Insulin and glycolysis dependency of cardioprotection by nicotinamide riboside.

Decreased nicotinamide adenine dinucleotide (NAD+) levels contribute to various pathologies such as ageing, diabetes, heart failure and ischemia-reperfusion injury (IRI). Nicotinamide riboside (NR) has emerged as a promising therapeutic NAD+ precursor due to efficient NAD+ elevation and was recently shown to be the only agent able to reduce cardiac IRI in models employing clinically relevant anesthesia. However, through which metabolic pathway(s) NR mediates IRI protection remains unknown. Furthermore, the influence of insulin, a known modulator of cardioprotective efficacy, on the protective effects of NR has not been investigated. Here, we used the isolated mouse heart allowing cardiac metabolic control to investigate: (1) whether NR can protect the isolated heart against IRI, (2) the metabolic pathways underlying NR-mediated protection, and (3) whether insulin abrogates NR protection. NR protection against cardiac IRI and effects on metabolic pathways employing metabolomics for determination of changes in metabolic intermediates, and 13C-glucose fluxomics for determination of metabolic pathway activities (glycolysis, pentose phosphate pathway (PPP) and mitochondrial/tricarboxylic acid cycle (TCA cycle) activities), were examined in isolated C57BL/6N mouse hearts perfused with either (a) glucose + fatty acids (FA) ("mild glycolysis group"), (b) lactate + pyruvate + FA ("no glycolysis group"), or (c) glucose + FA + insulin ("high glycolysis group"). NR increased cardiac NAD+ in all three metabolic groups. In glucose + FA perfused hearts, NR reduced IR injury, increased glycolytic intermediate phosphoenolpyruvate (PEP), TCA intermediate succinate and PPP intermediates ribose-5P (R5P) / sedoheptulose-7P (S7P), and was associated with activated glycolysis, without changes in TCA cycle or PPP activities. In the "no glycolysis" hearts, NR protection was lost, whereas NR still increased S7P. In the insulin hearts, glycolysis was largely accelerated, and NR protection abrogated. NR still increased PPP intermediates, with now high 13C-labeling of S7P, but NR was unable to increase metabolic pathway activities, including glycolysis. Protection by NR against IRI is only present in hearts with low glycolysis, and is associated with activation of glycolysis. When activation of glycolysis was prevented, through either examining "no glycolysis" hearts or "high glycolysis" hearts, NR protection was abolished. The data suggest that NR's acute cardioprotective effects are mediated through glycolysis activation and are lost in the presence of insulin because of already elevated glycolysis.

[The use of corticosteroids in bronchopulmonary dysplasia]. / Het gebruik van corticosteroïden bij bronchopulmonale dysplasie.

In order to study the effect of dexamethasone on the ventilatory function of 13 neonates with bronchopulmonary dysplasia, a retrospective investigation was carried out in the University Hospital Rotterdam, Sophia Children's Hospital, Neonatal Intensive Care Unit. Thirteen preterm neonates, 7 boys and 6 girls, born after 26 4/7-32 weeks' gestation with birth weights between 680 and 1800 g were studied. At the age of 21 days they all showed clinical and radiological evidence of BPD and despite maximal therapy they deteriorated during the last week before entering into the study. The potentially successful dexamethasone schedule of Avery was started. After four days' therapy only 3 patients out of 13 were still on the ventilator. Ventilatory support could be stopped in all neonates after 4.7 (SD 2.0) days. No hypertension or hyperglycaemia was seen. Only 1 child had a positive blood culture; this was successfully treated. In the end two children died. The use of corticosteroids in bronchopulmonary dysplasia in this study showed a positive short-term effect. Long-term sequelae and the risk of infection are still controversial.