Chemistry, Department of

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Multifunctional Compounds for Activation of the p53‐Y220C Mutant in Cancer

Peer reviewed: 
Yes, item is peer reviewed.
Date created: 
2018-09-19
Abstract: 

The p53 protein plays a major role in cancer prevention, and over 50 % of cancer diagnoses can be attributed to p53 malfunction. The common p53 mutation Y220C causes local protein unfolding, aggregation, and can result in a loss of Zn in the DNA‐binding domain. Structural analysis has shown that this mutant creates a surface site that can be stabilized using small molecules, and herein a multifunctional approach to restore function to p53‐Y220C is reported. A series of compounds has been designed that contain iodinated phenols aimed for interaction and stabilization of the p53‐Y220C surface cavity, and Zn‐binding fragments for metallochaperone activity. Their Zn‐binding affinity was characterized using spectroscopic methods and demonstrate the ability of compounds L4 and L5 to increase intracellular levels of Zn2+ in a p53‐Y220C‐mutant cell line. The in vitro cytotoxicity of our compounds was initially screened by the National Cancer Institute (NCI‐60), followed by testing in three stomach cancer cell lines with varying p53 status’, including AGS (WTp53), MKN1 (V143A), and NUGC3 (Y220C). Our most promising ligand, L5, is nearly 3‐fold more cytotoxic than cisplatin in a large number of cell lines. The impressive cytotoxicity of L5 is further maintained in a NUGC3 3D spheroid model. L5 also induces Y220C‐specific apoptosis in a cleaved caspase‐3 assay, reduces levels of unfolded mutant p53, and recovers p53 transcriptional function in the NUGC3 cell line. These results show that these multifunctional scaffolds have the potential to restore wild‐type function in mutant p53‐Y220C.

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Article
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Metal Complexes that Bind to the Amyloid-β Peptide of Relevance to Alzheimer's Disease

Peer reviewed: 
Yes, item is peer reviewed.
Date created: 
2020-03-10
Abstract: 

Alzheimer’s disease (AD) is the most common form of dementia, and is a multi-faceted disease that is characterized by oxidative stress, metal-ion dysregulation, and the formation of intracellular neurofibrillary tangles of tau protein and extracellular amyloid-β (Aβ) aggregates. This review will focus on the interaction of metal complexes with the Aβ peptide, and how these interactions can modify the peptide aggregation pathway, oxidative stress, and overall toxicity of the Aβ peptide. While certain endogenous metal complexes such as heme can enhance toxicity, a large number of reports detail the potentially protective effect of discrete metal complexes in AD. These results will be discussed in the context of ligand design to target specific peptide residues for covalent binding, modulate peptide aggregation towards non-toxic species, and enhance blood brain barrier access. Additional features of metal complexes such as light-activated Aβ binding, catalytic antioxidant activity, and peptidase activity will be detailed.

Document type: 
Article

Differentiation of Nanoparticles Isolated from Distinct Plant Species Naturally Growing in a Heavy Metal Polluted Site

Peer reviewed: 
Yes, item is peer reviewed.
Date created: 
2019-11-08
Abstract: 

Leaves harvested from the plants of two different species (Dittrichia viscosa and Cichorium intybus) grown in their autogenous environment near a steel manufacturing company were characterized for naturally accumulated nanoparticles. These plant species are known to accumulate heavy metals. It was, however, unknown if these species would also accumulate these heavy metals in the form of nanoparticles. The isolated solid fractions were analyzed using dynamic light scattering, X-ray fluorescence, and transmission electron microscopy. These analyses revealed the presence of nanoparticles within the plants. The composition of nanoparticles found in each plant species is distinct: (i) for Dittrichia viscosa, the nanoparticle composition matched the heavy metal pollution anticipated from the surrounding industries; (ii) for Cichorium intybus, the nanoparticle composition was similar to the most abundant elements in the soil. The different behavior is a reflection of the phytoaccumulator characteristics of both species. This study provides the first evidence of sequestration of heavy metals in the form of nanoparticles by plants grown autogenously in polluted areas and will have implications in waste management of phytoremediation systems and in understanding the heavy metal life-cycle in the environment.

