Complexity of IL-1β induced gene expression pattern in human articular chondrocytes

SummaryThe mRNA fingerprinting technique, differential display reverse transcription polymerase chain (DDRT-PCR), was used to detect changes in the overall pattern of gene expression in human articular knee chondrocytes induced by interleukin-1β (IL-1β), the prototypical inducer of catabolic responses in degenerate joint diseases. One hundred different primer combinations generated approximately 10 000 different PCR fragments for IL-1β treated, as well as for untreated human chondrocytes, cultivated in alginate beads. This represented 53% of all expressed chondrocyte genes as based on statistical considerations. Side by side comparisons of differential display patterns originating from two different donor tissues yielded 44 reproducibly, differentially-displayed cDNA fragments, which were subcloned and sequenced. Sequence homology searches revealed sequence identities to the human necrosis factor α (TNF-α) and IL-1 regulated gene TSG-6, fibronectin, osteopontin, calnexin, and the DNA repair enzyme ERCC5. The differential expression was confirmed with Northern and quantitative PCR analyses. The known function of these genes and their known IL-1 responsiveness indicate that the employed model system reflects the pleiotropic effects of IL-1 on the overall gene expression in human articular chondrocytes and identifies genes involved in very different biochemical pathways. Twenty-seven cDNAs lacked sequence homologies to known genes and may represent novel genes

Chronic Activation of Hepatic Nrf2 Has No Major Effect on Fatty Acid and Glucose Metabolism in Adult Mice

The transcription factor NF-E2-related factor 2 (Nrf2) induces cytoprotective genes, but has also been linked to the regulation of hepatic energy metabolism. In order to assess the pharmacological potential of hepatic Nrf2 activation in metabolic disease, Nrf2 was activated over 7 weeks in mice on Western diet using two different siRNAs against kelch-like ECH-associated protein 1 (Keap1), the inhibitory protein of Nrf2. Whole genome expression analysis followed by pathway analysis demonstrated successful knock-down of Keap1 expression and induction of Nrf2-dependent genes involved in anti- oxidative stress defense and biotransformation, proving the activation of Nrf2 by the siRNAs against Keap1. Neither the expression of fatty acid- nor carbohydrate-handling proteins was regulated by Keap1 knock-down. Metabolic profiling of the animals did also not show effects on plasma and hepatic lipids, energy expenditure or glucose tolerance. The data indicate that hepatic Keap1/Nrf2 is not a major regulator of glucose or lipid metabolism in mice

Comparative Analysis of US Community Solar Initiatives: Recommendations for the City of Detroit

Like many cities across the United States, Detroit, Michigan, is facing compounding challenges due to global climate change. Detroit is highly vulnerable to the impacts of climate change and is already experiencing the effects, including flooding and rising temperatures. The City of Detroit Office of Sustainability seeks tools and strategies for the accelerated development of solar energy to meet greenhouse gas reduction goals set forth in the Detroit Climate Strategy and mitigate the effects of climate change for Detroit residents. This report informs and contributes to Detroit’s clean energy transition by highlighting existing community solar programs in Michigan, California, New York, and Illinois, and providing focused recommendations from these case studies that can be applied to the Detroit context. Additionally, local community stakeholder perspectives are shared to inform on an equitable and just energy transition. Through extensive online research, interviews, and stakeholder engagement, we compiled case studies and recommendations for the successful, expedient, and just implementation of solar energy in Detroit. Finally, we conducted a cost-benefit analysis of the Detroit Solar Neighborhood Initiative, a city-owned solar development project that is expected to generate 55 MW of renewable energy, to offset all 127 municipally owned buildings, and improve air quality and health outcomes for residents. This report finds that solar-specific policy initiatives, extensive community engagement paired with benefits, and a focus on energy affordability for low-income communities are key indicators for effective and equitable solar energy projects.Master of Science (MS)School for Environment and SustainabilityUniversity of Michiganhttp://deepblue.lib.umich.edu/bitstream/2027.42/193031/1/Comparative Analysis of US Community Solar Initiatives Warren Gunn.pdfDescription of Comparative Analysis of US Community Solar Initiatives Warren Gunn.pdf : Master's Project Full Documen

Correction: Chronic Activation of Hepatic Nrf2 Has No Major Effect on Fatty Acid and Glucose Metabolism in Adult Mice.

[This corrects the article DOI: 10.1371/journal.pone.0166110.]

Inhibition of citrate cotransporter Slc13a5/mINDY by RNAi improves hepatic insulin sensitivity and prevents diet-induced non-alcoholic fatty liver disease in mice

