Nanomagnetic Modulation of Tumor Redox State

Modulation of reactive oxygen and nitrogen species in a tumor could be exploited for nanotherapeutic benefits. We investigate the antitumor effect in Walker-256 carcinosarcoma of magnetic nanodots composed of doxorubicin-loaded Fe₃O₄ nanoparticles combined with electromagnetic fields. Treatment using the magnetic nanodot with the largest hysteresis loop area (3402 erg/g) had the greatest antitumor effect with the minimum growth factor 0.49 ± 0.02 day^–1 (compared to 0.58 ± 0.02 day^–1 for conventional doxorubicin). Electron spin resonance spectra of Walker-256 carcinosarcoma treated with the nanodots, indicate an increase of 2.7 times of free iron (that promotes the formation of highly reactive oxygen species), using the nanodot with the largest hysteresis loop area, compared to conventional doxorubicin treatment as well as increases in ubisemiquinone, lactoferrin, NO-FeS-proteins. Hence, we provide evidence that the designed magnetic nanodots can modulate the tumor redox state. We discuss the implications of these results for cancer nanotherapy.     

Mode of action and anti-Candida activity of Artemisia annua mediated-synthesized silver nanoparticles

Candida albicans is a polymorphic opportunistic commensal that causes both superficial and systemic fungal infections especially in immunocompromised patients. Biologically synthesized silver nanoparticles (AgNPs) have emerged as potential antifungal agents. The present work evaluates the antifungal activity of Artemisia annua synthesized AgNPs against three Candida species (C. albicans ATCC 90028, C. tropicalis ATCC 750 and C. glabrata ATCC 90030). The in vitro effect of AgNPs was investigated for fungal growth, sterol content, secretion of hydrolytic enzymes and yeast-to-hyphal transition. The green synthesized AgNPs were effective against all the three species with minimum inhibitory concentration (MIC) in the range 80–120 μgml⁻¹. Candida glabrata showed greater sensitivity for AgNPs followed by Candida tropicalis and C. albicans. AgNPs at 4MIC were as effective as fluconazole (FLC) and caused only 5% haemolysis while FLC caused 50% haemolysis at the same concentration. The secretion of hydrolytic enzymes was the lowest in case of AgNP exposed C. glabrata. Yeast-to-hyphal transition was significantly reduced in treated C. albicans cells and showed disfigured morphology in SEM images. The decrease in ergosterol content was slightly higher (94%) in both C. glabrata and C. tropicalis in comparison to C. albicans (69%). Green synthesized AgNPs thus have immense potential as an antifungal and can play a crucial role in the management of Candida infections especially those caused by C. glabrata.     

A Novel Approach for the Synthesis of Thermo‐Responsive Co‐Polyesters Incorporating Reversible Diels–Alder Adducts

The proof of concept for a new copolymerization approach taking advantage of the thermally reversible aptitude of the furan/maleimide Diels–Alder (DA) adducts is reported here. A new monomer bearing two carboxylic acids as end‐groups and a Diels–Alder adduct within its structure is synthesized using benign and mild reaction conditions. Two polyesters are then fabricated from the DA‐diacid and 1,6‐hexanediol and 1,4‐benzenedimethanol, respectively, and characterized by ¹H‐NMR, GPC, DSC, and TGA. Kinetic studies of these polyesters, performed by ¹H‐NMR spectroscopy at variable temperatures, establish the appropriate conditions for their controlled depolymerization, through the retro Diels–Alder reaction (rDA), and their re‐construction through the DA reaction, showing moreover the reproducibility of this rDA/DA cycle. Finally, by exploiting this peculiar feature, a copolyester is successfully synthesized from the concomitant treatment of the two homopolymers, demonstrating the effectiveness of the method. The present approach provides a new method for the fabrication of multicomponent copolymers based on the DA/rDA strategy that is extendable to a variety of other polycondensation materials, such as polyesters, polyamides, polyurethanes, and epoxies, allowing the establishment of a library of novel architectures through this one‐pot approach.     

