Hydrogels with Reversible Crosslinks for Improved Localised Stem Cell Retention: A Review

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Hydrogels with Reversible Crosslinks for Improved Localised Stem Cell Retention: A Review

Tissue repair by administering stem cells retained in adaptable hydrogels. Various promising stem cells for tissue repair are discussed, together with the hydrogels that enclose them and interact well with the tissue. Hydrogel–cell fixation is accomplished by the hydrogel's chemical design, and the injectability by shear-thinning. Due to the dynamic bonds, the hydrogel will become injectable by applying force, but form a gel after injection.


Abstract

Successful stem cell applications could have a significant impact on the medical field, where many lives are at stake. However, the translation of stem cells to the clinic could be improved by overcoming challenges in stem cell transplantation and in vivo retention at the site of tissue damage. This review aims to showcase the most recent insights into developing hydrogels that can deliver, retain, and accommodate stem cells for tissue repair. Hydrogels can be used for tissue engineering, as their flexibility and water content makes them excellent substitutes for the native extracellular matrix. Moreover, the mechanical properties of hydrogels are highly tuneable, and recognition moieties to control cell behaviour and fate can quickly be introduced. This review covers the parameters necessary for the physicochemical design of adaptable hydrogels, the variety of (bio)materials that can be used in such hydrogels, their application in stem cell delivery and some recently developed chemistries for reversible crosslinking. Implementing physical and dynamic covalent chemistry has resulted in adaptable hydrogels that can mimic the dynamic nature of the extracellular matrix.

Synthesis of Phase‐Selective Ionic Liquid Gels and Application to the Synthesis of Ethyl Acetate

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Synthesis of Phase-Selective Ionic Liquid Gels and Application to the Synthesis of Ethyl Acetate

An ionic liquid gel (ILG) with temperature sensitivity and phase selectivity was constructed as an ecofriendly and green catalyst for esterification. The ILG was a sol at high temperature, in which the catalytic reaction ran in a homogeneous system. With decreasing temperature, it became a gel, enabling the efficient separation of catalyst and product.


Abstract

Novel and environment-friendly ionic liquid gels (ILG) were synthesized based on polymers, phenylboronic acid, and [BMIM]HSO4, in order to solve the problems in esterification, such as poor selectivity, difficult separation of product and catalyst, and catalyst recycling. The stability and structures of the ILG were characterized by rheology, thermogravimetric analysis, Fourier transform infrared and 1H nuclear magnetic resonance spectroscopy, and energy calculation. The solubility data proved that the ILG had phase selectivity, which could enable a homogeneous reaction. The synthesis of ethyl acetate was chosen to evaluate the catalytic activity, with the product yields being higher than 80 %. The catalyst could be recycled directly, without any post-treatment. Thus, the ILG could enhance the industrial application of esterification.

Assessing Contaminants of Emerging Concern in the Great Lakes Ecosystem: A Decade of Methods Development and Practical Application

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ABSTRACT

Assessing the ecological risk of contaminants in the field typically involves consideration of a complex mixture of compounds which may or may not be detected via instrumental analyses. Further, there are insufficient data to predict the potential biological effects of many detected compounds, leading to their being characterized as contaminants of emerging concern (CECs). Over the past several years, advances in chemistry, toxicology, and bioinformatics have resulted in a variety of concepts and tools that can enhance the pragmatic assessment of the ecological risk of CECs. This paper describes a 10+ year multiagency effort supported through the U.S. Great Lakes Restoration Initiative to assess the occurrence and implications of CECs in the North American Great Lakes. State-of-the-science methods and models were used to evaluate more than 700 sites in about 200 tributaries across Lakes Ontario, Erie, Huron, Michigan and Superior, sometimes on multiple occasions. Studies featured measurement of up to 500 different target analytes in different environmental matrices, coupled with evaluation of biological effects in resident species, animals from in situ and laboratory exposures, and in vitro systems. Experimental taxa included birds, fish and a variety of invertebrates, and measured endpoints ranged from molecular to apical responses. Data were integrated and evaluated using a diversity of curated knowledgebases and models with the goal of producing actionable insights for risk assessors and managers charged with evaluating and mitigating the effects of CECs in the Great Lakes. This overview paper is based on research and data captured in about 90 peer-reviewed journal articles and reports, including about 30 appearing in a Virtual Issue comprised of highlighted papers published in Environmental Toxicology and Chemistry or Integrated Environmental Assessment and Management.