Document type: 
Article

A New Quinoline-Based Chemical Probe Inhibits the Autophagy-Related Cysteine Protease ATG4B

Peer reviewed: 
Yes, item is peer reviewed.
Date created: 
2018-08-03
Abstract: 

The cysteine protease ATG4B is a key component of the autophagy machinery, acting to proteolytically prime and recycle its substrate MAP1LC3B. The roles of ATG4B in cancer and other diseases appear to be context dependent but are still not well understood. To help further explore ATG4B functions and potential therapeutic applications, we employed a chemical biology approach to identify ATG4B inhibitors. Here, we describe the discovery of 4–28, a styrylquinoline identified by a combined computational modeling, in silico screening, high content cell-based screening and biochemical assay approach. A structure-activity relationship study led to the development of a more stable and potent compound LV-320. We demonstrated that LV-320 inhibits ATG4B enzymatic activity, blocks autophagic flux in cells, and is stable, non-toxic and active in vivo. These findings suggest that LV-320 will serve as a relevant chemical tool to study the various roles of ATG4B in cancer and other contexts.

Document type: 
Article
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Modification of Aβ Peptide Aggregation via Covalent Binding of a Series of Ru(III) Complexes

Peer reviewed: 
Yes, item is peer reviewed.
Date created: 
2019-12-03
Abstract: 

Alzheimer's disease (AD) is the most common form of dementia, leading to loss of cognition, and eventually death. The disease is characterized by the formation of extracellular aggregates of the amyloid-beta (Aβ) peptide and neurofibrillary tangles of tau protein inside cells, and oxidative stress. In this study, we investigate a series of Ru(III) complexes (Ru-N) derived from NAMI-A in which the imidazole ligand has been substituted for pyridine derivatives, as potential therapeutics for AD. The ability of the Ru-N series to bind to Aβ was evaluated by NMR and ESI-MS, and their influence on the Aβ peptide aggregation process was investigated via electrophoresis gel/western blot, TEM, turbidity, and Bradford assays. The complexes were shown to bind covalently to the Aβ peptide, likely via a His residue. Upon binding, the complexes promote the formation of soluble high molecular weight aggregates, in comparison to peptide precipitation for peptide alone. In addition, TEM analysis supports both amorphous and fibrillar aggregate morphology for Ru-N treatments, while only large amorphous aggregates are observed for peptide alone. Overall, our results show that the Ru-N complexes modulate Aβ peptide aggregation, however, the change in the size of the pyridine ligand does not substantially alter the Aβ aggregation process.

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Article
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Electrochemically Aged Ni Electrodes Supporting NiFe2O4 Nanoparticles for the Oxygen Evolution Reaction

Peer reviewed: 
Yes, item is peer reviewed.
Date created: 
2019-11-26
Abstract: 

The preparation and screening of nanoparticle (NP) electrocatalysts for improved electrocatalytic oxygen evolution reactions (OER) will require a better understanding and optimization of the interactions between NPs and their support. First-row transition metals are used extensively as electrocatalysts in electrochemical energy storage and conversion systems. These electrocatalysts undergo transformations in their phase and surface morphology, which are induced by oxidizing potentials in the alkaline medium. A template-assisted approach to prepare electrodes with regular surface morphologies was used to monitor interactions between the NPs and their support both before and after prolonged electrochemical aging. A template-assisted method was used to prepare uniform surface inclusions of nickel ferrite (NiFe2O4) NPs on conductive nickel (Ni) supports for evaluation toward the OER. Electron microscopy-based methods were used to assess the resulting transformations of the embedded NPs within the Ni support matrix. Electrochemical aging of these textured electrodes was conducted by cyclic voltammetry (CV) techniques, which resulted in the growth of a 200 nm thick Ni oxy(hydroxide) film on the surfaces of the Ni supports. The growth of the active surface layer led to the encapsulation of the NiFe2O4 NPs as determined by correlative energy dispersive X-ray spectroscopy (EDS) techniques. The NP-modified electrodes exhibited reduced overpotentials and higher sustained current densities for the OER when compared to pure Ni supports. The well-defined morphologies and NP surface inclusions prepared by the template-assisted approach could serve as a platform for investigating additional NP–support interactions for electrocatalytic systems.

Document type: 
Article

Patterning Catalyst Layers with Microscale Features by Soft Lithography Techniques for Proton Exchange Membrane Fuel Cells

Peer reviewed: 
Yes, item is peer reviewed.
Date created: 
2020-01-02
Abstract: 

Microtransfer molding (µTM) and microcontact printing (µCP) techniques were demonstrated for the preparation of platinum based catalysts in hexagonally arranged patterns to achieve cathode catalyst layers (CCLs) with microscale patterned features. These soft lithographic techniques, previously demonstrated for use in the preparation of patterned thin films, were adopted to produce patterned CCLs for proton exchange membrane fuel cells (or PEMFCs) with features having a thickness up to 20 µm. The resulting CCLs contained precise microscopic patterns that could be tuned for improving the performance of PEMFCs. It was demonstrated that CCLs containing arrays of microscale, cylindrical holes as prepared by µTM exhibited an improvement in their water management characteristics within PEMFCs when compared to CCLs prepared from continuous catalyst films. Upon further tuning of the CCL transfer procedures for µCP of CCLs, the formation of isolated microscale, disc-like features were demonstrated to have twice the mass activity of that observed for PEMFCs containing CCLs with uniform thin catalyst films. These methods to prepare patterned CCLs are compatible with current manufacturing techniques and could be easily adapted to incorporate other catalyst materials for further improvements in PEMFC performance. The soft lithography techniques used herein could also be scaled up to meet the industrial demand of large volume manufacturing.

