The Postcranial Skeleton of an Exceptionally Complete Individual of the Plated Dinosaur Stegosaurus stenops (Dinosauria: Thyreophora) from the Upper Jurassic Morrison Formation of Wyoming, U.S.A.

Copyright: © 2015 Maidment et al. This is an open access article distributed under the terms of the Creative Commons Attribution License [4.0], which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. The attached file is the published version of the article

Ibudilast, a Pharmacologic Phosphodiesterase Inhibitor, Prevents Human Immunodeficiency Virus-1 Tat-Mediated Activation of Microglial Cells

Human Immunodeficiency Virus-1 (HIV-1)-associated neurocognitive disorders (HAND) occur, in part, due to the inflammatory response to viral proteins, such as the HIV-1 transactivator of transcription (Tat), in the central nervous system (CNS). Given the need for novel adjunctive therapies for HAND, we hypothesized that ibudilast would inhibit Tat-induced excess production of pro-inflammatory cytokines, such as tumor necrosis factor-alpha (TNFα) in microglial cells. Ibudilast is a non-selective cyclic AMP phosphodiesterase inhibitor that has recently shown promise as a treatment for neuropathic pain via its ability to attenuate glial cell activation. Accordingly, here we demonstrate that pre-treatment of both human and mouse microglial cells with increasing doses of ibudilast inhibited Tat-induced synthesis of TNFα by microglial cells in a manner dependent on serine/threonine protein phosphatase activity. Ibudilast had no effect on Tat-induced p38 MAP kinase activation, and blockade of adenosine A2A receptor activation did not reverse ibudilast's inhibition of Tat-induced TNFα production. Interestingly, ibudilast reduced Tat-mediated transcription of TNFα, via modulation of nuclear factor-kappa B (NF-κB) signaling, as shown by transcriptional activity of NF-κB and analysis of inhibitor of kappa B alpha (IκBα) stability. Together, our findings shed light on the mechanism of ibudilast's inhibition of Tat-induced TNFα production in microglial cells and may implicate ibudilast as a potential novel adjunctive therapy for the management of HAND

IL-12 as a therapeutic target for pharmacological modulation in immune-mediated and inflammatory diseases: regulation of T helper 1/T helper 2 responses

1. Interleukin-12 (IL-12) is a pivotal cytokine in driving the immune system towards a T helper (Th)1 type response and preventing a Th2 type immune profile. Therefore, IL-12 is indispensable in the defense against certain, mainly intracellular pathogens, but overproduction of this cytokine is crucially involved in the etiology of several inflammatory and autoimmune diseases. 2. Hence, IL-12 is an ideal target for pharmacological intervention in the therapy of autoimmune and inflammatory diseases. 3. The production of IL-12 and a resultant Th1 type immune response can be suppressed with several pharmacological approaches including modulation of intracellular cyclic AMP levels, glucocorticoids and nuclear factor-κB inhibition. IL-12 responsiveness may be inhibited using anti-IL-12 antibodies, soluble IL-12 receptors or the IL-12 p40 homodimer. 4. Exploitation of these approaches may provide novel means for the experimental therapy of a variety of pathophysiological states

Mitochondrial tumour suppressors: A genetic and biochemical update

Since the discovery 5 years ago that the D-subunit of succinate dehydrogenase ( SDHD) can behave as a classic tumour suppressor, other nuclear-encoded mitochondrial proteins (SDHB, SDHC and fumarate hydratase) have been implicated in tumour susceptibility. Mutations in these proteins are principally involved in familial predisposition to benign tumours, but the spectrum of inherited lesions is increasingly recognized to include malignant tumours, such as malignant phaeochromocytomas and renal cell carcinomas. Here we review recent advances in the field of mitochondrial tumour suppressors, the biochemical pathway that links mitochondrial dysfunction with tumorigenesis, and potential therapeutic approaches to these malignancies