Leukemia cells from patients with acute myeloid leukemia (AML) display high proliferative capacity and are resistant to death. Membrane-anchored aminopeptidase-N/CD13 is a potential drug target in AML<strong>. </strong>Clinical research efforts are currently focusing on targeted therapies that induce death in AML cells. We previously developed a non-cytotoxic APN/CD13 inhibitor based on flavone-8-acetic acid scaffold, the 2',3-dinitroflavone-8-acetic acid <strong>(1)</strong>. In this context, among the variously substituted 113 compounds further synthesized and tested for evaluation of their effects on APN/CD13 activity, proliferation and survival in human AML U937 cells, eight flavonoid derivatives emerged: 2',3-dinitro-6-methoxy-flavone-8-acetic acid (<strong>2</strong>), four compounds (<strong>3</strong>–<strong>6</strong>) with the 3-chloro-2,3-dihydro-3-nitro-2-phenyl-4<em>H</em>-1-benzopyran-4-one structure, and three (<strong>7</strong>–<strong>9</strong>) with the 3-chloro-3,4-dihydro-4-hydroxy-3-nitro-2-phenyl-2<em>H</em>-1-benzopyran framework. Different structure-activity relationships were observed between APN/CD13 activity and growth/survival processes. We showed that compound <strong>2</strong>, but not benzopyran derivatives <strong>3</strong>–<strong>9</strong>, inhibited APN activity (although to a less degree than <strong>1)</strong>. Both <strong>1 </strong>and <strong>2 </strong>did not affect AML cell proliferation and survival, indicating that CD13’s APN activity is not required for these processes. In contrast, benzopyran compounds <strong>3</strong>–<strong>9</strong> inhibited in a concentration-dependent manner the growth of U937 cells by inducing death as evidenced by phosphatidylserine externalization. Cell death was associated with the presence of geminal nitro groupand chlorine at the 3-position of the 2<em>H</em>-1-benzopyran scaffold. The presence of other substituents such as CH₂COOH or CH₂CH=CH₂ groups at the 8-position, NO₂ or I substituents at the 2'- or 3'-position, OCH₃ or OCH₂C₆H₅ groups at the 4'-position did not affect cell death. Importantly, the inhibitory effects evidenced with compounds <strong>7</strong>–<strong>9 </strong>were not due to their potential decomposition into the corresponding (<em>Z</em>)-(2chloro-2-nitroethenyl)benzene and salicylaldehyde. Based on these preliminary data, the 3-chloro,3-nitro-2<em>H</em>-1-benzopyran derivatives could be classified as a new group of compounds with promising antitumor properties; this study therefore provides the opportunity to explore their potential efficiency in AML patients’ cells <em>ex vivo</em>.

Determining the identity and functional role of proteins involved in biomineralization and the formation of skeletons is critical to our understanding of the process. Proteomics has allowed rapid characterization of the proteins occluded within mineralized tissue, but the large numbers of proteins detected makes it difficult to assign the relative importance of each protein. We have taken a comparative approach, examining the skeletal proteome of different species of echinoderms in order to identify the proteins that are conserved and likely to be important. Our previous study comparing the skeletal proteome of the brittle star Ophiocoma wendtii to the published proteomes of the sea urchin Strongylocentrotus purpuratus revealed some conservation of proteins, but indicated that the C-type lectin domain-containing spicule matrix proteins abundant in the sea urchin skeletal proteome were not conserved in the brittle star. Here we examine the skeletal proteome of a different species of brittle star, Ophiothrix spiculata. We have isolated the proteins from the skeleton of O. spiculata and performed LC/MS/MS to identify peptides present. Comparison to transcriptome and genome databases revealed the proteins present in the O. spiculata proteome. Despite being diverged for several million years, the two brittle stars have very similar proteins in their skeletons. Included is a fibrinogen C-like lectin and several C-type lectins proteins, which we describe in detail. The unusual number of C-type lectins found in the S. purpuatus skeleton and the repetitive regions seen in those spicule matrix proteins are not present in O. spiculata.

