocation is regulated by the expression and localization of the Bcl-2 family of proteins. We showed that E2 prevents the glutamateand A-induced reciprocal mitochondrial/cytosolic translocation of cytochrome c and Bax. These data suggest a mechanism of E2 neuroprotection involving an increase in Ca sequestration by mitochondria coupled with an increase in mitochondrial Ca load tolerability and an increase in mitochondrial respiratory function.

Alzheimer's disease (AD) has been associated with aggregation of beta-amyloid peptide (Abeta) and cell death in the brain. Using various models, such as the nematode Caenorhabditis elegans, the fruit fly Drosophila melanogaster and the mouse Mus musculus, investigators have attempted to imitate the pathology process of AD for better understanding of the cellular mechanisms and for possible therapeutic intervention. Among many in vitro and in vivo models of AD, transgenic C. elegans expressing human Abeta has shown its own advantages. The transgenic C. elegans model have been used in studying AD due to its short life span, facility to maintain, ability to develop muscle-associated deposits reactive to amyloid-specific dyes and the concomitant progressive paralysis phenotype. Moreover, the transgenic C. elegans exhibits increased levels of reactive oxygen species (ROS) and protein carbonyls, similar to those observed in AD patients, supporting the current theory on Abeta-induced oxidative stress and subsequent neurodegeneration in AD. DNA microarray assays of the worm demonstrated several stress-related genes being upregulated, particularly two genes homologous to human alphaB-crystallin and tumor necrosis factor-related protein, which were also upregulated in postmortem AD brain. Studies in our laboratory along with others suggest that the transgenic C. elegans model is a suitable in vivo model to relate Abeta-expression with its toxicity, which may underlie AD pathology. It may also be used as a tool for pharmacological evaluation of novel therapeutic agents.