Synthesis of Quinazolin‐2,4,6‐triamine Derivatives as Non‐purine Xanthine Oxidase Inhibitors and Exploration of Their Toxicological Potential

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Synthesis of Quinazolin-2,4,6-triamine Derivatives as Non-purine Xanthine Oxidase Inhibitors and Exploration of Their Toxicological Potential**

One quinazolin-2,4,6-triamine derivative was found to be a better bovine xanthine oxidase (bXO) inhibitor than allopurinol. Three quinazoline derivatives were not micronuclei inducers in a murine model. Three quinazolin-2,4,6-triamine derivatives acted as superoxide scavengers, and one 5,6-dihydro-3H-pirimidin-4-one showed bXO inhibitory activity.


Abstract

In this work, a new set of quinazolin-2,4,6-triamine derivatives were synthesized to explore their potential biological activity as xanthine oxidase (XO) inhibitors, superoxide scavengers and screening of their toxicological profile. Among all the synthesized compounds, B1 exhibited better inhibitory activity against bovine xanthine oxidase (bXO) than allopurinol (IC50=1.56 μM and IC50=6.99 μM, respectively). As superoxide scavengers, B1, B2 and B13 exhibited a better effect than allopurinol (97.3 %, 82.1 %, 87.4 % and 69.4 %, respectively). Regarding the toxicological profile, B1 was less cytotoxic than methotrexate on HCT-15 cancer cells. Apoptosis results obtained in cells of female and male mice, showed that B1 and B2 presented a similar behaviour to CrO3 (positive control) with respect to the average frequency to induce apoptosis; while B13 apoptosis induced effect was similar to DMSO and control group. Finally, B1, B2, B13 did not induce genotoxicity in a micronuclei murine model compared to CrO3.

Exploration of the Pharmacophore for Cytoskeletal Targeting Ruthenium Polypyridyl Complexes

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Exploration of the Pharmacophore for Cytoskeletal Targeting Ruthenium Polypyridyl Complexes

Systematically substituting dip for phen or bpy ligands leads to a sudden spike in uptake and cytotoxicity as well as cytoskeletal localization in MCF7 and H358 cells, once two or more dip ligands are present. The most potent complexes are associated with those that best promote tubulin polymerizations, supporting this as the cellular target.


Abstract

Ruthenium(II) trisdiimine complexes of the formula, [Ru(dip)n(L−L)3-n]2+, where n=0-3; dip=4,7-diphenyl-1,10-phenanthroline; L–L=2,2’-bipyridine (bpy) or 1,10-phenanthroline (phen) were prepared and tested for cytotoxicity in two cell lines (H358, MCF7). Cellular uptake and subcellular localization were determined by harvesting treated cells and determining the ruthenium concentration in whole or fractionated cells (cytosolic, nuclear, mitochondrial/ ER/Golgi, and cytoskeletal proteins) by Ru ICP-MS. The logP values for the chloride salts of these complexes were measured and the data were analyzed to determine the role of lipophilicity versus structure in the various biological assays. Cellular uptake increased with lipophilicity but shows the biggest jump when the complex contains two or more dip ligands. Significantly, preferential cytoskeletal localization is also correlated with increased cytotoxicity. All of the RPCs promote tubulin polymerization in vitro, but [Ru(dip)2phen]2+ and [Ru(dip)3]2+ show the strongest activity. Analysis of the pellet formed by centrifugation of MTs formed in the presence of [Ru(dip)2phen]2+ establish a binding stoichiometry of one RPC per tubulin heterodimer. Complexes of the general formula [Ru(dip)2(L−L)]2+ possess the necessary characteristics to target the cytoskeleton in live cells and increase cytotoxicity, however the nature of the L−L ligand does influence the extent of the effect.