The free radical nitric oxide (NO) plays important roles in plant growth and defense. Owing to its small size and lipophilicity, NO acts as a crucial signaling molecule in plants, crossing cell membranes and enhancing cell communication. Indeed, NO donors have been shown to modulate a variety of physiological processes, such as plant greening, seed germination, iron homeostasis and mitochondrial respiration. Recently, several papers have reported the protective actions upon application of low molecular weight NO donors in plants under abiotic stress. Exogenous NO is able to improve plant tolerance to several abiotic stresses, such as drought, salinity, metal toxicity, and extreme temperatures. This protection is assigned to the NO-mediated redox signaling in plants, which involves interplay with reactive oxygen species and modulation of gene expression and protein function. This review reports and discusses the recent advantages, pitfalls, challenges, and perspectives in the applications of low molecular weight NO donors in plants under abiotic stress. The combination of nanotechnology and NO donors as an efficient approach to protect plants under challenging environments is also discussed.

Alzheimer's disease (AD), the most common neurodegenerative disease worldwide, ranks as one of the most feared diseases in the world. Similarly, recent studies suggest that AD may be the third leading cause of death in the United States, behind heart disease and cancer. In the absence of a cure or effective treatment, strategies to prevent or delay the onset and progression of the disease are desperately needed. Decades of research have identified key risk and protective factors including genetic polymorphism in the APOE gene, age and lifestyle factors. Physical activity (PA) is emerging as an attractive primary prevention strategy. This review will summarise the latest findings supporting the role of physical activity in the prevention of AD, including possible mechanisms and the influence of genetics on disease prevention. Given that AD and other dementias are recognised as a world health priority, public health strategies are needed to incorporate promoting the health benefits of physical activity across the lifespan.

In previous studies, we synthesized the first organic light emitting diode (OLED) using boron subphthalocyanines (BsubPcs) based polymers. When designing new polymer materials for organic electronic applications such as OLEDs or organic photovoltaic (OPV) devices it is important to consider not only the contribution of each monomer but also the polymer chain ends. In this paper we establish a post-polymerization strategy to couple BsubPcs onto either the α- or the ω-chain end using chemically selective BsubPc derivatives. We outline how the chain ends of two representative polymers, poly(styrene) (PS) and poly( n -butylacrylate) (BA), synthesized by nitroxide mediated polymerization (NMP), using BlocBuilder-MA as the initiating species, can be chemically modified by the incorporation of BsubPc chromophores. The addition of the BsubPc chromophore was confirmed through the use of a photodiode array detector (PDA) connected in-line with a gel permeation chromatography (GPC) setup. These findings represent the first reported method for the controlled and selective placement of a BsubPc chromophores on either end of a polymer produced by NMP. This strategy will therefore be utilized to make next generation BsubPc polymers for OLEDs and OPV devices. The extremely high molar extinction coefficient of BsubPc also make these polymers ideally suited for dye-labelling of polymers.

Cells count on surveillance systems to monitor and protect the cellular proteome which, besides being highly heterogeneous, is constantly being challenged by intrinsic and environmental factors. In this context, the proteostasis network (PN) is essential to achieve a stable and functional proteome. Disruption of the PN is associated with aging and can lead to and/or potentiate the occurrence of many neurodegenerative diseases (ND). This not only emphasizes the importance of the PN in health span and aging but also how its modulation can be a potential target for intervention and treatment of human diseases.

The different amounts of residual partial agonist activity (PAA) of antisteroids under assorted conditions have long been useful in clinical applications but remain largely unexplained. Not only does a given antagonist often afford unequal induction for multiple genes in the same cell but also the activity of the same antisteroid with the same gene changes with variations in concentration of numerous cofactors. Using glucocorticoid receptors as a model system, we have recently succeeded in constructing from first principles a theory that accurately describes how cofactors can modulate the ability of agonist steroids to regulate both gene induction and gene repression. We now extend this framework to the actions of antisteroids in gene induction. The theory shows why changes in PAA cannot be explained simply by differences in ligand affinity for receptor and requires action at a second step or site in the overall sequence of reactions. The theory also provides a method for locating the position of this second site, relative to a concentration limited step (CLS), which is a previously identified step in glucocorticoid-regulated transactivation that always occurs at the same position in the overall sequence of events of gene induction. Finally, the theory predicts that classes of antagonist ligands may be grouped on the basis of their maximal PAA with excess added cofactor and that the members of each class differ by how they act at the same step in the overall gene induction process. Thus, this theory now makes it possible to predict how different cofactors modulate antisteroid PAA, which should be invaluable in developing more selective antagonists.

