Blood glucose-lowering nuclear receptor agonists only partially normalize hepatic gene expression in db/db mice

ABSTRACT Agonists of the nuclear receptors peroxisome proliferator-activated receptor (PPAR) ␥, PPAR␣, and liver X receptors (LXRs) reduce blood glucose in type 2 diabetic patients and comparable mouse models. Since the capacity of these drugs to normalize hepatic gene expression is not known, we compared groups of obese diabetic db/db mice treated with agonists for PPAR␥ [rosiglitazone (Rosi); 10 mg/kg/day], PPAR␣ [Wy 14643 (Wy; 4-chloro-6 -(2,3-xylidino)-2-pyrimidinyl)thioacetic acid); 30 mg/kg/day], and LXR [T0901317 (T09; N-(2,2,2-trifluoroethyl)-N-[4-[2,2,2-trifluoro-1-hydroxy-1(trifluoromethyl)-ethyl]phenyl]-benzenesulfonamide) ; 40 mg/kg/day] and from untreated nondiabetic litter mates (db/ϩ) by oligonucleotide microarrays and quantitative reverse transcriptase-polymerase chain reaction. The 10-day treatment period of db/db mice with Rosi, Wy, and T09 altered expression of 300, 620, and 735 genes including agonist-specific target genes, respectively. However, from the 337 genes differentially regulated in untreated db/ϩ versus db/db animals, only 34 (10%), 51 (15%), and 82 (24%) were regulated in the direction of the db/ϩ group by Rosi, Wy, and T09, respectively. Gene expression normalization by drug treatment involved glucose homeostasis, lipid homeostasis, and local glucocorticoid activation. In addition, our data pointed to hitherto unknown interference of these nuclear receptors with growth hormone receptor gene expression and endoplasmic reticulum stress. However, many diabetes-associated gene alterations remained unaffected or were even aggravated by nuclear receptor agonist treatment. These results suggest that diabetes-induced gene expression is minimally reversed by potent blood glucose-lowering nuclear receptor agonists

The active metabolite of leflunomide, A77 1726, interferes with dendritic cell function

Leflunomide, a potent disease-modifying antirheumatic drug used in the treatment of rheumatoid arthritis (RA), exhibits anti-inflammatory, antiproliferative and immunosuppressive effects. Although most of the beneficial effects of leflunomide have been attributed to its antimetabolite activity, mainly in T cells, other targets accounting for its potency might still exist. Because of mounting evidence for a prominent role of dendritic cells (DCs) in the initiation and maintenance of the immune response in RA, we analyzed the effect of the active metabolite of leflunomide (A77 1726; LEF-M) on phenotype and function of human myleloid DCs at several stages in their life cycle. Importantly, DCs differentiated in the presence of LEF-M exhibited an altered phenotype, with largely reduced surface expression of the critical co-stimulatory molecules CD40 and CD80. Furthermore, treatment of DCs during the differentiation or maturation phase with LEF-M aborted successful DC maturation. Exogenous addition of uridine revealed that DC modulation by LEF-M was independent of its proposed ability as an antimetabolite. In addition, the ability of DCs to initiate T-cell proliferation and to produce the proinflammatory cytokines IL-12 and tumour necrosis factor-α was markedly impaired by LEF-M treatment. As a molecular mechanism, transactivation of nuclear factor-κB, an transcription factor essential for proper DC function, was completely suppressed in DCs treated with LEF-M. These data indicate that interference with several aspects of DC function could significantly contribute to the beneficial effects of leflunomide in inflammatory diseases, including RA

TOPCAT and Gaia

TOPCAT, and its command line counterpart STILTS, are powerful tools for working with large source catalogues. ESA's Gaia mission, most recently with its second data release, is producing source catalogues of unprecedented quality for more than a billion sources. This paper presents some examples of how TOPCAT and STILTS can be used for analysis of Gaia data.Comment: 4 pages, 2 figures; to appear in the Proceedings of ADASS 2018, Astronomical Society of the Pacific (ASP) Conference Serie

100 years of inherited metabolic disorders in Austria-A national registry of minimal birth prevalence, diagnosis, and clinical outcome of inborn errors of metabolism in Austria between 1921 and 2021

Inherited metabolic disorders (IMDs) are a heterogeneous group of rare disorders characterized by disruption of metabolic pathways. To date, data on incidence and prevalence of IMDs are limited. Taking advantage of a functioning network within the Austrian metabolic group, our registry research aimed to update the data of the "Registry for Inherited Metabolic Disorders" started between 1985 and 1995 with retrospectively retrieved data on patients with IMDs according to the Society for the Study of Inborn Errors of Metabolism International Classification of Diseases 11 (SSIEM ICD11) catalogue. Included in this retrospective register were 2631 patients with an IMD according to the SSIEM ICD11 Classification, who were treated in Austria. Thus, a prevalence of 1.8/10 000 for 2020 and a median minimal birth prevalence of 16.9/100 000 (range 0.7/100 000-113/100 000) were calculated for the period 1921 to February 2021. We detected a male predominance (m:f = 1.2:1) and a mean age of currently alive patients of 17.6 years (range 5.16 months-100 years). Most common diagnoses were phenylketonuria (17.7%), classical galactosaemia (6.6%), and biotinidase deficiency (4.2%). The most common diagnosis categories were disorders of amino acid and peptide metabolism (819/2631; 31.1%), disorders of energy metabolism (396/2631; 15.1%), and lysosomal disorders (395/2631; 15.0%). In addition to its epidemiological relevance, the "Registry for Inherited Metabolic Disorders" is an important tool for enhancing an exchange between care providers. Moreover, by pooling expertise it prospectively improves patient treatment, similar to pediatric oncology protocols. A substantial requirement for ful filling this goal is to regularly update the registry and provide nationwide coverage with inclusion of all medical specialties

