Halochromic Behavior and Anticancer Effect of New Synthetic Anthocyanidins Complexed with β-Cyclodextrin Derivatives

Anthocyanidins, the aglycons of anthocyanins, are known, beyond their function in plants, also as compounds with a wide range of biological and pharmacological activities, including cytostatic effect against various cancer cells. The nature and position of the substituents in the flavylium cation is essential for such biological properties, as well as the equilibrium between the multistate of the different chemical species that are generated by the flavylium cation, including quinoidal base, hemiketal, and cis- and trans-chalcones. In this work, eight new flavylium derivatives were synthesized, characterized for confirmation of the structure by FT-IR and 2D-NMR, and investigated in vitro as possible cytostatic compounds against HCT116 and HepG2 cancer cells. The most active two compounds were explored for their halochromic properties that can influence the biological activity and subjected to molecular encapsulation in β-cyclodextrin derivatives in order to increase their solubility in water and bioavailability. The anticancer effect was influenced by the position (6-, 7-, or 8-) of the methoxy group in the β-ring of the methoxy-4′-hydroxy-3′-methoxyflavylium cation, while the study of the halochromic properties revealed the important role played by the chalcone species of the pH-dependent multistate in both the uncomplexed and inclusion complex forms of these anthocyanidins.     

Modeling Lung Carcinoids with Zebrafish Tumor Xenograft

Lung carcinoids are neuroendocrine tumors that comprise well-differentiated typical (TCs) and atypical carcinoids (ACs). Preclinical models are indispensable for cancer drug screening since current therapies for advanced carcinoids are not curative. We aimed to develop a novel in vivo model of lung carcinoids based on the xenograft of lung TC (NCI-H835, UMC-11, and NCI-H727) and AC (NCI-H720) cell lines and patient-derived cell cultures in Tg(fli1a:EGFP)^y1 zebrafish embryos. We exploited this platform to test the anti-tumor activity of sulfatinib. The tumorigenic potential of TC and AC implanted cells was evaluated by the quantification of tumor-induced angiogenesis and tumor cell migration as early as 24 h post-injection (hpi). The characterization of tumor-induced angiogenesis was performed in vivo and in real time, coupling the tumor xenograft with selective plane illumination microscopy on implanted zebrafish embryos. TC-implanted cells displayed a higher pro-angiogenic potential compared to AC cells, which inversely showed a relevant migratory behavior within 48 hpi. Sulfatinib inhibited tumor-induced angiogenesis, without affecting tumor cell spread in both TC and AC implanted embryos. In conclusion, zebrafish embryos implanted with TC and AC cells faithfully recapitulate the tumor behavior of human lung carcinoids and appear to be a promising platform for drug screening.     

In Vitro Reactivity of the Glucose Degradation Product 3,4-Dideoxyglucosone-3-ene (3,4-DGE) towards Abundant Components of the Human Blood Circulatory System

3,4-Dideoxyglucosone-3-ene (3,4-DGE) is a glucose degradation product present in processed foods and medicinal products. Additionally, its constant formation from 3-deoxyglucosone in plasma has been suggested. Due to its α,β-unsaturated dicarbonyl moiety, 3,4-DGE is highly reactive and has shown harmful effects in vitro. Here, we investigated the impact of major components of the human blood circulatory system on 3,4-DGE in vitro. Under physiological conditions, plasma concentrations of human serum albumin (HSA) reacted efficiently with 3,4-DGE, resulting in only 8.5% of the initial 3,4-DGE concentration after seven hours (vs. 83.4% without HSA, p < 0.001). Thereby, accessible thiol groups were reduced from 0.121 to 0.064 mol/mol HSA, whereas ketoprofen binding and esterase-like activity of HSA were not affected. Plasma concentrations of glutathione (GSH) reacted immediately and completely with 3,4-DGE, leading to two stereoisomeric adducts. Plasma concentrations of immunoglobulin G (IgG) bound to 3,4-DGE to a lower extent, resulting in 62.6% 3,4-DGE after seven hours (vs. 82.2% in the control, p < 0.01). Immobilized human collagen type IV did not alter 3,4-DGE concentrations. The results indicated that particularly HSA, GSH, and IgG readily scavenge 3,4-DGE after its appearance in the blood stream, which may be associated with a reduced antioxidative and cytoprotective activity for the living cells and, thus, the human organism by blocking free thiol groups.     