Computational Mechanistic Insights on Homogeneous Water Oxidation Versus Catalyst Deactivation: A Case Study with Mononuclear Nickel and Copper Complexes

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Computational Mechanistic Insights on Homogeneous Water Oxidation Versus Catalyst Deactivation: A Case Study with Mononuclear Nickel and Copper Complexes

Copper(II) bis-oxamidate(L1) complex undergoes selective water oxidation while the analogous nickel(II) complex demonstrate both homogeneous water oxidation and catalyst deactivation due to the 2e− oxidized anionic intermediate [(L1⋅)NiIII(OH)]1− which promote both nucleophilic (OH−) and electrophilic (H+) attack while the corresponding copper intermediate, [(L1⋅)CuII(OH⋅)]1−, display radical character on the hydroxyl ligand with greater electrophilicity and avoids catalyst deactivation.


Abstract

Water splitting is a potential pathway for hydrogen gas evolution and thereby realization of a carbon-neutral sustainable energy scheme. However, oxidation of water to dioxygen is the major impediment in conversion of solar energy to fuel. Herein, density functional studies are conducted to explore the reactivity conduits of two molecular electro-catalysts consisting of nickel and copper tetra-anionic tetradentate amide ligand complexes of the type [(L1)MII]2−, where L1=o-phenylenebis(oxamidate), and their substitutionally modified analogues. While nickel complexes demonstrate complex borderline chemistry between homogeneous and heterogeneous pathways, showing competition between water oxidation and molecular species degradation, copper complexes display robust and efficient molecular water oxidation behavior. Our analysis predict that this disparity is primarily due to the reversible O−O bond formation in nickel complexes, which provide the platform necessary for a direct attack of OH−/H+ on the metal and terminally accessible amidate groups of the 2e− oxidized anionic intermediate, [(L1⋅)NiIII(OH)]1−, respectively. This intermediate streamline ligand deactivation with a comparatively higher driving force for nickel complexes in acidic medium. Contrarily, the copper complexes display radical character on the hydroxyl ligand in the corresponding intermediate, [(L1⋅)CuII(OH⋅)]1−, that expedite O−O interaction, leading to predominant homogeneous water oxidation under all conditions.

Activity‐Based Protein Profiling in Methicillin‐Resistant Staphylococcus aureus Reveals the Broad Reactivity of a Carmofur‐Derived Probe

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Activity-Based Protein Profiling in Methicillin-Resistant Staphylococcus aureus Reveals the Broad Reactivity of a Carmofur-Derived Probe

Enzyme targets of activity-based probes built on the anti-neoplastic drug and antimicrobial agent carmofur in methicillin-resistant Staphylococcus aureus (MRSA) have been identified. Chemoproteomic profiling revealed a broad reactivity of the probe against both cysteine and serine hydrolases, and identified uncharacterized bacterial enzymes; this has implications for putative human or microbial (off)targets engaged by therapeutic use of carmofur in the clinic.


Abstract

Activity-based protein profiling is a powerful chemoproteomic technique to detect active enzymes and identify targets and off-targets of drugs. Here, we report the use of carmofur- and activity-based probes to identify biologically relevant enzymes in the bacterial pathogen Staphylococcus aureus. Carmofur is an anti-neoplastic prodrug of 5-fluorouracil and also has antimicrobial and anti-biofilm activity. Carmofur probes were originally designed to target human acid ceramidase, a member of the NTN hydrolase family with an active-site cysteine nucleophile. Here, we first profiled the targets of a fluorescent carmofur probe in live S. aureus under biofilm-promoting conditions and in liquid culture, before proceeding to target identification by liquid chromatography/mass spectrometry. Treatment with a carmofur-biotin probe led to enrichment of 20 enzymes from diverse families awaiting further characterization, including the NTN hydrolase-related IMP cyclohydrolase PurH. However, the probe preferentially labeled serine hydrolases, thus displaying a reactivity profile similar to that of carbamates. Our results suggest that the electrophilic N-carbamoyl-5-fluorouracil scaffold could potentially be optimized to achieve selectivity towards diverse enzyme families. The observed promiscuous reactivity profile suggests that the clinical use of carmofur presumably leads to inactivation of a number human and microbial enzymes, which could lead to side effects and/or contribute to therapeutic efficacy.

