The capacity of tumour necrosis factor-related apoptosisinducing ligand (TRAIL) to trigger apoptosis preferentially in cancer cells, although sparing normal cells, has motivated clinical development of TRAIL receptor agonists as anti-cancer therapeutics. The molecular mechanisms responsible for the differential TRAIL sensitivity of normal and cancer cells are, however, poorly understood. Here, we show a novel signalling pathway that activates cytoprotective autophagy in untransformed human epithelial cells treated with TRAIL. TRAIL-induced autophagy is mediated by the AMP-activated protein kinase (AMPK) that inhibits mammalian target of rapamycin complex 1, a potent inhibitor of autophagy. Interestingly, the TRAIL-induced AMPK activation is refractory to the depletion of the two known AMPK-activating kinases, LKB1 and Ca(2 þ )/calmodulindependent kinase kinase-b, but depends on transforming growth factor-b-activating kinase 1 (TAK1) and TAK1-binding subunit 2. As TAK1 and AMPK are ubiquitously expressed kinases activated by numerous cytokines and developmental cues, these data are most likely to have broad implications for our understanding of cellular control of energy homoeostasis as well as the resistance of untransformed cells against TRAIL-induced apoptosis.

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The intake of bioactive compounds and moderate alcohol decreases the risk of cardiovascular diseases. These effects could be joined in a beverage created by a controlled alcoholic fermentation of orange juice. The influence of controlled alcoholic fermentation on the bioactive compound profile of orange juice has not been previously evaluated, and this is the purpose of the present study. Total and individual flavanones and carotenoids significantly increased throughout the fermentation. The reason for this was an enhanced extraction of these compounds from the pulp. Besides, the potential bioavailability of flavanones increased due to a higher content of hesperetin-7-O-glucoside (2-fold higher at the end of the fermentation process). Ascorbic acid did not undergo a significant change, and only total phenolics decreased. Antioxidant capacity was also evaluated. TEAC and FRAP values remained constant throughout the process. However, ORAC and DPPH values significantly increased. Correlation analysis concluded that the increase in ORAC and DPPH values could be due to enhancement of flavanones.

Melatonin (N-acetyl-5-methoxytryptamine) is a molecule implicated in multiple biological functions. Its level decreases with age, and the intake of foods rich in melatonin has been considered an exogenous source of this important agent. Orange is a natural source of melatonin. Melatonin synthesis occurs during alcoholic fermentation of grapes, malt and pomegranate. The amino acid tryptophan is the precursor of all 5-methoxytryptamines. Indeed, melatonin appears in a shorter time in wines when tryptophan is added before fermentation. The aim of the study was to measure melatonin content during alcoholic fermentation of orange juice and to evaluate the role of the precursor tryptophan. Identification and quantification of melatonin during the alcoholic fermentation of orange juice was carried out by UHPLC-QqQ-MS/MS. Melatonin significantly increased throughout fermentation from day 0 (3.15 ng/mL) until day 15 (21.80 ng/mL) reaching larger amounts with respect to other foods. Melatonin isomer was also analysed, but its content remained stable ranging from 11.59 to 14.18 ng/mL. The enhancement of melatonin occurred mainly in the soluble fraction. Tryptophan levels significantly dropped from 13.80 mg/L (day 0) up to 3.19 mg/L (day 15) during fermentation. Melatonin was inversely and significantly correlated with tryptophan (r = 0.907). Therefore, the enhancement in melatonin could be due to both the occurrence of tryptophan and the new synthesis by yeast. In summary, the enhancement of melatonin in novel fermented orange beverage would improve the health benefits of orange juice by increasing this bioactive compound.