Focused Design of Novel Cyclic Peptides Endowed with GABARAP-Inhibiting Activity

(1) Background: Disfunctions in autophagy machinery have been identified in various conditions, including neurodegenerative diseases, cancer, and inflammation. Among mammalian autophagy proteins, the Atg8 family member GABARAP has been shown to be greatly involved in the autophagy process of prostate cancer cells, supporting the idea that GABARAP inhibitors could be valuable tools to fight the progression of tumors. (2) Methods: In this paper, starting from the X-ray crystal structure of GABARAP in a complex with an AnkirinB-LIR domain, we identify two new peptides by applying in silico drug design techniques. The two ligands are synthesized, biophysically assayed, and biologically evaluated to ascertain their potential anticancer profile. (3) Results: Two cyclic peptides (WC8 and WC10) displayed promising biological activity, high conformational stability (due to the presence of disulfide bridges), and K_d values in the low micromolar range. The anticancer assays, performed on PC-3 cells, proved that both peptides exhibit antiproliferative effects comparable to those of peptide K1, a known GABARAP inhibitor. (4) Conclusions: WC8 and WC10 can be considered new GABARAP inhibitors to be employed as pharmacological tools or even templates for the rational design of new small molecules.     

Neurocognitive signs in prodromal Huntington disease.

Objective: PREDICT-HD is a large-scale international study of people with the Huntington disease (HD) CAG-repeat expansion who are not yet diagnosed with HD. The objective of this study was to determine the stage in the HD prodrome at which cognitive differences from CAG-normal controls can be reliably detected. Method: For each of 738 HD CAG-expanded participants, we computed estimated years to clinical diagnosis and probability of diagnosis in 5 years based on age and CAG-repeat expansion number (Langbehn, Brinkman, Falush, Paulsen, & Hayden, 2004). We then stratified the sample into groups: NEAR, estimated to be ≤9 years; MID, between 9 and 15 years; and FAR, ≥15 years. The control sample included 168 CAG-normal participants. Nineteen cognitive tasks were used to assess attention, working memory, psychomotor functions, episodic memory, language, recognition of facial emotion, sensory–perceptual functions, and executive functions. Results: Compared with the controls, the NEAR group showed significantly poorer performance on nearly all of the cognitive tests and the MID group on about half of the cognitive tests (p = .05, Cohen's d NEAR as large as ?1.17, MID as large as ?0.61). One test even revealed significantly poorer performance in the FAR group (Cohen's d = ?0.26). Individual tasks accounted for 0.2% to 9.7% of the variance in estimated proximity to diagnosis. Overall, the cognitive battery accounted for 34% of the variance; in comparison, the Unified Huntington's Disease Rating Scale motor score accounted for 11.7%. Conclusions: Neurocognitive tests are robust clinical indicators of the disease process prior to reaching criteria for motor diagnosis of HD. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Ranking the efficacies of selected red wine phenolic anti-oxidants using reversed-phase HPLC

Several studies have assessed total anti-oxidant activity of wine or individual components in isolation using chemical-based assays. In this study, a quantitative approach was developed to assess the relative anti-oxidant efficacies of selected red wine phenolics via peak reduction, using reversed-phase HPLC. Both intact red wine and phenolic standard solutions were challenged with five oxidant model systems as follows: (1) hydrogen peroxide (H₂O₂); redox-active metal ions (2) Fe³⁺ and (3) Cu²⁺; and the Fenton reagents (4) H₂O₂ + Fe²⁺; and (5) H₂O₂ + Cu⁺. Treatment with oxidants (1–3) resulted in loss of 47–60% of phenolic standards, which increased to 66–89% for treatment with the Fenton systems, with quercetin exhibiting the optimal anti-oxidant activity. For intact red wine, treatment with oxidants (1–3) led to all phenolic compounds being oxidised (27–77% loss), with caffeic acid and quercetin as the most effective anti-oxidants. For both Fenton systems (4–5), activities in red wine were considerably enhanced for caffeic acid and quercetin, which exhibited the highest anti-oxidant efficacies with 100% peak reduction, while p-coumaric acid and gallic acid were less effective anti-oxidants with peak reductions of 60–68%. The ranking, facilitated by this new quantitative approach, allows comparison of the individual efficacies of the anti-oxidants in a complex matrix.     