How Ligand Geometry Affects the Reactivity of Co(II) Cyclam Complexes

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How Ligand Geometry Affects the Reactivity of Co(II) Cyclam Complexes

The cobalt(II) complex Co{i-N4} comprising the macrocyclic ligand isocyclam (1,4,7,11-tetraazacyclotetradecane) was tested for its catalytic potential in the oxygen reduction reaction revealing the generation of hydrogen peroxide. In the reaction of Co{i-N4} with O2, a superoxo Co(III) and a dimeric μ-peroxo Co(III) species were identified as reactive Co−O2 intermediates, which can be employed in HAT and OAT reactions as well.


Abstract

Cobalt complexes are extensively studied as bioinspired models for non-heme oxygenases as they facilitate both the stabilization and characterization of metal-oxygen intermediates. As an analog to the well-known Co(cyclam) complex Co{N4} (cyclam=1,4,8,11-tetraazacyclotetradecane), the CoII complex Co{i-N4} with the isomeric isocyclam ligand (isocyclam=1,4,7,11-tetraazacyclotetradecane) was synthesized and characterized. Despite the identical N4 donor set of both complexes, Co{i-N4} enables the 2e−/2H+ reduction of O2 with a lower overpotential (η eff of 385 mV vs. 540 mV for Co{N4}), albeit with a diminished turnover frequency. Characterization of the intermediates formed upon O2 activation of Co{i-N4} reveals a structurally identified stable μ-peroxo CoIII dimer as the main product. A superoxo CoIII species is also formed as a minor product, as indicated by EPR spectroscopy. In further reactivity studies, the electrophilicity of these in situ generated Co−O2 species was demonstrated by the oxidation of the O−H bond of TEMPO−H (2,2,6,6-tetramethylpiperidin-1-ol) via a H atom abstraction process. Unlike the known Co(cyclam), Co{i-N4} can be employed in oxygen atom transfer reactions oxidizing triphenylphosphine to the corresponding phosphine oxide highlighting the impact of geometrical modifications of the ligand while preserving the ring size and donor atom set on the reactivity of biomimetic oxygen activating complexes.

CuII Pyrazolyl‐Benzimidazole Dinuclear Complexes with Remarkable Antioxidant Activity

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CuII Pyrazolyl-Benzimidazole Dinuclear Complexes with Remarkable Antioxidant Activity

The novel dinuclear CuII complex [Cu(NO3)(μ-NO3)(L’)]2 , containing an oxidized ligand, shows remarkable antioxidant properties compared to the original ligand and reference compounds. A mechanism is provided.


Abstract

Three dinuclear coordination complexes generated from 1-n-butyl-2-((5-methyl-1H-pyrazole-3-yl)methyl)-1H-benzimidazole (L), have been synthesized and characterized spectroscopically and structurally by single crystal X-ray diffraction analysis. Reaction with iron(II) chloride and then copper(II) nitrate led to a co-crystal containing 78 % of [Cu(NO3)(μ-Cl)(L’)]2 (C1 ) and 22 % of [Cu(NO3)(μ-NO3)(L’)]2 (C2 ), where L was oxidized to a new ligand L’ . A mechanism is provided. Reaction with copper chloride led to the dinuclear complex [Cu(Cl)(μ-Cl)(L)]2 (C3 ). The presence of N−H⋅⋅⋅O and C−H⋅⋅⋅O intermolecular interactions in the crystal structure of C1 and C2 , and C−H⋅⋅⋅N and C−H⋅⋅⋅Cl hydrogen bonding in the crystal structure of C3 led to supramolecular structures that were confirmed by Hirshfeld surface analysis. The ligands and their complexes were tested for free radical scavenging activity and ferric reducing antioxidant power. The complex C1 /C2 shows remarkable antioxidant activities as compared to the ligand L and reference compounds.