A review on synthetic methods for 2-Deoxy-D-glucose

2-Deoxy-D-glucose (2-DG) is a non-metabolizable glucose analog that has shown promising pharmacological activities and has been used to study the role of glucose in cancer cells. 2-DG is an inhibitor of glycolysis, potential Energy Restriction Mimetic agent and inhibits pathogen-associated molecular patterns. Its radioisotope derivatives have application as tracers. Recently, 2-DG has been used as an anti-COVID-19 drug lowering the need for supplemental oxygen. In this review, different synthetic strategies for preparation of 2-DG including enzymatic synthesis have been discussed. The understanding of these methods would help in developing therapeutics or diagnostic agents aimed at exploring therapeutic targets related with energy metabolism. © AUTHOR(S).

Endothelial metabolism in pulmonary vascular homeostasis and acute respiratory distress syndrome.

Capillary endothelial cells possess a specialized metabolism necessary to adapt to the unique alveolar-capillary environment. Here, we highlight how endothelial metabolism preserves the integrity of the pulmonary circulation by controlling vascular permeability, defending against oxidative stress, facilitating rapid migration and angiogenesis in response to injury, and regulating the epigenetic landscape of endothelial cells. Recent reports on single-cell RNA-sequencing reveal subpopulations of pulmonary capillary endothelial cells with distinctive reparative capacities, which potentially offer new insight into their metabolic signature. Lastly, we discuss broad implications of pulmonary vascular metabolism on acute respiratory distress syndrome, touching on emerging findings of endotheliitis in coronavirus disease 2019 (COVID-19) lungs.

Clinical efficacy of eucaloric ketogenic nutrition in the COVID-19 cytokine storm: A retrospective analysis of mortality and intensive care unit admission.

OBJECTIVES: Our primary objective was to explore the effect of a eucaloric ketogenic diet (EKD) on mortality, admission to the intensive care unit, and need for non-invasive ventilation in hospitalized patients with COronaVIrus Disease 19 (COVID-19), in comparison to a eucaloric standard diet. Secondary objectives were verification of the safety and feasibility of the diet and its effects on inflammatory parameters, particularly interleukin-6. METHODS: The study is a retrospective analysis of 34 patients fed with an EKD in comparison to 68 patients fed with a eucaloric standard diet, selected and matched using propensity scores 1:2 to avoid the confounding effect of interfering variables. Our hypothesis was that an EKD would reduce mortality, admission to the intensive care unit, and need for non-invasive ventilation in patients with COVID-19. RESULTS: The preliminary multivariate analysis showed a statistically significant difference in survival (P = 0.046) and need for the intensive care unit (P = 0.049) for the EKD compared with a eucaloric standard diet. Even considering the EKD start day as a time-dependent variable, the results maintain a positive trend for application of the diet, and it is not possible to reject the null hypothesis (P < 0.05). Interleukin-6 concentrations between t0 and t7 (7 d after the beginning of the diet) in the ketogenic nutrition group show a trend that is almost significant (P = 0.062). The EKD was safe and no adverse events were observed. CONCLUSIONS: These results show a possible therapeutic role of an EKD in the clinical management of COVID-19. Currently, a prospective controlled randomized trial is running to confirm these preliminary data.

Flavonoids against the Warburg phenotype-concepts of predictive, preventive and personalised medicine to cut the Gordian knot of cancer cell metabolism.

The Warburg effect is characterised by increased glucose uptake and lactate secretion in cancer cells resulting from metabolic transformation in tumour tissue. The corresponding molecular pathways switch from oxidative phosphorylation to aerobic glycolysis, due to changes in glucose degradation mechanisms known as the 'Warburg reprogramming' of cancer cells. Key glycolytic enzymes, glucose transporters and transcription factors involved in the Warburg transformation are frequently dysregulated during carcinogenesis considered as promising diagnostic and prognostic markers as well as treatment targets. Flavonoids are molecules with pleiotropic activities. The metabolism-regulating anticancer effects of flavonoids are broadly demonstrated in preclinical studies. Flavonoids modulate key pathways involved in the Warburg phenotype including but not limited to PKM2, HK2, GLUT1 and HIF-1. The corresponding molecular mechanisms and clinical relevance of 'anti-Warburg' effects of flavonoids are discussed in this review article. The most prominent examples are provided for the potential application of targeted 'anti-Warburg' measures in cancer management. Individualised profiling and patient stratification are presented as powerful tools for implementing targeted 'anti-Warburg' measures in the context of predictive, preventive and personalised medicine.

Induction of ketosis as a potential therapeutic option to limit hyperglycemia and prevent cytokine storm in COVID-19.

The severe form of coronavirus disease 19 (COVID-19) is characterized by cytokine storm syndrome (CSS) and disseminated intravascular coagulation (DIC). Diabetes, obesity, and hypertension have, as minor common denominators, chronic low-grade inflammation and high plasma myeloperoxidase levels, which could be linked to pulmonary phagocytic hyperactivation and CSS. The hyperactivation of M1 macrophages with a proinflammatory phenotype, which is linked to aerobic glycolysis, leads to the recruitment of monocytes, neutrophils, and platelets from circulating blood and plays a crucial role in thrombo-inflammation (as recently demonstrated in COVID-19) through the formation of neutrophil extracellular traps and monocyte-platelet aggregates, which could be responsible for DIC. The modulation of glucose availability for activated M1 macrophages by means of a eucaloric ketogenic diet (EKD) could represent a possible metabolic tool for reducing adenosine triphosphate production from aerobic glycolysis in the M1 macrophage phenotype during the exudative phase. This approach could reduce the overproduction of cytokines and, consequently, the accumulation of neutrophils, monocytes, and platelets from the blood. Second, an EKD could be advantageous for the metabolism of anti-inflammatory M2 macrophages because these cells predominantly express oxidative phosphorylation enzymes and are best fed by the oxidation of fatty acids in the mitochondria. An EKD could guarantee the availability of free fatty acids, which are an optimal fuel supply for these cells. Third, an EKD, which could reduce high lactate formation by macrophages due to glycolysis, could favor the production of interferon type I, which are inhibited by excessive lactate production. From a practical point of view, the hypothesis, in addition to being proven in clinical studies, must obviously take into account the contraindications of an EKD, particularly type 1 or 2 diabetes treated with drugs that can cause hypoglycemia, to avoid the risk for side effects of the diet.