GFI1B acts as a metabolic regulator in hematopoiesis and acute myeloid leukemia.

Recent studies highlighted the role of transcription factors in metabolic regulation during hematopoiesis and leukemia development. GFI1B is a transcriptional repressor that plays a critical role in hematopoiesis, and its expression is negatively related to the prognosis of acute myeloid leukemia (AML) patients. We earlier reported a change in the metabolic state of hematopoietic stem cells upon Gfi1b deletion. Here we explored the role of Gfi1b in metabolism reprogramming during hematopoiesis and leukemogenesis. We demonstrated that Gfi1b deletion remarkably activated mitochondrial respiration and altered energy metabolism dependence toward oxidative phosphorylation (OXPHOS). Mitochondrial substrate dependency was shifted from glucose to fatty acids upon Gfi1b deletion via upregulating fatty acid oxidation (FAO). On a molecular level, Gfi1b epigenetically regulated multiple FAO-related genes. Moreover, we observed that metabolic phenotypes evolved as cells progressed from preleukemia to leukemia, and the correlation between Gfi1b expression level and metabolic phenotype was affected by genetic variations in AML cells. FAO or OXPHOS inhibition significantly impeded leukemia progression of Gfi1b-KO MLL/AF9 cells. Finally, we showed that Gfi1b-deficient AML cells were more sensitive to metformin as well as drugs implicated in OXPHOS and FAO inhibition, opening new potential therapeutic strategies.

Dexamethasone-mediated inhibition of Notch signalling blocks the interaction of leukaemia and mesenchymal stromal cells.

Acute myeloid leukaemia (AML) is a haematological malignancy characterized by a poor prognosis. Bone marrow mesenchymal stromal cells (BM MSCs) support leukaemic cells in preventing chemotherapy-induced apoptosis. This encouraged us to investigate leukaemia-BM niche-associated signalling and to identify signalling cascades supporting the interaction of leukaemic cells and BM MSC. Our study demonstrated functional differences between MSCs originating from leukaemic (AML MSCs) and healthy donors (HD MSCs). The direct interaction of leukaemic and AML MSCs was indispensable in influencing AML cell proliferation. We further identified an important role for Notch expression and its activation in AML MSCs contributing to the enhanced proliferation of AML cells. Supporting this observation, overexpression of the intracellular Notch domain (Notch ICN) in AML MSCs enhanced AML cells' proliferation. From a therapeutic point of view, dexamethasone treatment impeded Notch signalling in AML MSCs resulting in reduced AML cell proliferation. Concurrent with our data, Notch inhibitors had only a marginal effect on leukaemic cells alone but strongly influenced Notch signalling in AML MSCs and abrogated their cytoprotective function on AML cells. In vivo, dexamethasone treatment impeded Notch signalling in AML MSCs leading to a reduced number of AML MSCs and improved survival of leukaemic mice. In summary, targeting the interaction of leukaemic cells and AML MSCs using dexamethasone or Notch inhibitors might further improve treatment outcomes in AML patients.

Quantitative studies and taste reconstitution experiments of the sour and lingering mouthful orosensation in a debittered extract of traditional Japanese dried and fermented skipjack tuna (hongarebushi).

Hongarebushi, Japanese dried skipjack tuna and a high quality ingredient of Japanese dashi, was investigated for its taste active composition. The recent investigation focused on a debittered fish fraction, which revealed a strong umami and salt impact accompanied with a pleasant and pronounced sourness. Whereas the umami and salt tastes could be correlated to monosodium glutamate (MSG), ribonucleotides, and mineral salts, the pleasant sourness was not exclusively induced by organic acids. The essential compound imparting the sour orosensation, persistence, and mouthfulness of the debittered skipjack tuna extract was investigated, and omission experiments emphasized the impact of N-acetylglutamic acid (NAG) on the overall taste sensation of the debittered fish extract. This metabolite, which is known to be present as a minor constituent in animal- and plant-derived foods, was quantified in this study for the first time in seafood, soybean products, dried shiitake mushrooms, and dried fish in notable amounts. Furthermore, it was described for the first time as an essential taste contributor to the nonvolatile profile of a foodstuff, in this case of a debittered extract of hongarebushi.

New developments in umami (enhancing) molecules.

As health has become one of the main drivers in nutrition, the scientific interest in taste receptors and taste molecules has increased considerably. Academia as well as flavor and food companies are searching for molecules that make food more healthy but not less appetizing. In the savory area, salt and umami taste are being investigated. This review deals with the progress made in umami tasting molecules. Umami taste has been known as a separate taste for a long time in Asian countries and has been generally accepted as the fifth basic taste in the last decade of the previous century. In this review, first the current level of understanding of the umami receptors will be described. The main part of the paper will deal with the umami-tasting molecules that have been published recently, including the work that has been performed within Givaudan itself. Lactoyl amides of GMP (guanosine monophosphate) appeared to have remarkably strong umami-tasting properties.