Ortho Isomeric Mn(III) N-Alkyl- and Alkoxyalkylpyridylporphyrins—Enhancers of Hyaluronan Degradation Induced by Ascorbate and Cupric Ions

High levels of hyaluronic acid (HA) in tumors correlate with poor outcomes with several types of cancers due to HA-driven support of adhesion, migration and proliferation of cells. In this study we explored how to enhance the degradation of HA into low-molecular fragments, which cannot prevent the immune system to fight tumor proliferation and metastases. The physiological solution of HA was exposed to oxidative degradation by ascorbate and cupric ions in the presence of either one of three ortho isomeric Mn(III) substituted N-alkyl- and alkoxyalkylpyridylporphyrins or para isomeric Mn(III) N-methylpyridyl analog, commonly known as mimics of superoxide dismutase. The changes in hyaluronan degradation kinetics by four Mn(III) porphyrins were monitored by measuring the alteration in the dynamic viscosity of the HA solution. The ortho compounds MnTE-2-PyP5+ (BMX-010, AEOL10113), MnTnBuOE-2-PyP5+ (BMX-001) and MnTnHex-2-PyP5+ are able to redox cycle with ascorbate whereby producing H2O2 which is subsequently coupled with Cu(I) to produce the •OH radical essential for HA degradation. Conversely, with the para analog, MnTM-4-PyP5+, no catalysis of HA degradation was demonstrated, due to its inertness towards redox cycling with ascorbate. The impact of different Mn(III)-porphyrins on the HA decay was further clarified by electron paramagnetic resonance spectrometry. The ability to catalyze the degradation of HA in a biological milieu, in the presence of cupric ions and ascorbate under the conditions of high tumor oxidative stress provides further insight into the anticancer potential of redox-active ortho isomeric Mn(III) porphyrins.

How Giraffes Work

There are few creatures more beautiful, more aloof, and more fascinating than giraffes. Once they were plentiful and filled African landscapes, but in 2016 they were re-classified from “least concern” to “vulnerable” by the International Union for Conservation of Nature. Their survival in the wild is not assured. Much has been written about their private lives, about their behavior, social biology, and ecology, and their history in art and diplomacy. But so far no book has been written about their private lives, their physiology, and their anatomy and biochemistry—in short, the normal functions of a free-living animal in its natural environment—and it is these aspects of their lives that are the focus of this book. The study of a single species could be concise and relatively simply told. In reality it is not. A species never evolves in isolation from the general biological milieu in which it finds itself. Tectonics, astronomical physics, climate, and purely biological factors affecting food and water resources all shape the path of their evolution and all interact with its morphology, its internal physiological and biochemical systems, and the behavior patterns that regulate its daily life. Giraffes are no exception, as is revealed as the story told here unfolds. How do giraffes work? The answers lie in a story filled not only with the internal workings of a unique creature, but with geography, climate changes of great magnitude, and the labors of extraordinary people who put many pieces of the puzzle together.

Unexpected Enhancement of Antimicrobial Polymer Activity against Staphylococcus aureus in the Presence of Fetal Bovine Serum

Cationic and amphiphilic polymers are known to exert broad-spectrum antibacterial activity by a putative mechanism of membrane disruption. Typically, nonspecific binding to hydrophobic components of the complex biological milieu, such as globular proteins, is considered a deterrent to the successful application of such polymers. To evaluate the extent to which serum deactivates antibacterial polymethacrylates, we compared their minimum inhibitory concentrations in the presence and absence of fetal bovine serum. Surprisingly, we discovered that the addition of fetal bovine serum (FBS) to the assay media in fact enhances the antimicrobial activity of polymers against Gram-positive bacteria S. aureus, whereas the opposite is the case for Gram-negative E. coli. Here, we present these unexpected trends and develop a hypothesis to potentially explain this unusual phenomenon.