艾叶的化学成分、药理作用及产品开发研究进展

艾叶为我国传统中药材,主要含有挥发油、黄酮、多糖、鞣酸、萜类及微量元素等多种化学成分。其药理作用较为广泛,包括抗菌、抗病毒、抗氧化、保肝利胆、止血及抗凝血、抗过敏、免疫调节、抗癌等。目前其应用集药品、食品、保健品等于一体,具有广阔的开发前景。对艾叶的化学成分、药理作用及产品的开发研究进展做一概述,为更合理有效地利用艾叶药材、开发艾叶产品提供参考。     

Pharmacoperone drugs: targeting misfolded proteins causing lysosomal storage-, ion channels-, and G protein-coupled receptors-associated conformational disorders

Introduction: Conformational diseases are caused by structurally abnormal proteins that cannot fold properly and achieve their native conformation. Misfolded proteins frequently originate from genetic mutations that may lead to loss-of-function diseases involving a variety of structurally diverse proteins including enzymes, ion channels, and membrane receptors. Pharmacoperones are small molecules that cross the cell surface plasma membrane and reach their target proteins within the cell, serving as molecular scaffolds to stabilize the native conformation of misfolded or well-folded but destabilized proteins, to prevent their degradation and promote correct trafficking to their functional site of action. Because of their high specificity toward the target protein, pharmacoperones are currently the focus of intense investigation as therapy for several conformational diseases.

Areas covered: This review summarizes data on the mechanisms leading to protein misfolding and the use of pharmacoperone drugs as an experimental approach to rescue function of distinct misfolded/misrouted proteins associated with a variety of diseases, such as lysosomal storage diseases, channelopathies, and G protein-coupled receptor misfolding diseases.

Expert commentary: The fact that many misfolded proteins may retain function, offers a unique therapeutic opportunity to cure disease by directly correcting misrouting through administering pharmacoperone drugs thereby rescuing function of disease-causing, conformationally abnormal proteins.     

Design,synthesis, and molecular docking studies of N‐(9,10‐anthraquinone‐2‐carbonyl)amino acid derivatives as xanthine oxidase inhibitors

A series of N‐(9,10‐anthraquinone‐2‐carbonyl)amino acid derivatives ( 1a–j ) was designed and synthesized as novel xanthine oxidase inhibitors. Among them, the L/D‐phenylalanine derivatives ( 1d and 1i ) and the L/D‐tryptophan derivatives ( 1e and 1j ) were effective with micromolar level potency. In particular, the L‐phenylalanine derivative 1d (IC₅₀ = 3.0 μm ) and the D‐phenylalanine derivative 1i (IC₅₀ = 2.9 μm ) presented the highest potency and were both more potent than the positive control allopurinol (IC₅₀ = 8.1 μm ). Preliminary SAR analysis pointed that an aromatic amino acid fragment, for example, phenylalanine or tryptophan, was essential for the inhibition; the D‐amino acid derivative presented equal or greater potency compared to its L‐enantiomer; and the 9,10‐anthraquinone moiety was welcome for the inhibition. Molecular simulations provided rational binding models for compounds 1d and 1i in the xanthine oxidase active pocket. As a result, compounds 1d and 1i could be promising lead compounds for further investigation.     

Analogue synthesis reveals decoupling of antibiofilm and β‐lactam potentiation activities of a lead 2‐aminoimidazole adjuvant against Mycobacterium smegmatis

Biofilm formation is one of the many mechanisms bacteria utilize to survive antibiotic treatment. It has been demonstrated that when Mycobacterium tuberculosis exists in a biofilm in vitro, it expresses phenotypic resistance to antimicrobial drugs. As the in vivo survival of M. tuberculosis following drug treatment is potentially linked to a biofilm‐like expression of drug tolerance, it is hypothesized that biofilm dispersion should increase antibiotic susceptibility and reduce the duration of the current antibiotic treatment regimen. Previously, we have identified a 2‐aminoimidazole (2‐AI) compound capable of dispersing and inhibiting M. tuberculosis and M. smegmatis biofilms in vitro. Additionally, this compound potentiated the activity of carbenicillin against M. tuberculosis and, to a lesser degree, M. smegmatis. Here, we describe a SAR study on this compound evaluating each derivative for biofilm dispersion and β‐lactam potentiation capabilities against M. smegmatis. This study identified a compound that improved upon the biofilm dispersion capabilities of the lead compound. Interestingly, a different compound was identified with an increased ability to potentiate a subset of β‐lactam antibiotics. These compounds indicate that biofilm dispersion and potentiation capabilities may not be associated.