ADAR enzyme and miRNA story: A nucleotide that can make the difference

Adenosine deaminase acting on RNA (ADAR) enzymes convert adenosine (A) to inosine (I) in double-stranded (ds) RNAs. Since Inosine is read as Guanosine, the biological consequence of ADAR enzyme activity is an A/G conversion within RNA molecules. A-to-I editing events can occur on both coding and non-coding RNAs, including microRNAs (miRNAs), which are small regulatory RNAs of ~20-23 nucleotides that regulate several cell processes by annealing to target mRNAs and inhibiting their translation. Both miRNA precursors and mature miRNAs undergo A-to-I RNA editing, affecting the miRNA maturation process and activity. ADARs can also edit 3' UTR of mRNAs, further increasing the interplay between mRNA targets and miRNAs. In this review, we provide a general overview of the ADAR enzymes and their mechanisms of action as well as miRNA processing and function. We then review the more recent findings about the impact of ADAR-mediated activity on the miRNA pathway in terms of biogenesis, target recognition, and gene expression regulation

Interdependent Superconducting Networks

Cascades are self-amplifying processes triggered by feedback mechanisms that may cause a substantial part of a macroscopic system to change its phase in response of a relatively small local event. The theoretical background for these phenomena is rich and interdisciplinary with interdependent networks providing a versatile "two-interactions" framework to study their multiscale evolution. Yet, physics experiments aimed at validating this ever-growing volume of predictions have remained elusive, hitherto hindered by the problem of identifying possible physical mechanisms realizing interdependent couplings. Here we develop and study the first experimental realization of an interdependent system as a multilayer network of two disordered superconductors separated by an insulating film. We show that Joule heating effects emerging at sufficiently large driving currents act as dependency links between the superconducting layers, igniting overheating cascades via adaptive back and forth electro-thermal feedbacks. Through theory and experiments, we unveil a rich phase diagram of mutual resistive transitions and cascading processes that physically realize and generalize interdependent percolation. The present work establishes the first physics laboratory bench for the manifestation of the theory of interdependent systems, enabling experimental studies to control and to further develop the multilayer phenomena of complex interdependent materials

Alteration of xenobiotic metabolizing enzymes by resveratrol in liver and lung of CD1 mice.

Conflicting data on the anticancer properties of the polyphenolic natural product resveratrol (RSV) have been reported. Since the inhibition of "bioactivating" Phase-I xenobiotic metabolizing enzymes (XMEs) and/or induction of "detoxifying" Phase-II XMEs have long been considered important cancer chemopreventive strategies, in the current study we investigated the effect of RSV treatment on several Cytochrome P450 (CYP)-dependent oxidations and Phase-II markers in liver and lung subcellular preparations from CD1 male mice. These mice were i.p treated with RSV (25 or 50mg/Kg b.w.) daily for one or for seven consecutive days. Using either specific probes for different CYPs, or the regio- and stereo-selective metabolism of testosterone, we found that most of the Phase-I XMEs were significantly suppressed (up to approximately 61% loss for the CYP3A1/2-linked 6 beta-hydroxylation of testosterone in liver and up to approximately 97% loss for 2 alpha-hydroxylase in lung) following RSV treatment for 7 days at 50mg/kg b.w. Glutathione S-transferase was significantly inhibited, particularly in lung (approximately 76% loss of activity) after single administration of 25mg/kg b.w. A different response for the UDP-glucuronosyl transferase was observed, where a significant induction was seen (approximately 83%) in the liver and a significant reduction was observed in the lung (up to approximately 83% loss) following treatment with 25mg/kg b.w. for seven days. These data indicate that murine XMEs are altered by RSV, and that this alteration is dependent on the RSV dose, duration and way of administration. These results could provide mechanistic explanations for the conflicting chemopreventive results reported for RSV

Glucoraphasatin and glucoraphenin, a redox pair of glucosinolates of brassicaceae, differently affect metabolizing enzymes in rats.

Brassica vegetables are an important dietary source of glucosinolates (GLs), whose breakdown products exhibit anticancer activity. The protective properties of Brassicaceae are believed to be due to the inhibition of Phase-I or induction of Phase-II xenobiotic metabolizing enzymes (XMEs), thus enhancing carcinogen clearance. To study whether GLs affect XMEs and the role of their chemical structure, we focused on two alkylthio GLs differing in the oxidation degree of the side chain sulfur. Male Sprague-Dawley rats were supplemented (per oral somministration by gavage) with either glucoraphasatin (4-methylthio-3-butenyl GL; GRH) or glucoraphenin (4-methylsulfinyl-3-butenyl GL; GRE), at 24 or 120 mg/kg body weight in a single or repeated fashion (daily for four consecutive days), and hepatic microsomes were prepared for XME analyses. Both GLs were able to induce XMEs, showing different induction profiles. While the inductive effect was stronger after multiple administration of the higher GRH dosage, the single lower GRE dose was the most effective in boosting cytochrome P-450 (CYP)-associated monooxygenases and the postoxidative metabolism. CYP3A1/2 were the most affected isoforms by GRH treatment, whereas GRE induced mainly CYP1A2 supported oxidase. Glutathione S-transferase increased up to 3.2-fold after a single (lower) GRE dose and UDP-glucuronosyl transferase up to 2-fold after four consecutive (higher) GRH doses. In conclusion, the induction profile of these GLs we found is not in line with the chemopreventive hypothesis. Furthermore, the oxidation degree of the side chain sulfur of GLs seems to exert a crucial role on XME modulation