NMNAT1 Is a Survival Factor in Actinomycin D-Induced Osteosarcoma Cell Death

Osteosarcoma is a frequent and extremely aggressive type of pediatric cancer. New therapeutic approaches are needed to improve the overall survival of osteosarcoma patients. Our previous results suggest that NMNAT1, a key enzyme in nuclear NAD⁺ synthesis, facilitates the survival of cisplatin-treated osteosarcoma cells. A high-throughput cytotoxicity screening was performed to identify novel pathways or compounds linked to the cancer-promoting role of NMNAT1. Nine compounds caused higher toxicity in the NMNAT1 KO U2OS cells compared to their wild type counterparts, and actinomycin D (ActD) was the most potent. ActD-treatment of NMNAT1 KO cells increased caspase activity and secondary necrosis. The reduced NAD⁺ content in NMNAT1 KO cells was further decreased by ActD, which partially inhibited NAD⁺-dependent enzymes, including the DNA nick sensor enzyme PARP1 and the NAD⁺-dependent deacetylase SIRT1. Impaired PARP1 activity increased DNA damage in ActD-treated NMNAT1 knockout cells, while SIRT1 impairment increased acetylation of the p53 protein, causing the upregulation of pro-apoptotic proteins (NOXA, BAX). Proliferation was decreased through both PARP- and SIRT-dependent pathways. On the one hand, PARP inhibitors sensitized wild type but not NMNAT1 KO cells to ActD-induced anti-clonogenic effects; on the other hand, over-acetylated p53 induced the expression of the anti-proliferative p21 protein leading to cell cycle arrest. Based on our results, NMNAT1 acts as a survival factor in ActD-treated osteosarcoma cells. By inhibiting both PARP1- and SIRT1-dependent cellular pathways, NMNAT1 inhibition can be a promising new tool in osteosarcoma chemotherapy.     

Biodiesel production using enzymatic transesterification - Current state and perspectives

Biodiesel has attracted considerable interest in recent years as an alternative, biodegradable and nonpolluting transportation fuel. Conventional alkaline process for biodiesel production are energy-consuming and generate undesirable by-products such as soaps, that make difficult the separation and purification of biodiesel.Particular attention has been dedicated to the use of lipases as biocatalysts for biodiesel production due to their favorable conversion rate obtained in gentle conditions and relatively simple downstream processing steps for the purification of biodiesel and by-products. However, comparatively to conventional chemical processes, the major obstacles for enzymatic production of biodiesel remain the cost of lipases, the relatively slower reaction rate and lipases inactivation caused by methanol and glycerol.This review evaluates the current status and perspectives for enzymatic biodiesel production and indicates the key operational variables that influence lipase activity and stability together with the technological solutions for industrial implementation of enzymatic process.     

Cyanide-bridged bimetallic multidimensional structures derived from organotin(IV) and dicyanoaurate building blocks: ion exchange, luminescence, and gas sorption properties

The recent success of using methyltin(IV) cations in constructing multidimensional structures containing the Au–CN–Sn link with interesting physical properties will be surveyed. The methyltin(IV)-dicyanoaurates, Me₃Sn[Au(CN)₂] (1) and Me₂Sn[Au(CN)₂]₂ (2) containing the Au–CN–Sn link can be easily prepared by aqueous reaction of Me₃SnCl or Me₂SnCl₂ with stoichiometric amounts of an aqueous solution of K[Au(CN)₂]. The room temperature solid-state emission spectrum of 1 excited at 254 nm shows two intense emission bands at 442 and 670 nm, and a shoulder at 390 nm. When excited at 320 nm, the crystalline sample shows two intense emission bands at 442 and 720 nm, and a shoulder at 380 nm. After 2 min of grinding, only the blue emission band at 442 nm is observed. In contrast, the emission spectrum of 2 shows only one emission maximum at 422 nm. The porosity of 1 and 2 was probed by gas sorption measurements performed at 77 K. 1 exhibited no detectable microporosity as revealed by the inspection of the N₂, H₂, as well as, O₂ isotherms. The gas adsorption studies reveal that only a small amount of N₂ and H₂ (3.82 and 4.66 cm³ g⁻¹, respectively) is adsorbed by the framework of 2 at 77 K. However, a CO uptake of 11.20 cm³ g⁻¹ can be reached at 1 atm. The framework of 2 can take up significant amounts of O₂ (23.27 cm³ g⁻¹). In addition to intriguing photoluminescence and gas sorption behavior, these complexes also exhibit ion exchange properties in the presence of bivalent transition metal cations, such as cobalt(II), nickel(II), copper(II), and zinc(II).     

Micromechanical deformation processes in PP/wood composites: Particle characteristics,adhesion, mechanisms

Polypropylene (PP) was reinforced with four natural fillers having different particle characteristics. Interfacial adhesion was changed by the introduction of maleated polypropylene (MAPP). The properties of the studied PP/wood composites depended strongly on interfacial adhesion and on the particle characteristics of the wood. Coupling with functionalized polymer is necessary for the preparation of composites with acceptable properties if the size of the particles is large and their aspect ratio is small. The effect of adhesion is smaller for particles with large aspect ratio. Several micromechanical deformation processes may occur in PP/wood composites including matrix yielding, debonding, fiber pull-out and fiber fracture both parallel and perpendicular to the fiber axis. The processes are competitive and may take place simultaneously and/or consecutively. The inherent properties of the reinforcement may limit the improvement of composite strength. Micromechanical deformation processes determine composite properties irrespectively of their mechanism.     

