Altered plasma metabolite levels can be detected years before a glioma diagnosis

Genetic and metabolic changes in tissue and blood are reported to occur several years before glioma diagnosis. As gliomas are currently detected late, a liquid biopsy for early detection could impact the quality of life and prognosis of patients. Here, we present a nested case-control study of 550 pre-diagnostic glioma cases and 550 healthy controls, from the Northern Sweden Health and Disease study (NSHDS) and the European Prospective Investigation into Cancer and Nutrition (EPIC) study. We identified 93 significantly altered metabolites related to glioma development up to eight years before diagnosis. Out of these metabolites, a panel of 20 selected metabolites showed strong disease correlation and consistent progression pattern towards diagnosis in both the NSHDS and EPIC cohorts, and separated favorably future cases from controls independently of biological sex. The blood metabolite panel also successfully separated both lower grade glioma and glioblastoma cases from controls, up to eight years before diagnosis in NSHDS (glioma AUC=0.85, P=3.1e-12; glioblastoma AUC=0.85, P=6.3e-8), and up to two years before diagnosis in EPIC (glioma AUC=0.81, P=0.005; glioblastoma AUC=0.89, P=0.04). Pathway enrichment analysis detected metabolites related to the TCA-cycle, Warburg effect, gluconeogenesis, cysteine-, pyruvate- and tyrosine metabolism as the most affected

Pathogenic huntingtin inhibits fast axonal transport by activating JNK3 and phosphorylating kinesin

Author Posting. © The Author(s), 2009. This is the author's version of the work. It is posted here by permission of Nature America for personal use, not for redistribution. The definitive version was published in Nature Neuroscience 12 (2009): 864-871, doi:10.1038/nn.2346.Selected vulnerability of neurons in Huntington’s disease (HD) suggests alterations in a cellular process particularly critical for neuronal function. Supporting this idea, pathogenic Htt (polyQ-Htt) inhibits fast axonal transport (FAT) in various cellular and animal HD models (mouse and squid), but the molecular basis of this effect remains unknown. Here we show that polyQ-Htt inhibits FAT through a mechanism involving activation of axonal JNK. Accordingly, increased activation of JNK was observed in vivo in cellular and animal HD models. Additional experiments indicate that polyQ-Htt effects on FAT are mediated by the neuron-specific JNK3, and not ubiquitously expressed JNK1, providing a molecular basis for neuron-specific pathology in HD. Mass spectrometry identified a residue in the kinesin-1 motor domain phosphorylated by JNK3, and this modification reduces kinesin-1 binding to microtubules. These data identify JNK3 as a critical mediator of polyQ-Htt toxicity and provides a molecular basis for polyQ-Htt-induced inhibition of FAT.This work was supported by 2007/2008 MBL summer fellowship to GM; an HDSA grant to GM; NIH grants MH066179 to GB; and ALSA, Muscular Dystrophy Association, and NIH (NS23868, NS23320, NS41170) grants to STB

Field surveys reveal the presence of anti-androgens in an effluent-receiving river using stickleback-specific biomarkers

This study was designed to assess whether the removal of endocrine disrupting chemicals (EDCs) and other substances from a Waste Water Treatment Works (WWTW) effluent (receiving water: R. Ray, Swindon, UK) by granular activated carbon (GAC) affected biomarkers of exposure to EDCs [vitellogenin (VTG) and spiggin] in male and female three-spined sticklebacks in the receiving water. A nearby river (R. Ock), with a negligible effluent loading, was used as a control. On each river fish were sampled from four sites on five occasions both before and after remediation of the WWTW effluent. The results show for the first time in a UK field study a clear seasonality of blood VTG concentrations in wild male fish, following closely the VTG profile in female fish from both rivers. VTG levels in male fish from the R. Ray were significantly reduced after the GAC installation. However, VTG levels in males from the control sites also varied significantly across the same period, reducing the significance of this finding. A laboratory exposure to oestradiol (using site-specific lower and upper levels of oestrogenic activity) failed to elevate VTG concentrations in male sticklebacks suggesting that concentrations in the effluent, even prior to remediation, may not have exceeded a critical sensitivity threshold. Most importantly, a significant increase in female kidney spiggin content (a highly specific biomarker of xeno-androgen exposure) occurred in fish in the R. Ray after the GAC installation to levels comparable with those in fish from the control river. The significance of this finding is strengthened by the fact that during the pre-remediation period in the R. Ray, female spiggin levels increased with increasing distance from the WWTW. Our results provide the first in vivo evidence of the presence of anti-androgens in a U.K. WWTW effluent. To our knowledge this is the first U.K.-based comprehensive field study on the effects of a WWTW upgrade on biomarkers of EDC exposure using a sentinel fish species and our findings confirm the value of the stickleback as a model species for studying EDCs both in the laboratory and in the wild

Phosphorylation of SCG10/stathmin-2 determines multipolar stage exit and neuronal migration rate

Cristina García-Frigola [et al.]. 11 p., 7 figures, 1 table and references.Cell migration is the consequence of the sum of positive and negative regulatory mechanisms. Although appropriate migration of neurons is a principal feature of brain development, the negative regulatory mechanisms remain obscure. We found that JNK1 was highly active in developing cortex and that selective inhibition of JNK in the cytoplasm markedly increased both the frequency of exit from the multipolar stage and radial migration rate and ultimately led to an ill-defined cellular organization. Moreover, regulation of multipolar-stage exit and radial migration in Jnk1 -/- (also known as Mapk8) mice, resulted from consequential changes in phosphorylation of the microtubule regulator SCG10 (also called stathmin-2). Expression of an SCG10 mutant that mimics the JNK1-phosphorylated form restored normal migration in the brains of Jnk1 -/- mouse embryos. These findings indicate that the phosphorylation of SCG10 by JNK1 is a fundamental mechanism that governs the transition from the multipolar stage and the rate of neuronal cell movement during cortical development.This work was supported by grants from the Academy of Finland (218125, 125860, 206497, 111870, 203520 and 110445), Turku Graduate School of Biomedical Sciences, the Finnish Graduate School of Neuroscience, Magnus Ehrnrooth’s Foundation, FP6 STRESSPROTECT and Åbo Akademi University. T.K. was supported by the Danish Cancer Society. L.N. is funded by Walloon Excellence in Lifesciences and Biotechnology.Peer reviewe