Objective: Non-alcoholic fatty liver disease is a world-wide health concern and risk factor for cardio-metabolic diseases. Citrate uptake modifies intracellular hepatic energy metabolism and is controlled by the conserved sodium-dicarboxylate cotransporter solute carrier family 13 member 5 (SLC13A5, mammalian homolog of INDY: mINDY). In Drosophila melanogaster and Caenorhabditis elegans INDY reduction decreased whole-body lipid accumulation. Genetic deletion of Slc13a5 in mice protected from diet-induced adiposity and insulin resistance. We hypothesized that inducible hepatic mINDY inhibition should prevent the development of fatty liver and hepatic insulin resistance. Methods: Adult C57BL/6J mice were fed a Western diet (60% kcal from fat, 21% kcal from carbohydrate) ad libitum. Knockdown of mINDY was induced by weekly injection of a chemically modified, liver-selective siRNA for 8 weeks. Mice were metabolically characterized and the effect of mINDY suppression on glucose tolerance as well as insulin sensitivity was assessed with an ipGTT and a hyperinsulinemic-euglycemic clamp. Hepatic lipid accumulation was determined by biochemical measurements and histochemistry. Results: Within the 8 week intervention, hepatic mINDY expression was suppressed by a liver-selective siRNA by over 60%. mINDY knockdown improved hepatic insulin sensitivity (i.e. insulin-induced suppression of endogenous glucose production) of C57BL/6J mice in the hyperinsulinemic-euglycemic clamp. Moreover, the siRNA-mediated mINDY inhibition prevented neutral lipid storage and triglyceride accumulation in the liver, while we found no effect on body weight. Conclusions: We show that inducible mINDY inhibition improved hepatic insulin sensitivity and prevented diet-induced non-alcoholic fatty liver disease in adult C57BL6/J mice. These effects did not depend on changes of body weight or body composition. Keywords: INDY/Slc13a5, siRNA, Insulin resistance, Steatosis, Citrate transport, Lipid accumulatio

Characterization of RA839, a noncovalent small molecule binder to Keap1 and selective activator of Nrf2 signaling

The activation of the transcription factor NF-E2-related factor 2 (Nrf2) maintains cellular homeostasis in response to oxidative stress by the regulation of multiple cytoprotective genes. Without stressors, the activity of Nrf2 is inhibited by its interaction with the Keap1 (kelch-like ECH-associated protein 1). Here, we describe (3S)-1-[4-[(2,3,5,6-tetramethylphenyl) sulfonylamino]-1-naphthyl]pyrrolidine-3-carboxylic acid (RA839), a small molecule that binds noncovalently to the Nrf2-interacting kelch domain of Keap1 with a Kd of ∼6 μm, as demonstrated by x-ray co-crystallization and isothermal titration calorimetry. Whole genome DNA arrays showed that at 10 μm RA839 significantly regulated 105 probe sets in bone marrow-derived macrophages. Canonical pathway mapping of these probe sets revealed an activation of pathways linked with Nrf2 signaling. These pathways were also activated after the activation of Nrf2 by the silencing of Keap1 expression. RA839 regulated only two genes in Nrf2 knock-out macrophages. Similar to the activation of Nrf2 by either silencing of Keap1 expression or by the reactive compound 2-cyano-3,12-dioxooleana-1,9-dien-28-oic acid methyl ester (CDDO-Me), RA839 prevented the induction of both inducible nitric-oxide synthase expression and nitric oxide release in response to lipopolysaccharides in macrophages. In mice, RA839 acutely induced Nrf2 target gene expression in liver. RA839 is a selective inhibitor of the Keap1/Nrf2 interaction and a useful tool compound to study the biology of Nrf2

Hepatic transcriptomic signatures of statin treatment are associated with impaired glucose homeostasis in severely obese patients

International audienceBACKGROUND: Clinical data identified an association between the use of HMG-CoA reductase inhibitors (statins) and incident diabetes in patients with underlying diabetes risk factors such as obesity, hypertension and dyslipidemia. The molecular mechanisms however are unknown.METHODS: An observational cross-sectional study included 910 severely obese patients, mean (SD) body mass index (BMI) 46.7 (8.7), treated with or without statins (ABOS cohort: a biological atlas of severe obesity). Data and sample collection took place in France between 2006 and 2016. Transcriptomic signatures of statin treatment in human liver obtained from genome-wide transcriptomic profiling of five different statin drugs using microarrays were correlated to clinico-biological phenotypes and also assigned to biological pathways and mechanisms. Patients from the non-statin-users group were matched to patients in the statin users group by propensity score analysis to minimize confounding effects from age, gender, parental familial history of diabetes, BMI, waist circumference, systolic and diastolic blood pressure and use of anti-hypertensive drugs as pre-specified covariates.RESULTS: We determined the hepatic, statin-related gene signature from genome-wide transcriptomic profiling in severely obese patients with varying degrees of glucose tolerance and cardio-metabolic comorbidities. One hundred and fifty seven patients on statin treatment in the matched cohort showed higher diabetes prevalence (OR = 2.67; 95%CI, 1.60-4.45; P = 0.0002) and impairment of glucose homeostasis. This phenotype was associated with molecular signatures of increased hepatic de novo lipogenesis (DNL) via activation of sterol regulatory element-binding protein 1 (SREBP1) and concomitant upregulation of the expression of key genes in both fatty acid and triglyceride metabolism.CONCLUSIONS: A DNL gene activation profile in response to statins is associated with insulin resistance and the diabetic status of the patients. Identified molecular signatures thus suggest that statin treatment increases the risk for diabetes in humans at least in part via induction of DNL.TRIAL REGISTRATION: NCT01129297 . Registered May 242,010 (retrospectively registered)

Vienne-Prague

Ce numéro double propose une histoire culturelle des relations austro-tchécoslovaques au XXe siècle, à la lumière de figures d’intellectuels et de médiateurs culturels ayant favorisé les transferts culturels entre Vienne et Prague, notamment Thomas Masaryk, les écrivains du Cercle de Prague, Leoš Janáček, Adolf Loos, Richard Teschner, Jiří Gruša, ainsi que trois revues : Musikblätter des Anbruch, Prager Presse et Wir und Sie im Herzen Europas