Binding Networks Identify Targetable Protein Pockets for Mechanism-Based Drug Design

The human genome codes only a few thousand druggable proteins, mainly receptors and enzymes. While this pool of available drug targets is limited, there is an untapped potential for discovering new drug-binding mechanisms and modes. For example, enzymes with long binding cavities offer numerous prerequisite binding sites that may be visited by an inhibitor during migration from a bulk solution to the destination site. Drug design can use these prerequisite sites as new structural targets. However, identifying these ephemeral sites is challenging. Here, we introduce a new method called NetBinder for the systematic identification and classification of prerequisite binding sites at atomic resolution. NetBinder is based on atomistic simulations of the full inhibitor binding process and provides a networking framework on which to select the most important binding modes and uncover the entire binding mechanism, including previously undiscovered events. NetBinder was validated by a study of the binding mechanism of blebbistatin (a potent inhibitor) to myosin 2 (a promising target for cancer chemotherapy). Myosin 2 is a good test enzyme because, like other potential targets, it has a long internal binding cavity that provides blebbistatin with numerous potential prerequisite binding sites. The mechanism proposed by NetBinder of myosin 2 structural changes during blebbistatin binding shows excellent agreement with experimentally determined binding sites and structural changes. While NetBinder was tested on myosin 2, it may easily be adopted to other proteins with long internal cavities, such as G-protein-coupled receptors or ion channels, the most popular current drug targets. NetBinder provides a new paradigm for drug design by a network-based elucidation of binding mechanisms at an atomic resolution.     

Bioavailability Improvement Strategies for Icariin and Its Derivates: A Review

In recent years, there has been considerable interest in icariin (ICA) and its derivates, icariside II (ICS) and icaritin (ICT), due to their wide range of potential applications in preventing cancer, cardiovascular disease, osteoporosis, delaying the effects of Alzheimer’s disease, treating erectile dysfunction, etc. However, their poor water solubility and membrane permeability, resulting in low bioavailability, dampens their potential beneficial effects. In this regard, several strategies have been developed, such as pharmaceutical technologies, structural transformations, and absorption enhancers. All these strategies manage to improve the bioavailability of the above-mentioned flavonoids, thus increasing their concentration in the desired places. This paper focuses on gathering the latest knowledge on strategies to improve bioavailability for enhancing the efficacy of icariin, icariside II, and icaritin. We conclude that there is an opportunity for many further improvements in this field. To the best of our knowledge, no such review articles scoping the bioavailability improvement of icariin and its derivates have been published to date. Therefore, this paper can be a good starting point for all those who want to deepen their understanding of the field.     

A Potential Involvement of Anandamide in the Modulation of HO/NOS Systems: Women,Menopause, and “Medical Cannabinoids”

Endocannabinoids and their receptors are present in the cardiovascular system; however, their actions under different pathological conditions remain controversial. The aim of our study was to examine the effects of anandamide (AEA) on heme oxygenase (HO) and nitric oxide synthase (NOS) systems in an estrogen-depleted rat model. Sham-operated (SO) and surgically induced estrogen-deficient (OVX) female Wistar rats were used. During a two-week period, a group of OVX rats received 0.1 mg/kg estrogen (E₂) per os, while AEA-induced alterations were analyzed after two weeks of AEA treatment at the dose of 1.0 mg/kg. At the end of the experiment, cardiac activity and expression of HO and NOS enzymes, content of cannabinoid 1 receptor, as well as concentrations of transient potential vanilloid 1 (TRPV1) and calcitonin gene-related peptide (CGRP) were measured. Our results show that estrogen withdrawal caused a significant decrease in both NOS and HO systems, and a similar tendency was observed regarding the TRPV1/CGRP pathway. Two weeks of either AEA or E₂ treatment restored the adverse changes; however, the combined administration of these two molecules did not result in a further improvement. In light of the potential relationship between AEA and HO/NOS systems, AEA-induced upregulation of HO/NOS enzymes may be a therapeutic strategy in estrogen-deficient conditions.     

Dual Escherichia coli DNA Gyrase A and B Inhibitors with Antibacterial Activity

The emergence of multidrug-resistant bacteria is a global health threat necessitating the discovery of new antibacterials and novel strategies for fighting bacterial infections. We report first-in-class DNA gyrase B (GyrB) inhibitor/ciprofloxacin hybrids that display antibacterial activity against Escherichia coli. Whereas DNA gyrase ATPase inhibition experiments, DNA gyrase supercoiling assays, and in vitro antibacterial assays suggest binding of the hybrids to the E. coli GyrA and GyrB subunits, an interaction with the GyrA fluoroquinolone-binding site seems to be solely responsible for their antibacterial activity. Our results provide a foundation for a new concept of facilitating entry of nonpermeating GyrB inhibitors into bacteria by conjugation with ciprofloxacin, a highly permeable GyrA inhibitor. A hybrid molecule containing GyrA and GyrB inhibitor parts entering the bacterial cell would then elicit a strong antibacterial effect by inhibition of both the GyrA and GyrB subunits of DNA gyrase and potentially slow bacterial resistance development.     

An analytical method to design annular microfilaments with uniform temperature

Microsystem Technologies - Due to their complex electro-thermal characteristics microhotplates used in environmental gas sensors require careful design to exhibit uniform temperature and low power...