Glucocorticoids Attenuate T Cell Receptor Signaling

Glucocorticoids (GCs) affect peripheral immune responses by inhibiting T cell immunity at several stages of the activation cascade, causing impaired cytokine production and effector function. The recent demonstration that the thymic epithelium and possibly thymocytes themselves produce steroids suggests that endogenous GCs also play a role in the control of T cell development. As both peripheral responsiveness and thymic differentiation appear to be regulated by the quantity and quality of intracellular signals issued by antigen–major histocompatibility complex-engaged T cell receptor (TCR) complexes, we investigated the effects of GCs on the signaling properties of T cells stimulated by anti-CD3 monoclonal antibodies or agonist peptides. We demonstrate in this work that dexamethasone, a synthetic GC, inhibits the early signaling events initiated upon TCR ligation, such as tyrosine phosphorylation of several TCR-associated substrates including the ζ chain, the ZAP70 kinase, and the transmembrane adapter molecule linker for activation of T cells. Hypophosphorylation was not a consequence of reduced kinase activity of src protein tyrosine kinases, but was correlated with an altered- membrane compartmentalization of these molecules. These observations indicate that in addition to their well-described ability to interfere with the transcription of molecules involved in peripheral responses, GCs inhibit T cell activation by affecting the early phosphorylating events induced after TCR ligation

The Comprehensive Native Interactome of a Fully Functional Tagged Prion Protein

The enumeration of the interaction partners of the cellular prion protein, PrPC, may help clarifying its elusive molecular function. Here we added a carboxy proximal myc epitope tag to PrPC. When expressed in transgenic mice, PrPmyc carried a GPI anchor, was targeted to lipid rafts, and was glycosylated similarly to PrPC. PrPmyc antagonized the toxicity of truncated PrP, restored prion infectibility of PrPC-deficient mice, and was physically incorporated into PrPSc aggregates, indicating that it possessed all functional characteristics of genuine PrPC. We then immunopurified myc epitope-containing protein complexes from PrPmyc transgenic mouse brains. Gentle differential elution with epitope-mimetic decapeptides, or a scrambled version thereof, yielded 96 specifically released proteins. Quantitative mass spectrometry with isotope-coded tags identified seven proteins which co-eluted equimolarly with PrPC and may represent component of a multiprotein complex. Selected PrPC interactors were validated using independent methods. Several of these proteins appear to exert functions in axomyelinic maintenance

Journal für Klinische Endokrinologie und Stoffwechsel / Lysosomale Speicherkrankheiten im Erwachsenenalter

Lysosomale Speicherkrankheiten (LSD) sind angeborene Erkrankungen, die zu einer Speicherung von nicht abbaubarem Material in den Lysosomen verschiedenster Zelltypen führen. Wenn auch einzelne LSD sehr selten sein können, so liegt die gesamte Inzidenz bei 1:8000 Lebendgeborenen. Trotz der prinzipiell gemeinsamen Pathogenese ist das klinische Bild sehr heterogen. So finden sich Vergrößerungen von Leber und/oder Milz wie beim M. Gaucher oder beim lysosomalen sauren Lipase-Mangel (LAL-D), Veränderungen am Skelettsystem wie bei den Mukopolysaccharidosen (MPS) und oft zentralnervöse Störungen wie bei verschiedenen Arten von Sphingolipidosen und MPS. Da die Speicherung oft Jahre benötigt, werden viele LSD erst im Erwachsenenalter klinisch manifest. Obwohl die Defekte angeboren sind, gibt es für einige LSD wirksame Therapien. In der Enzymersatztherapie wird das fehlende Enzym in einer rekombinanten Form verabreicht. Die Substratreduktion reduziert die Produktion der sich ansammelnden Stoffe. Zuletzt war auch die pharmakologische Chaperon-Therapie erfolgreich, die defekte Enzyme stabilisiert und damit deren vorzeitigen Abbau verhindert. Die Behandlung der zentralnervösen Veränderungen ist bis heute eine große Herausforderung.Lysosomal storage diseases (LSD) are congenital disorders leading to the accumulation of undegradable material in lysosomes of different cell types. Even though individual LSD may be very rare, they sum up to an incidence of about 1:8000 live births. Despite the common principal pathogenesis, LSD are quite heterogeneous diseases. Some LSD, such as Gauchers disease oder lysosomal acid lipase deficiency (LAL-D), present with enlargements of the liver and/or spleen, skeletal alterations as in mucopolysaccharidoses (MPS), and often central nervous changes as in various types of sphingolipidoses and MPS. Since accumulation of materials may take years, a number of LSD may not become clinically apparent before adulthood. Although LSD are genetic disorders, effective therapies exist for some of them. In enzyme replacement therapy (ERT), a recombinant form of the missing enzyme is given; substrate reduction therapy reduces the production of accumulating molecules. Recently, pharmacological chaperone therapy turned out to be successful as well by stabilizing defective enzyme and protecting them from premature degradation. Effective treatment of central nervous system alterations remains a major therapeutic challenge in many LSD.(VLID)365283