Photoactivation of tDodSNO induces localized vasodilation in rats: Metabolically stable S-nitrosothiols can act as targeted nitric oxide donors in vivo.

Nitric oxide (NO) is a key vasodilatory signalling molecule and NO releasing molecules (NO donors) are being examined as potential treatments for many pathologies. The photoresponsive NO donor tert-dodecane S-nitrosothiol (tDodSNO) has been designed to be highly resistant to metabolism; in principle photoactivation of tDodSNO should therefore enable the controlled release of NO in situ via light modulation. To investigate the therapeutic utility of tDodSNO, we tested drug efficacy in Sprague Dawley rats to assess systemic and localised hemodynamic responses under photoactivation, and to confirm drug safety.

SMA-BmobaSNO: an intelligent photoresponsive nitric oxide releasing polymer for drug nanoencapsulation and targeted delivery.

Nitric oxide (NO) is an important biological signalling molecule that acts to vasodilate blood vessels and change the permeability of the blood vessel wall. Due to these cardiovascular actions, co-administering NO with a therapeutic could enhance drug uptake. However current NO donors are not suitable for targeted drug delivery as they systemically release NO.

Quadruply Stranded Metallo-Supramolecular Helicate [Pd(hextrz)] Acts as a Molecular Mimic of Cytolytic Peptides.

[Pd(hextrz)] is a quadruply stranded helicate, a novel bioinorganic complex designed to mimic the structure and function of proteins due to its high stability and supramolecular size. We have previously reported that [Pd(hextrz)] exhibited cytotoxicity toward a range of cell lines, with IC values ranging from 3 to 10 μM. Here we demonstrate that [Pd(hextrz)] kills cells by forming pores within the cell membrane, a mechanism of cell death analogous to the naturally occurring cytolytic peptides.

Controlled Delivery of Nitric Oxide for Cancer Therapy.

Nitric oxide (NO) is a short-lived, endogenously produced, signaling molecule which plays multiple roles in mammalian physiology. Underproduction of NO is associated with several pathological processes; hence a broad range of NO donors have emerged as potential therapeutics for cardiovascular and respiratory disorders, wound healing, the immune response to infection, and cancer. However, short half-lives, chemical reactivity, rapid systemic clearance, and cytotoxicity have hindered the clinical development of most low molecular weight NO donors.

Anticancer Activity and Cisplatin Binding Ability of -Quinoline and -Isoquinoline Derived [PdL] Metallosupramolecular Cages.

New quinoline ( ) and isoquinoline-based ( ) ligands have been synthesized, along with their respective homoleptic [Pd( or )] cages ( and ). The ligands and cages were characterized by H, C and diffusion ordered (DOSY) NMR spectroscopies, high resolution electrospray ionization mass spectrometry (HR-ESIMS) and in the case of the -quinoline cage, X-ray crystallography. The crystal structure of the architecture showed that the [Pd( )] cage formed a twisted isomer where the [Pd()] units at either end of the cage architecture adopt the opposite twists (left and right handed).

Data characterizing the biophysical and nitric oxide release properties of the tDodSNO - Styrene maleic anhydride nanoparticle SMA-tDodSNO.

Nitric oxide (NO) donor drugs have a range of clinical applications, and are also being developed as therapeutics for the potential treatment of multiple diseases. This article presents data describing the synthesis and characterisation of a novel NO releasing nanoparticle formed by encapsulation of the NO donor tDodSNO into a co-polymer of styrene and maleic acid (SMA) to afford SMA-tDodSNO. The pharmacological activity of SMA-tDodSNO is discussed in our accompanying manuscript "Encapsulation of tDodSNO generates a photoactivated nitric oxide releasing nanoparticle for localized control of vasodilation and vascular hyperpermeability".

Encapsulation of tDodSNO generates a photoactivated nitric oxide releasing nanoparticle for localized control of vasodilation and vascular hyperpermeability.

We report the synthesis and characterization of a photoactive nitric oxide (NO) releasing nanoparticle (NP) by encapsulation of the NO donor tert-dodecane S-nitrosothiol (tDodSNO) into a co-polymer of styrene and maleic anhydride (SMA) to afford SMA-tDodSNO. Encapsulation did not affect tDodSNO's stability or NO release profile, but imparted water solubility and protection from degradation reactions with glutathione. Under photoactivation the NP acted as a potent NO donor, with photoactivation acting as a switch to induce localized vasodilation in aortic rings (EC 660 nM at 2700 W/m) and cause vascular hyperpermeability in mesenteric beds (8-fold increase in dye uptake at 1 µM SMA-tDodSNO with 460 W/m photoactivation).