Document type: 
Article

SU-8 and PDMS-based Hybrid Fabrication Technology for Combination of Permanently Bonded Flexible and Rigid Features on a Single Device

Peer reviewed: 
Yes, item is peer reviewed.
Date created: 
2013-05-16
Abstract: 

In this article, a novel hybrid fabrication technology is presented that uses both a flexible polymer (polydimethylsiloxane-–PDMS) and a rigid polymer (SU-8). A covalent bond between the flexible and rigid polymer layers is achieved using an oxygen plasma treatment during a layer-by-layer direct spin-on process. Precise alignment of the features in each layer and a highly repeatable method are achieved by this new process. As a proof-of-concept, we successfully fabricated PDMS-based flexible microfluidic devices with SU-8-based rigid world-to-chip/chip-to-world interconnects. The bond strength between the PDMS and SU-8 layers is measured by three methods: (1) Instron® microtester to pull apart the layers; (2) voice coil actuator to test the bond between interconnects and the substrate; and (3) microfluidic pressurization test to evaluate the bond strength along the channels. The bond strength between the flexible PDMS layer and the rigid SU-8 features is very strong; the bond between these two polymers does not fail during these evaluations although the integrity of the PDMS layer itself fails during the microtester evaluation. Additionally, the layer-by-layer direct spin-on process resulted in a repeatable process and precise alignment of the features in each layer, which are necessary in order to achieve consistent performance from the fabricated devices. The rigid SU-8 interconnects fabricated onto a flexible PDMS device serve as a world-to-chip/chip-to-world interconnects for the direct connection with Tygon® tubing. Three different designs of hybrid (PDMS and SU-8 based) microfluidic devices are designed, fabricated and tested. Each variation differed in the microchannel design in order to demonstrate the versatility of the process to make devices on multiple scales and patterns. These hybrid microfluidic devices are capable of functioning without leakage up to pressures of 85.85 ±3.56 kPa. Although microfluidic channels with interconnects are shown as a proof-of-concept, the fabrication process demonstrated herein could be utilized to develop a number of more sophisticated microfluidic and biomedical devices.

Document type: 
Article
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Comprehensive Structural, Surface-Chemical and Electrochemical Characterization of Nickel-Based Metallic Foams

Peer reviewed: 
Yes, item is peer reviewed.
Date created: 
2013-06-11
Abstract: 

Nickel-based metallic foams are commonly used in electrochemical energy storage devices (rechargeable batteries) as both current collectors and active mass support. These materials attract attention as tunable electrode materials because they are available in a range of chemical compositions, pore structures, pore sizes, and densities. This contribution presents structural, chemical, and electrochemical characterization of Ni-based metallic foams. Several materials and surface science techniques (transmission electron microscopy (TEM), scanning electron microscopy (SEM), energy dispersive spectrometer (EDS), focused ion beam (FIB), and X-ray photoelectron spectroscopy (XPS)) and electrochemical methods (cyclic voltammetry (CV)) are used to examine the micro-, meso-, and nanoscopic structural characteristics, surface morphology, and surface-chemical composition of these materials. XPS combined with Ar-ion etching is employed to analyze the surface and near-surface chemical composition of the foams. The specific and electrochemically active surface areas (As, Aecsa) are determined using CV. Though the foams exhibit structural robustness typical of bulk materials, they have large As, in the range of 200–600 cm2 g–1. In addition, they are dual-porosity materials and possess both macro- and mesopores.

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Article
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Colloidal Core–Shell Materials with ‘Spiky’ Surfaces Assembled From Gold Nanorods

Peer reviewed: 
Yes, item is peer reviewed.
Date created: 
2014-05-14
Abstract: 

A series of core–shell materials with ‘spiky’ surfaces are prepared through the self-assembly of gold nanorods onto polystyrene microspheres. Loading of the nanorods is finely tuned and the assemblies exhibit surface plasmon resonance properties. The ‘spiky’ surface topography of the assembled structures could serve as a versatile substrate for surface-enhanced Raman spectroscopy based sensing applications.

Document type: 
Article
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