Hard and Soft Protein Corona of Nanomaterials: Analysis and Relevance

Upon contact with a biological milieu, nanomaterials tend to interact with biomolecules present in the media, especially proteins, leading to the formation of the so-called “protein corona”. As a result of these nanomaterial–protein interactions, the bio-identity of the nanomaterial is altered, which is translated into modifications of its behavior, fate, and pharmacological profile. For biomedical applications, it is fundamental to understand the biological behavior of nanomaterials prior to any clinical translation. For these reasons, during the last decade, numerous publications have been focused on the investigation of the protein corona of many different types of nanomaterials. Interestingly, it has been demonstrated that the structure of the protein corona can be divided into hard and soft corona, depending on the affinity of the proteins for the nanoparticle surface. In the present document, we explore the differences between these two protein coronas, review the analysis techniques used for their assessment, and reflect on their relevance for medical purposes.

Hidden information on protein function in censuses of proteome foldedness

Methods that assay protein foldedness with proteomics have generated censuses of protein folding stabilities in biological milieu. Surprisingly, different censuses poorly correlate with each other. Here, we show that methods targeting foldedness through monitoring amino acid sidechain reactivity also detect changes in conformation and ligand binding. About one quarter of cysteine or methionine sidechains in proteins in mammalian cell lysate increase in reactivity upon chemical denaturant titration consistent with two-state unfolding. Paradoxically, up to one third decreased reactivity, which were enriched in proteins with functions relating to unfolded protein stress. One protein, chaperone HSPA8, displayed changes arising from ligand and cofactor binding. Unmasking this hidden information should improve efforts to understand both folding and the remodeling of protein function directly in complex biological settings.One Sentence SummaryWe show that proteome folding stability censuses are ill-defined because they earmark hidden information on conformation and ligand binding.

Ion-Induced Volume Transition in Gels and Its Role in Biology

Incremental changes in ionic composition, solvent quality, and temperature can lead to reversible and abrupt structural changes in many synthetic and biopolymer systems. In the biological milieu, this nonlinear response is believed to play an important functional role in various biological systems, including DNA condensation, cell secretion, water flow in xylem of plants, cell resting potential, and formation of membraneless organelles. While these systems are markedly different from one another, a physicochemical framework that treats them as polyelectrolytes, provides a means to interpret experimental results and make in silico predictions. This article summarizes experimental results made on ion-induced volume phase transition in a polyelectrolyte model gel (sodium polyacrylate) and observations on the above-mentioned biological systems indicating the existence of a steep response.

Mapping and identification of soft corona proteins at nanoparticles and their impact on cellular association

The current understanding of the biological identity that nanoparticles may acquire in a given biological milieu is mostly inferred from the hard component of the protein corona (HC). The composition of soft corona (SC) proteins and their biological relevance have remained elusive due to the lack of analytical separation methods. Here, we identify a set of specific corona proteins with weak interactions at silica and polystyrene nanoparticles by using an in situ click-chemistry reaction. We show that these SC proteins are present also in the HC, but are specifically enriched after the capture, suggesting that the main distinction between HC and SC is the differential binding strength of the same proteins. Interestingly, the weakly interacting proteins are revealed as modulators of nanoparticle-cell association mainly through their dynamic nature. We therefore highlight that weak interactions of proteins at nanoparticles should be considered when evaluating nano-bio interfaces.

Preparation of Biocomposite Soft Nanoparticles Composed of Poly(Propylene Oxide) and the Polymer-Binding Peptides

The molecular recognition capability of naturally occurring biomolecules is generally expressed against biomolecules in the biological milieu. Recently, it was demonstrated that the specific interactions of biomolecules such as short peptides were applicable to artificial materials. We have developed peptides with specific affinities for synthetic polymers toward functional biocomposite polymeric materials. In this study, we demonstrated the preparation of biocomposite nanoparticles composed of poly(propylene oxide) (PPO) and PPO-binding peptides. A simple injection of a concentrated PPO solution dissolved in an organic solvent into the peptide solution under sonication resulted in the formation of nanospherical structures. Morphological observation indicated characteristic softness and high applicability as a molecular carrier of the biocomposite nanoparticles. Structural characterization of PPO and the PPO-binding peptide revealed the structural conformability of these molecules to interact specifically with each other. Our findings expand the potential applicability of polymer-binding peptides for the future construction of biomedical materials composed of peptides and various polymers.