The Reactive Sulfur Species Concept: 15 Years On.

Fifteen years ago, in 2001, the concept of "Reactive Sulfur Species" or RSS was advocated as a working hypothesis. Since then various organic as well as inorganic RSS have attracted considerable interest and stimulated many new and often unexpected avenues in research and product development. During this time, it has become apparent that molecules with sulfur-containing functional groups are not just the passive "victims" of oxidative stress or simple conveyors of signals in cells, but can also be stressors in their own right, with pivotal roles in cellular function and homeostasis.

Enhanced kinetic stability of [Pd2L4](4+) cages through ligand substitution.

There is considerable interest in exploiting metallosupramolecular cages as drug delivery vectors. Recently, we developed a [Pd2L4](4+) cage capable of binding two molecules of cisplatin. Unfortunately, this first generation cage was rapidly decomposed by common biologically relevant nucleophiles.

Hypoxia Responsive Drug Delivery Systems in Tumor Therapy.

Hypoxia is a common characteristic of solid tumors. It is mainly determined by low levels of oxygen resulting from imperfect vascular networks supplying most tumors. In an attempt to improve the present chemotherapeutic treatment and reduce associated side effects, several prodrug strategies have been introduced to achieve hypoxia-specific delivery of cytotoxic anticancer agents.

Biologically active [Pd2L4](4+) quadruply-stranded helicates: stability and cytotoxicity.

There is emerging interest in the anti-proliferative effects of metallosupramolecular systems due to the different size and shape of these metallo-architectures compared to traditional small molecule drugs. Palladium(II)-containing systems are the most abundant class of metallosupramolecular complexes, yet their biological activity has hardly been examined. Here a small series of [Pd2(L)4](BF4)4 quadruply-stranded, dipalladium(II) architectures were screened for their cytotoxic effects against three cancer cell lines and one non-malignant line.

The design of nitric oxide donor drugs: s-nitrosothiol tDodSNO is a superior photoactivated donor in comparison to GSNO and SNAP.

We have recently developed tert-dodecane S-nitrosothiol (tDodSNO) as a photoactivated nitric oxide (NO) donor. We here compare the potency of tDodSNO to S-nitrosoglutathione (GSNO) and S-nitroso-N-acetylpenicillamine (SNAP), drugs which are also based upon the S-nitrosothiol functionality and have been extensively used for NO release studies. Photoactivation in vitro, at a clinically relevant light fluence rate (200W/m(2)), demonstrated that tDodSNO released much higher levels of NO than either GSNO or SNAP.

Intracellular targeting and pharmacological activity of the superoxide dismutase mimics MnTE-2-PyP5+ and MnTnHex-2-PyP5+ regulated by their porphyrin ring substituents.

Manganese porphyrin-based drugs are potent mimics of the enzyme superoxide dismutase. They exert remarkable efficacy in disease models and are entering clinical trials. Two lead compounds, MnTE-2-PyP(5+) and MnTnHex-2-PyP(5+), have similar catalytic rates, but differ in their alkyl chain substituents (ethyl vs n-hexyl).

A hydrogen peroxide electrode assay to measure thiol peroxidase activity for organoselenium and organotellurium drugs.

Molecular mimics of the enzyme glutathione peroxidase (GPx) are increasingly being evaluated as redox active drugs. Their molecular mechanism of action parallels that of the native enzyme; however, a major distinction is that GPx mimics can use alternative thiol substrates to glutathione. This generic thiol peroxidase activity implies that it is necessary to assess a GPx mimic's recognition of a range of cellular thiols in order to determine its potential therapeutic effects.

The molecular design of S-nitrosothiols as photodynamic agents for controlled nitric oxide release.

Nitric oxide is a small messenger molecule utilized by nature in cell signalling and the non-specific immune response. At present, nitric oxide releasing prodrugs cannot be efficiently targeted towards a specific body compartment, which restricts their therapeutic applications. To address this limitation, we have designed two photolabile nitric oxide releasing prodrugs, tert-butyl S-nitrosothiol and tert-dodecane S-nitrosothiol, which are based on the S-nitrosothiol functionality.

Reduced metal ion concentrations in atherosclerotic plaques from subjects with type 2 diabetes mellitus.

Aims: Transition metal ions have been implicated in atherosclerosis. The goal of this study was to investigate whether metal ion levels were higher in people with diabetes, in view of their increased risk of aggravated atherosclerosis.

Methods And Results: Absolute concentrations of iron, copper, zinc and calcium, and products of protein and lipid oxidation were quantified in atherosclerotic lesions from subjects with (T2DM, n=27), without Type 2 diabetes (nonDM, n=22), or hyperglycaemia (HG, n=17).