Reduced Impact of Induced Gate Noise on Inductively Degenerated LNAs in Deep Submicron CMOS Technologies

Designers of radio-frequency inductively-degenerated CMOS low-noise-amplifiers have usually not followed the guidelines for achieving minimum noise figure. Nonetheless, state-of-the-art implementations display noise figure values very close to the theoretical minimum. In this paper, we point out that this is due to the effect of the parasitic overlap capacitances in the MOS device. In particular, we show that overlap capacitances lead to a significant induced-gate-noise reduction, especially when deep sub-micron CMOS processes are used.Paolo Rossi was born in Milan, Italy, in 1975. He received the Laurea degree (summa cum laude) in electrical engineering from the University of Pavia, Pavia, Italy, in 2000, where he is currently working toward the Ph.D. degree. His research interests are in the field of analog integrated circuits for wireless transceivers in CMOS and BiCMOS technology, with particular focus on the analysis and design of LNA and mixer for multi-standard applications.Francesco Svelto received the Laurea and Ph.D. degrees in electrical engineering from the University of Pavia, Pavia, Italy, in 1991 and 1995, respectively. From 1996 to 1997, he held a grant from STMicroelectronics to design CMOS RF circuits. In 1997, he was appointed Assistant Professor at the University of Bergamo, Italy, and in 2000, he joined the University of Pavia, where he is an Associate Professor. His current research interests are in the field of RF design and high-frequency integrated circuits for telecommunications. Dr. Svelto has been a member of the technical program committee of the IEEE Custom Integrated Circuits Conference since 2000 and the Bipolar/BiCMOS Circuits and Technology Meeting (BCTM) since 2003, and the European Solid State Circuits Conference in 2002. He served as Guest Editor of the March 2003 special issue of the IEEE Journal of Solid-State Circuits, of which he is currently an Associate Editor.Andrea Mazzanti was born in Modena (Italy) in 1976. He received the Laurea degree (summa cum Laude) in Electrical Engineering from the University of Modena and Reggio Emilia, Modena, Italy in 2001. Since 2001 he is pursuing his PhD in Electrical Engineering at University of Modena and Reggio Emilia, Italy. His major research interest are modelling of microwave semiconductor devices and design of CMOS RF integrated circuits, with particular focus on low noise oscillators and analog frequency dividers. During the summer of 2003 he was with Agere Systems, Allentown, PA as an internship student, working on the design of an highly integrated CMOS FM transmitter.Pietro Andreani received the M.S.E.E. from the University of Pisa, Italy, in 1988. He joined the Dept. of Applied Electronics, Lund University, Sweden, in 1990, where he contributed to the development of software tools for digital ASIC design. After working at the Dept. of Applied Electronics, University of Pisa, as a CMOS IC designer during 1994, he rejoined the Dept. of Applied Electronics in Lund as an Associate Professor, where he was responsible for the analog IC course package between 1995 and 2001, and where he received the Ph.D. degree in 1999. He is currently a Professor at the Center for Physical Electronics, ØrstedDTU, Technical University of Denmark, Kgs. Lyngby, Denmark, with analog/RF CMOS IC design as main research field.     

嵌入式系统软件调试跟踪技术的发展趋势

在过去的几十年里，嵌入式工程师在开发和调试中已经越来越依赖于跟踪缓存的帮助。但随着100MHz频率以上的高速RISC处理器的普及，片内Cache、RAM和FLASH存储器逐渐变得越来越普遍。越来越多的处理器总线活动将无法在外部管脚上观测。这样，传统的收集跟踪信息的方法就不再可行了。