What Is New for an Old Molecule? Systematic Review and Recommendations on the Use of Resveratrol

Stilbenes are naturally occurring phytoalexins that generally exist as their more stable E isomers. The most well known natural stilbene is resveratrol (Res), firstly isolated in 1939 from roots of Veratrum grandiflorum (white hellebore) (1) and since then found in various edible plants, notably in Vitis vinifera L. (Vitaceae) (2). The therapeutic potential of Res covers a wide range of diseases, and multiple beneficial effects on human health such as antioxidant, anti-inflammatory and anti-cancer activities have been suggested based on several in vitro and animal studies (3). In particular, Res has been reported to be an inhibitor of carcinogenesis at multiple stages via its ability to inhibit cyclooxygenase, and is an anticancer agent with a role in antiangiogenesis (4). Moreover, both in vitro and in vivo studies showed that Res induces cell cycle arrest and apoptosis in tumor cells (4). However, clinical studies in humans evidenced that Res is rapidly absorbed after oral intake, and that the low level observed in the blood stream is caused by a fast conversion into metabolites that are readily excreted from the body (5). Thus, considerable efforts have gone in the design and synthesis of Res analogues with enhanced metabolic stability. Considering that reduced Res (dihydro- resveratrol, D-Res) conjugates may account for as much as 50% of an oral Res dose (5), and that D-Res has a strong proliferative effect on hormone-sensitive cancer cell lines such as breast cancer cell line MCF7 (6), we recently devoted our synthetic efforts to the preparation of trans-restricted analogues of Res in which the E carbon-carbon double bond is embedded into an imidazole nucleus. To keep the trans geometry, the two aryl rings were linked to the heteroaromatic core in a 1,3 fashion. Based on this design, we successfully prepared a variety of 1,4-, 2,4- and 2,5-diaryl substituted imidazoles including Res analogues 1, 2 and 3, respectively, by procedures that involve transition metal-catalyzed Suzuki-Miyaura cross-coupling reactions and highly selective N-H or C-H direct arylation reactions as key synthetic steps. The anticancer activity of compounds 1–3 was evaluated against the 60 human cancer cell lines panel of the National Cancer Institute (NCI, USA). The obtained results, that will be showed and discussed along with the protocols developed for the preparation of imidazoles 1–3, confirmed that a structural optimization of Res may provide analogues with improved potency in inhibiting the growth of human cancer cell lines in vitro when compared to their natural lead. (1) Takaoka,M.J.Chem.Soc.Jpn.1939,60,1090-1100. (2) Langcake, P.; Pryce, R. J. Physiological. Plant Patology 1976, 9, 77-86. (3) Vang, O.; et al. PLoS ONE 2011, 6, e19881. doi:10.1371/journal.pone.0019881 (4) Kraft, T. E.; et al. Critical Reviews in Food Science and Nutrition 2009, 49, 782-799. (5) Walle, T. Ann. N.Y. Acad. Sci. 2011, 1215, 9-15. doi: 10.1111/j.1749-6632.2010.05842.x (6) Gakh,A.A.;etal.Bioorg.Med.Chem.Lett.2010,20,6149-6151

White Matter Microstructure Predicts Autistic Traits in Attention-Deficit/Hyperactivity Disorder

Traits of autism spectrum disorder (ASD) in children with attention-deficit/hyperactivity disorder (ADHD) have previously been found to index clinical severity. This study examined the association of ASD traits with diffusion parameters in adolescent males with ADHD (n = 17), and also compared WM microstructure relative to controls (n = 17). Significant associations (p < 0.05, corrected) were found between fractional anisotropy/radial diffusivity and ASD trait severity (positive and negative correlations respectively), mostly in the right posterior limb of the internal capsule/corticospinal tract, right cerebellar peduncle and the midbrain. No case–control differences were found for the diffusion parameters investigated. This is the first report of a WM microstructural signature of autistic traits in ADHD. Thus, even in the absence of full disorder, ASD traits may index a distinctive underlying neurobiology in ADHD

Asia–Pacific association for study of liver guidelines on management of ascites in liver disease

The development of ascites is a landmark event in the natural history of cirrhosis. This guidance statement by the Asia–Pacific Association for Study of Liver (APASL) provides an evidence-based approach to managing ascites and its complications in patients with chronic liver disease. These guidelines extensively review the differential diagnosis, diagnostic evaluation, and management of ascites, hyponatremia, hepatic hydrothorax and hepatorenal syndrome (HRS) in patients with cirrhosis and acute-on-chronic liver failure (ACLF). A panel of international experts was invited to formulate the guidelines. The opinions of the experts were collected using two sets of Delphi questionnaires. Then, an online meeting of all the experts was held to discuss the evidence and formulate the final recommendations by consensus. The guidelines were developed using the GRADE system for analysing the level of evidence and strength of recommendation (Table 1). All authors have gone through the guidance document and endorse the same.In this document, we have also covered the grey areas which have been underexplored in previous guidelines and some of the issues which are relatively peculiar to the Asia–Pacific region. Given the high burden of tuberculosis in some of the countries of the Asia–Pacific region, mixed ascites is not uncommon in these patients with liver disease. We discuss the diagnostic approach to mixed ascites and the role of ascitic fluid adenosine deaminase (ADA) and other tests for tuberculosis. In addition, many countries in the Asia–Pacific region are low-middle-income countries, and financial constraints are an essential barrier to liver transplants and other costly therapies like albumin. Hence, we have discussed the role of low-dose albumin in the prevention of paracentesis-induced circulatory dysfunction (PICD) after large-volume paracentesis (LVP) and the prevention of acute kidney injury (AKI) in patients with spontaneous bacterial peritonitis (SBP). We have also reviewed the current evidence of outpatient albumin in managing patients with ascites and have made practical recommendations. We also highlight the timing of albumin infusion concerning LVP. To decrease adverse events and improve patient compliance with diuretic therapy, the guidelines emphasize initiating low-dose diuretics and gradually increasing the dose to the maximum tolerable dose. Non-alcoholic fatty liver disease (NAFLD), also referred to as Metabolic associated fatty liver disease (MAFLD) by some societies has become a significant cause of chronic liver disease worldwide [1]. Many patients with NAFLD/MAFLD related cirrhosis are on angiotensin converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs) when they present to a hepatologist or gastroenterologist with ascites. For the first time, we provide guidance statements regarding the use of these drugs in patients with cirrhosis and ascites. For refractory ascites, we have now defined renal dysfunction following the International Club of Ascites (ICA) recommendations on AKI. Lastly, we have highlighted the gaps in our knowledge and have provided directions for future research