Synchrotron radiation induced X-ray emission studies of the antioxidant mechanism of the organoselenium drug ebselen.

Synchrotron radiation induced X-ray emission (SRIXE) spectroscopy was used to map the cellular uptake of the organoselenium-based antioxidant drug ebselen using differentiated ND15 cells as a neuronal model. The cellular SRIXE spectra, acquired using a hard X-ray microprobe beam (12.8-keV), showed a large enhancement of fluorescence at the K(α) line for Se (11.

Novel method for measuring S-nitrosothiols using hydrogen sulfide.

Recent advances in techniques that allow sensitive and specific measurement of S-nitrosothiols (RSNOs) have provided evidence for a role for these compounds in various aspects of nitric oxide (NO) biology. The most widely used approach is to couple reaction chemistry that selectively reduces RSNOs by one electron to produce NO, with the sensitive detection of the latter under anaerobic conditions using ozone based chemiluminescence in NO analyzers. Herein, we report a novel reaction that is readily adaptable for commercial NO analyzers that utilizes hydrogen sulfide (H2S), a gas that can reduce RSNO to NO and, analogous to NO, is produced by endogenous metabolism and has effects on diverse biological functions.

Mycobacterium tuberculosis WhiB3 responds to O2 and nitric oxide via its [4Fe-4S] cluster and is essential for nutrient starvation survival.

A fundamental challenge in the redox biology of Mycobacterium tuberculosis (Mtb) is to understand the mechanisms involved in sensing redox signals such as oxygen (O2), nitric oxide (NO), and nutrient depletion, which are thought to play a crucial role in persistence. Here we show that Mtb WhiB3 responds to the dormancy signals NO and O2 through its iron-sulfur (Fe-S) cluster. To functionally assemble the WhiB3 Fe-S cluster, we identified and characterized the Mtb cysteine desulfurase (IscS; Rv3025c) and developed a native enzymatic reconstitution system for assembling Fe-S clusters in Mtb.

The redox regulation of thiol dependent signaling pathways in cancer.

Reactive oxygen species (ROS) play a central role as second messengers in many signal transduction pathways, where they can post-translationally modify proteins via the oxidation of redox sensitive cysteine residues. The range of cellular processes under redox regulation is extensive and includes both the proliferative and apoptotic pathways. Control of the cellular redox environment is therefore essential for normal physiological function and perturbations to this redox balance are characteristic of many pathological states.

Topoisomerase enzymes as therapeutic targets for cancer chemotherapy.

The topoisomerase enzymes are essential for DNA metabolism, where they act to adjust the number of supercoils in DNA, a key requirement in the cellular processes of transcription and replication. Their enzymatic mechanism creates transient nicks (type I) or breaks (type II) in the double stranded DNA polymer, allowing DNA to be converted between topological isomers. Humans possess both types of topoisomerase enzymes, however the two types utilize very different enzymatic mechanisms.

Moderate hypoxia induces xanthine oxidoreductase activity in arterial endothelial cells.

Xanthine oxidoreductase (XOR) activity has been previously noted to be responsive to changes in O2 tension. While prior studies have focused on the extremes (0-3% and 95-100%) of O2 tensions, we report the influence of 10% O2 on endothelial cell XOR, a concentration resembling modest arterial hypoxia commonly found in patients with chronic cardiopulmonary diseases. Exposure of bovine aortic endothelial cells to 10% O2 increased XOR mRNA and protein abundance by 50%.

Xanthine oxidase-dependent regulation of hypoxia-inducible factor in cancer cells.

During chemical hypoxia induced by cobalt chloride (CoCl2), hypoxia-inducible factor 1alpha (HIF1-alpha) mediates the induction of a variety of genes including erythropoietin and vascular endothelial growth factor. We used glioma cells with oxidative phosphorylation-dependent (D54-MG) and glycolytic-dependent (U251-MG) phenotypes to monitor HIF1-alpha regulation in association with redox responsiveness to CoCl2 treatment. We showed that CoCl2 increased xanthine oxidase (XO)-derived reactive oxygen species (ROS), which causes accumulation of HIF1-alpha protein in U251-MG cells.

Multifunctional redox catalysts as selective enhancers of oxidative stress.

Certain cancer cells proliferate under conditions of oxidative stress (OS) and might therefore be selectively targeted by redox catalysts. Among these catalysts, compounds containing a chalcogen and a quinone redox centre are particularly well suited to respond to the presence of OS. These catalysts combine the specific electrochemical features of quinones and chalcogens.