Sphingosine 1-phosphate (S1P), a multi-functional phospholipid mediator, is generated from sphingosine by sphingosine kinases and binds to five known G protein-coupled S1P receptors (S1P₁, S1P₂, S1P₃, S1P₄, and S1P₅). It is widely accepted that S1P receptor 1 (S1P₁) plays an essential role in lymphocyte egress from the secondary lymphoid organs (SLO) and thymus, because lymphocyte egress from these organs to periphery is at extremely low levels in mice lacking lymphocytic S1P₁. Fingolimod hydrochloride (FTY720) is a first-in-class, orally active S1P₁ functional antagonist which was discovered by chemical modification of a natural product, myriocin. Since FTY720 has a structure closely related to sphingosine, the phosphorylated FTY720 (FTY720-P) is converted by sphingosine kinases and binds 4 types of S1P receptors. FTY720-P strongly induces down-regulation of S1P₁ by internalization and degradation of this receptor and acts as a functional antagonist at S1P₁. Consequently, FTY720 inhibits S1P₁-dependent lymphocyte egress from the SLO and thymus to reduce circulating lymphocytes including autoreactive Th17 cells, and is highly effective in experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS). In relapsing remitting MS patients, oral FTY720 shows a superior efficacy when compared to intramuscular interferon-β-1a. Based on these data, it is presumed that modulation of the S1P-S1P₁ axis provides an effective therapy for autoimmune diseases including MS.

Glutamate transporters control the glutamate homeostasis in the central nervous system, and, thus, are not only crucial for physiological excitatory synaptic signaling, but also for the prevention of a large number of neurodegenerative diseases that are associated with excessive and prolonged presence of the neurotransmitter glutamate in the extracellular space. Until now, five subtypes of high-affinity glutamate transporters (excitatory amino acid transporters, EAATs 1–5) have been identified. These 5 high-affinity glutamate transporter subtypes belong to the solute carrier 1 (SLC1) family of transmembrane proteins: EAAT1/GLAST (SLC1A3), EAAT2/GLT1 (SLC1A2), EAAT3/EAAC1 (SLC1A1), EAAT4 (SLC1A6) and EAAT5 (SLC1A7). EAATs are secondary-active transporters, taking up glutamate into the cell against a substantial concentration gradient. The driving force for concentrative uptake is provided by the co-transport of Na+ ions and the counter-transport of one K+ in a step independent of the glutamate translocation step. Due to the electrogenicity of transport, the transmembrane potential can also act as driving force. Glutamate transporters are also able to run in reverse, resulting in glutamate release from cells. Due to these important physiological functions, glutamate transporter expression and, therefore, the transport rate, are tightly regulated. The EAAT protein family are structurally expected to be highly similar, however, these transporters show a functional diversity that ranges from high capacity glutamate uptake systems (EAATs 1–3) to receptor-like glutamate activated anion channels (EAATs 4–5). Here, we provide an update on most recent progress made on EAAT’s molecular transport mechanism, structure-function relationships, pharmacology, and will add recent insights into mechanism of rapid membrane trafficking of glutamate transporters.

Autosomal dominant polycystic kidney disease (ADPKD) is an inherited genetic disorder that results in progressive renal cyst formation with ultimate loss of renal function and other systemic disorders. These systemic disorders include abnormalities in cardiovascular, portal, pancreatic and gastrointestinal systems. ADPKD is considered to be among the ciliopathy diseases due to the association with abnormal primary cilia function. In order to understand the full course of primary cilia and its association with ADPKD, the structure, functions and role of primary cilia have been meticulously investigated. As a result, the focus on primary cilia has emerged to support the vital roles of primary cilia in ADPKD. The primary cilia have been shown to have not only a mechanosensory function but also a chemosensory function. Both structural and functional defects in primary cilia result in cystic kidney disease and vascular hypertension. Thus, the mechanosenory and chemosensory functions will be analyzed in regards to ADPKD.