Hedgehog-mediated regulation of PPARγ controls metabolic patterns in neural precursors and shh-driven medulloblastoma

Sonic hedgehog (Shh) signaling is critical during development and its aberration is common across the spectrum of human malignancies. In the cerebellum, excessive activity of the Shh signaling pathway is associated with the devastating pediatric brain tumor medulloblastoma. We previously demonstrated that exaggerated de novo lipid synthesis is a hallmark of Shh-driven medulloblastoma and that hedgehog signaling inactivates the Rb/E2F tumor suppressor complex to promote lipogenesis. Indeed, such Shh-mediated metabolic reprogramming fuels tumor progression, in an E2F1- and FASN-dependent manner. Here, we show that the nutrient sensor PPARγ is a key component of the Shh metabolic network, particularly its regulation of glycolysis. Our data show that in primary cerebellar granule neural precursors (CGNPs), proposed medulloblastoma cells-of-origin, Shh stimulation elicits a marked induction of PPARγ alongside major glycolytic markers. This is also documented in the actively proliferating Shh-responsive CGNPs in the developing cerebellum, and PPARγ expression is strikingly elevated in Shh-driven medulloblastoma in vivo. Importantly, pharmacological blockade of PPARγ and/or Rb inactivation inhibits CGNP proliferation, drives medulloblastoma cell death and extends survival of medulloblastoma-bearing animals in vivo. This coupling of mitogenic Shh signaling to a major nutrient sensor and metabolic transcriptional regulator define a novel mechanism through which Shh signaling engages the nutrient sensing machinery in brain cancer, controls the cell cycle, and regulates the glycolytic index. This also reveals a dominant role of Shh in the etiology of glucose metabolism in medulloblastoma and underscores the function of the Shh → E2F1 → PPARγ axis in altering substrate utilization patterns in brain cancers in favor of tumor growth. These findings emphasize the value of PPARγ downstream of Shh as a global therapeutic target in hedgehog-dependent and/or Rb-inactivated tumors

A review of inhibitors for the corrosion of transition metals in aqueous acids

The importance of the electrical double layer at the interface between a metal and an acid electrolyte together with its interaction with organic and inorganic molecules to produce initially electrostatic adsorption are highlighted. In some cases, a chemical bond is formed involving charge transfer or charge sharing between the metal surface and inhibitor molecules forming a coordinate bond through lone-pair electrons on heteroatoms or π electrons on inhibitors with multiple and aromatic bonds. The application of mathematical formulae to the variation in adsorbed inhibitor molecules at the metal surface is considered, with inhibitor concentration isotherms considering thermodynamic principles or the water displacement reaction where for an inhibitor molecule to adsorb at a metal surface several water molecules must be displaced first. The predominant ways in which molecules enable inhibition are formation of a physical barrier where a physical adsorbed barrier of molecules (usually polymeric or oxide promoting for this mode to predominant) impede movement near the metal surface or reduction in metal reactivity where chemisorbed inhibitor molecules adhere to active sites on the metals reducing the number of cathodic and anodic sites. Adsorption involving charged inhibitor species causes a change in the double layer and the potential at the outer Helmholtz plane, influencing the corrosion rates of both anodic and cathodic reactions. The first three modes are intimately with adsorption and the double layer the last involves interaction of the inhibitor molecules and the intermediate products formed during the partial electrochemical reactions, interaction of the adsorbed intermediates with organic molecules can either decrease (inhibit) or increase (stimulate) electrode reaction rate depending on the stability of the inhibitor-intermediate complex formed.</p

The formation of nanostructured surfaces by electrochemical techniques : a range of emerging surface finishes – Part 1 : achieving nanostructured surfaces by electrochemical techniques

Emerging practice to realise nanostructured metallic coatings by electrodeposition, anodising and electrophoresis is considered. Conventional, aqueous electrolytes may be utilised in some cases if workpiece preparation and process conditions are well controlled. Such coatings can provide wear and corrosion resistance or a catalytic or high active area compared to more conventional coatings. An overview of the principles involved in deploying electrochemical techniques to produce nanostructured surfaces and factors influencing developments in this rapidly emerging field is given. The strategies, which can be adopted to electrodeposit nanostructured metallic coatings, include grain refinement, application of a pulsed current, inclusion of nanoparticles into the coating and the use of nanoporous templates. Part 2 will consider examples of nanostructured surfaces together with their potential applications

Opposite Regulation of CD36 Ubiquitination by Fatty Acids and Insulin: EFFECTS ON FATTY ACID UPTAKE*

FAT/CD36 is a membrane scavenger receptor that facilitates long chain fatty acid uptake by muscle. Acute increases in membrane CD36 and fatty acid uptake have been reported in response to insulin and contraction. In this study we have explored protein ubiquitination as one potential mechanism for the regulation of CD36 level. CD36 expressed in Chinese hamster ovary (CHO) or HEK 293 cells was found to be polyubiquitinated via a process involving both lysines 48 and 63 of ubiquitin. Using CHO cells expressing the insulin receptor (CHO/hIR) and CD36, it is shown that addition of insulin (100 nm, 10 and 30 min) significantly reduced CD36 ubiquitination. In contrast, ubiquitination was strongly enhanced by fatty acids (200 μm palmitate or oleate, 2 h). Similarly, endogenous CD36 in C2C12 myotubes was ubiquitinated, and this was enhanced by oleic acid treatment, which also reduced total CD36 protein in cell lysates. Insulin reduced CD36 ubiquitination, increased CD36 protein, and inhibited the opposite effects of fatty acids on both parameters. These changes were paralleled by changes in fatty acid uptake, which could be blocked by the CD36 inhibitor sulfosuccinimidyl oleate. Mutation of the two lysine residues in the carboxyl-terminal tail of CD36 markedly attenuated ubiquitination of the protein expressed in CHO cells and was associated with increased CD36 level and enhanced oleate uptake and incorporation into triglycerides. In conclusion, fatty acids and insulin induce opposite alterations in CD36 ubiquitination, modulating CD36 level and fatty acid uptake. Altered CD36 turnover may contribute to abnormal fatty acid uptake in the insulin-resistant muscle