Altered plasma metabolite levels can be detected years before a glioma diagnosis

Genetic and metabolic changes in tissue and blood are reported to occur several years before glioma diagnosis. Since gliomas are currently detected late, a liquid biopsy for early detection could affect the quality of life and prognosis of patients. Here, we present a nested case-control study of 550 prediagnostic glioma cases and 550 healthy controls from the Northern Sweden Health and Disease study (NSHDS) and the European Prospective Investigation into Cancer and Nutrition (EPIC) study. We identified 93 significantly altered metabolites related to glioma development up to 8 years before diagnosis. Out of these metabolites, a panel of 20 selected metabolites showed strong disease correlation and a consistent progression pattern toward diagnosis in both the NSHDS and EPIC cohorts, and they separated future cases from controls independently of biological sex. The blood metabolite panel also successfully separated both lower-grade glioma and glioblastoma cases from controls, up to 8 years before diagnosis in patients within the NSHDS cohort and up to 2 years before diagnosis in EPIC. Pathway enrichment analysis detected metabolites related to the TCA cycle, Warburg effect, gluconeogenesis, and cysteine, pyruvate, and tyrosine metabolism as the most affected

Proteomic Analysis of the Reproductive Organs of the Hermaphroditic Gastropod Lymnea stagnalis Exposed to Different Endocrine Disrupting Chemicals

Many studies have reported perturbations of mollusc reproduction following exposure to low concentrations (ng/L range) of endocrine disrupting chemicals (EDCs). However, the mechanisms of action of these molecules on molluscs are still poorly understood. Investigation of the modifications of protein expression in organisms exposed to chemicals using proteomic methods can provide a broader and more comprehensive understanding of adverse impacts of pollution on organisms than conventional biochemical biomarkers (e.g., heat-shock proteins, metallothioneins, GST, EROD). In this study we have investigated the impacts of four chemicals, which exhibit different endocrine disrupting properties in vertebrates, on the proteome of the hermaphroditic freshwater pulmonate gastropod Lymnaea stagnalis after 21 days of exposure. Testosterone, tributyltin, chlordecone and cyproterone acetate were chosen as tested compounds as they can induce adverse effects on the reproduction of this snail. The 2D-DIGE method was used to identify proteins whose expression was affected by these compounds. In addition to modifying the expression of proteins involved in the structure and function of the cytoskeleton, chemicals had impacts on the expression of proteins involved in the reproduction of L. stagnalis. Exposure to 19.2 μg/L of chlordecone increased the abundance of ovipostatin, a peptide transmitted during mating through seminal fluid, which reduces oviposition in this species. The expression of yolk ferritin, the vitellogenin equivalent in L. stagnalis, was reduced after exposure to 94.2 ng Sn/L of tributyltin. The identification of yolk ferritin and the modification of its expression in snails exposed to chemicals were refined using western blot analysis. Our results showed that the tested compounds influenced the abundance of yolk ferritin in the reproductive organs. Alteration in proteins involved in reproductive pathways (e.g., ovipostatin and yolk ferritin) could constitute relevant evidence of interaction of EDCs with reproductive pathways that are under the control of the endocrine system of L. stagnalis

JNK3 is abundant in insulin-secreting cells and protects against cytokine-induced apoptosis.

AIMS/HYPOTHESIS: In insulin-secreting cells, activation of the c-Jun NH(2)-terminal kinase (JNK) pathway triggers apoptosis. Whereas JNK1 and JNK2 are ubiquitously produced, JNK3 has been described exclusively in neurons. This report aims to characterise the expression and role in apoptosis of the three JNK isoforms in insulin-secreting cells exposed to cytokines. METHODS: Sections of human and mouse pancreases were used for immunohistochemistry studies with isoform-specific anti-JNK antibodies. Human, pig, mouse and rat pancreatic islets were isolated by enzymatic digestion and RNA or protein extracts were prepared. RNA and protein levels were determined by quantitative RT-PCR and western blotting respectively, using JNK-isoform-specific primers and isoform-specific antibodies; activities of the three JNK isoforms were determined by kinase assays following quantitative immunoprecipitation/depletion of JNK3. JNK silencing was performed with small interfering RNAs and apoptotic rates were determined in INS-1E cells by scoring cells displaying pycnotic nuclei. RESULTS: JNK3 and JNK2 mRNAs are the predominant isoforms expressed in human pancreatic islets. JNK3 is nuclear while JNK2 is also cytoplasmic. In INS-1E cells, JNK3 knockdown increases c-Jun levels and caspase-3 cleavage and sensitises cells to cytokine-induced apoptosis; in contrast, JNK1 or JNK2 knockdown is protective. CONCLUSIONS/INTERPRETATION: In insulin-secreting cells, JNK3 plays an active role in preserving pancreatic beta cell mass from cytokine attacks. The specific localisation of JNK3 in the nucleus, its recruitment by cytokines, and its effects on key transcription factors such as c-Jun, indicate that JNK3 is certainly an important player in the transcriptional control of genes expressed in insulin-secreting cells