The resurgence of research into cancer metabolism has recently broadened interests beyond glucose and the Warburg effect to other nutrients, including glutamine. Because oncogenic alterations of metabolism render cancer cells addicted to nutrients, pathways involved in glycolysis or glutaminolysis could be exploited for therapeutic purposes. In this Review, we provide an updated overview of glutamine metabolism and its involvement in tumorigenesis in vitro and in vivo, and explore the recent potential applications of basic science discoveries in the clinical setting.

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From Krebs to clinic: glutamine metabolism to cancer therapy.

This review encompasses the most important advances in liver functions and hepatotoxicity and analyzes which mechanisms can be studied in vitro. In a complex architecture of nested, zonated lobules, the liver consists of approximately 80 % hepatocytes and 20 % non-parenchymal cells, the latter being involved in a secondary phase that may dramatically aggravate the initial damage. Hepatotoxicity, as well as hepatic metabolism, is controlled by a set of nuclear receptors (including PXR, CAR, HNF-4α, FXR, LXR, SHP, VDR and PPAR) and signaling pathways. When isolating liver cells, some pathways are activated, e.g., the RAS/MEK/ERK pathway, whereas others are silenced (e.g. HNF-4α), resulting in up- and downregulation of hundreds of genes. An understanding of these changes is crucial for a correct interpretation of in vitro data. The possibilities and limitations of the most useful liver in vitro systems are summarized, including three-dimensional culture techniques, co-cultures with non-parenchymal cells, hepatospheres, precision cut liver slices and the isolated perfused liver. Also discussed is how closely hepatoma, stem cell and iPS cell-derived hepatocyte-like-cells resemble real hepatocytes. Finally, a summary is given of the state of the art of liver in vitro and mathematical modeling systems that are currently used in the pharmaceutical industry with an emphasis on drug metabolism, prediction of clearance, drug interaction, transporter studies and hepatotoxicity. One key message is that despite our enthusiasm for in vitro systems, we must never lose sight of the in vivo situation. Although hepatocytes have been isolated for decades, the hunt for relevant alternative systems has only just begun.

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Recent advances in 2D and 3D in vitro systems using primary hepatocytes, alternative hepatocyte sources and non-parenchymal liver cells and their use in investigating mechanisms of hepatotoxicity, cell signaling and ADME.

Body size and tissue respiration

Enzyme secretion and the incorporation of p32 into phospholipides of pancreas slices

Publisher Summary It is now recognized that a number of factors can influence the uptake of glucose by muscle. Some are of physiological importance and these include hormones, notably insulin, growth hormone, corticosteroids, and adrenaline and possibly thyroxine and glucagon, and nonhormonal factors such as the availability of oxygen, the contractile activity of the tissue, the concentration of glucose in extracellular water, arid the availability for respiration of other substrates, such as ketone bodies and fatty acids. Other factors that influence glucose uptake arc of interest because of their hypoglycemic effects in diabetic patients and animals, notably salicylate and 2 ,4-dinitrophenol. The uptake of glucose by muscle is a complex process, which is thought to involve, in sequence, passage of the sugar from capillaries to the muscle cell membrane, transfer across the cell membrane, and metabolism within the cell by multienzyme systems with their various cofactors.

Regulation of Glucose Uptake by Muscle

Das Hauptergebnis dieser Arbeit ist die Auffindung des Weges, auf dem im tierischen Organismus die Synthese des Harnstoffs aus Ammoniak und Kohlensaure verlauft. Die Harnstoffsynthese ist an das Vorhandensein von Ornithin gebunden, ohne das Ornithin in der Bilanz der Synthese verbraucht wird. Ornithin, Ammoniak und Kohlensaure treten unter Wasseraustritt zu einer Guanidinoverbindung — dem Arginin — zusammen [Reaktion (1)]. Arginin spaltet durch die Wirkungder Arginase Harnstoffab [Reaktion (2)] und liefert Ornithin zuruck, das wieder fur Reaktion (1) zur Verfugung steht.

Untersuchungen uber die Harnstoffbildung im Tierkörper

Untersuchungen über den Stoffwechsel der Aminosäuren im Tierkörper. Mit 2 Figuren im Text.

Untersuchungen über die Harnstoffbildung im Tierkörper

Über das Kupfer im Menschlichen Blutserum

Es wird auf die allgemeine Bedeutung des Problems des Stoffaustausches zwischen Blut und Liquor hingewiesen. Der heutige Standpunkt sieht den Mechanismus der Permeabilitat der Meningen im wesentlichen in einer vitalen („Schutz“-) Funktion des Plexus chorioideus. Es werden neuere physiko-chemische Gesichtspunkte, speziell dieDonnansche Theorie der Membrangleichgewichte fur die Frage des Stoffaustausches zwischen Blut und Liquor herangezogen. Das Blut-Liquor-System wird in Vergleich gesetzt mit einem Modellsystem, indem eine semipermeable Membran eine eiweisreiche von einer eiweisfreien Flussigkeit trennt. Aus dieser Betrachtungsweise ergeben sich fur die Permeabilitat der Meningen folgende Fragen als Problemstellung: Permeieren vom Blut in den Liquor Anionen besser als Kationen und krystalloide besser als kolloide Elektrolyte? Das Arbeitsprogramm fur die Verfolgung dieser Fragen im Tierexperiment wird kurz umrissen.

Hans Adolf Krebs

Papers

Untersuchungen uber die Harnstoffbildung im Tierkörper

Untersuchungen über den Stoffwechsel der Aminosäuren im Tierkörper. Mit 2 Figuren im Text.

Untersuchungen über die Harnstoffbildung im Tierkörper

Über das Kupfer im Menschlichen Blutserum

Studien zur Permeabilität der Meningen unter besonderer Berücksichtigung physikalisch-chemischer Gesichtspunkte